1 00:00:06,279 --> 00:00:07,547 GOOD MORNING, WELCOME TO THE 2 00:00:07,547 --> 00:00:15,589 FINAL TALK OF THE BIOWULF 3 00:00:15,589 --> 00:00:18,558 SERIES. 4 00:00:18,558 --> 00:00:22,028 TO THE INTERMURAL RESEARCHERS. 5 00:00:22,028 --> 00:00:26,833 TODAY WE ARE HONORED TO HAVE 6 00:00:26,833 --> 00:00:30,070 DOCTOR MARIA TERESA LANDI SHE 7 00:00:30,070 --> 00:00:32,139 RECEIVED HER MEDICAL DEGREE 8 00:00:32,139 --> 00:00:34,908 FROM UNIVERSITY OF MILANO IN 9 00:00:34,908 --> 00:00:42,983 ITALY AND TRAINED AT SANTA RA 10 00:00:42,983 --> 00:00:44,985 INNOCENTED FAEL. 11 00:00:44,985 --> 00:00:46,686 DR. LANDI IS CURRENTLY THE 12 00:00:46,686 --> 00:00:49,589 SENIOR INVESTIGATOR IN THE 13 00:00:49,589 --> 00:00:58,465 DIVISION OF CANCER EPIDEMIOLOGY. 14 00:00:58,465 --> 00:01:01,968 DR. LANDI'S LAB IN BIOWULF HAS 15 00:01:01,968 --> 00:01:05,405 USED OVER A MILLION HOURS IN 16 00:01:05,405 --> 00:01:06,306 LAST YEAR ALONE. 17 00:01:06,306 --> 00:01:08,408 AND SMFT TOOLS THAT THEY USE 18 00:01:08,408 --> 00:01:10,243 FOR THE RESEARCH ARE SOME 19 00:01:10,243 --> 00:01:13,246 TOOLS, AS WELL AS CUSTOM MADE 20 00:01:13,246 --> 00:01:15,415 TOOLS OF THEIR OWN DESIGN AMONG 21 00:01:15,415 --> 00:01:18,318 MANY OTHERS. 22 00:01:18,318 --> 00:01:23,190 DR. LANDI'S TALK TODAY IS 23 00:01:23,190 --> 00:01:25,625 TITLED THE MUTAGENIC FORCES 24 00:01:25,625 --> 00:01:31,398 SHAPING THE GENOMIC LANDSCAPE 25 00:01:31,398 --> 00:01:33,200 OF LUNG CANCER. 26 00:01:33,200 --> 00:01:34,601 WELCOME DOCTOR. 27 00:01:34,601 --> 00:01:36,903 >> THANK YOU, THANK YOU FOR THE 28 00:01:36,903 --> 00:01:38,305 INVITATION, I'M VERY GRATEFUL 29 00:01:38,305 --> 00:01:39,973 FOR THE POSSIBILITIED AND I'M 30 00:01:39,973 --> 00:01:42,242 VERY GRATEFUL FOR THE WORK OF 31 00:01:42,242 --> 00:01:44,744 THE BIOWULF TEAM AND IN FACT, 32 00:01:44,744 --> 00:01:52,185 HOW SHOULD I MOVE IT? 33 00:01:52,185 --> 00:02:02,429 WHAT HAPPENED? 34 00:02:15,976 --> 00:02:18,211 SORRY FOR THE INTERRUPTION, AS 35 00:02:18,211 --> 00:02:20,981 I WAS SAYING, ALL THAT RESEARCH 36 00:02:20,981 --> 00:02:22,582 THAT I WILL PRESENT HERE ARE 37 00:02:22,582 --> 00:02:25,852 THANKS TO THE BIOWULF TEAM, ALL 38 00:02:25,852 --> 00:02:27,454 THE SOFTWARE AND HELP AND THE 39 00:02:27,454 --> 00:02:29,556 SUPPORT, THE SPACE PROVIDED FOR 40 00:02:29,556 --> 00:02:32,058 THE ANALYSIS AND SO ON. 41 00:02:32,058 --> 00:02:33,894 SO WHY LUNG CANCER? 42 00:02:33,894 --> 00:02:36,162 LUNG CANCER IS VERY IMPORTANT 43 00:02:36,162 --> 00:02:41,134 BECAUSE IT IS STILL OUT OF 16 44 00:02:41,134 --> 00:02:43,703 INDIVIDUALS IN THE U.S. AND IT 45 00:02:43,703 --> 00:02:45,605 IS MORE COMMON IN MEN THAN IN 46 00:02:45,605 --> 00:02:47,641 WOMEN AND THERE ARE SOME 47 00:02:47,641 --> 00:02:49,910 DIFFERENCES WITH A HIGHER RATES 48 00:02:49,910 --> 00:02:51,678 IN AFRICAN AMERICANS AND WHITE 49 00:02:51,678 --> 00:02:53,613 POPULATION. 50 00:02:53,613 --> 00:02:57,450 IN THE MORTALITY IS EXTREMELY 51 00:02:57,450 --> 00:02:59,319 HIGH. 52 00:02:59,319 --> 00:03:01,187 LUNG CANCER IS THE NUMBER ONE 53 00:03:01,187 --> 00:03:02,789 CAUSE OF DEATH WITH OVER 20 54 00:03:02,789 --> 00:03:04,624 PERCENT OF ALL CANCER DEATHS 55 00:03:04,624 --> 00:03:08,094 AND IT IS HIGHER THAN THE 56 00:03:08,094 --> 00:03:14,034 PANCREATIC AND BREAST CANCER 57 00:03:14,034 --> 00:03:16,303 AND PROSTATE CANCER. 58 00:03:16,303 --> 00:03:18,138 THERE IS ALSO A DECREASE IN 59 00:03:18,138 --> 00:03:20,440 INCIDENTS IN MEN AND WOMEN BUT 60 00:03:20,440 --> 00:03:22,542 WITH THE DECREASING OF THE 61 00:03:22,542 --> 00:03:23,710 SMOKING PREVALENCE, PROPORTION 62 00:03:23,710 --> 00:03:25,779 ATELY THERE IS AN INCREASE OF 63 00:03:25,779 --> 00:03:29,449 LUNG CANCER IN MANY SMOKERS. 64 00:03:29,449 --> 00:03:31,318 LUNG CANCER IN MANY SMOKERS IS 65 00:03:31,318 --> 00:03:32,719 DEFINED FOR THE SUBJECTS THAT 66 00:03:32,719 --> 00:03:37,290 SMOKE LESS THAN 1100 CIGARETTES 67 00:03:37,290 --> 00:03:40,427 IN THEIR LIFETIME AND ACCOUNT 68 00:03:40,427 --> 00:03:42,495 FOR 20 PERCENT WORLDWIDE. 69 00:03:42,495 --> 00:03:45,932 BUT IF YOU FOCUS IN POPULATION 70 00:03:45,932 --> 00:03:48,635 IN WOMEN IT REQUEST GO AS HIGH 71 00:03:48,635 --> 00:03:49,602 AS 55 PERCENT. 72 00:03:49,602 --> 00:03:53,073 SXL BY IT SELF, IT'S THE 5th 73 00:03:53,073 --> 00:03:56,943 CAUSE OF CANCER DEATH AND 74 00:03:56,943 --> 00:04:07,420 ALMOST EXCLUSIVELY OF LUNG 75 00:04:08,989 --> 00:04:10,523 CANCERGENE CANCER. 76 00:04:10,523 --> 00:04:13,493 LOOKING AT FACTORS IN LUNG 77 00:04:13,493 --> 00:04:17,397 CANCER SMOKERS AND SOME, TAB CO 78 00:04:17,397 --> 00:04:19,666 SMOKING MORE RECENTLY HAVE 79 00:04:19,666 --> 00:04:21,534 POLLUTION AND LUNG DISEASES. 80 00:04:21,534 --> 00:04:24,037 THE LARGE MAJORITY OF THE 81 00:04:24,037 --> 00:04:26,106 CAUSES OF THE LUNG CANCER ARE 82 00:04:26,106 --> 00:04:28,174 STILL UNKNOWN BECAUSE A LARGE 83 00:04:28,174 --> 00:04:30,543 MAJORITY OF THE CASES CANNOT BE 84 00:04:30,543 --> 00:04:32,579 EXPLAINED BECAUSE OF THE 85 00:04:32,579 --> 00:04:34,180 NO-RISK FACTORS AND THAT'S THE 86 00:04:34,180 --> 00:04:36,683 REASON WHY WE DESIGNED THE 87 00:04:36,683 --> 00:04:39,919 STUDY THAT AIMS TO STUDY THE 88 00:04:39,919 --> 00:04:50,397 LUNG CANCER IN SMOKER USING 89 00:04:50,930 --> 00:04:52,932 GENOMIC DATA AND TODAY I'LL 90 00:04:52,932 --> 00:04:55,035 FOCUS ON THE MUTIZATION THAT I 91 00:04:55,035 --> 00:04:56,636 WILL EXPLAIN. 92 00:04:56,636 --> 00:04:59,606 CURRENTLY FOR A LUNG STUDY WE 93 00:04:59,606 --> 00:05:02,809 COLLECTED OVER 2000 SPECIMENS 94 00:05:02,809 --> 00:05:05,578 FROM 37 REGIONS ACROSS THE FIVE 95 00:05:05,578 --> 00:05:08,081 CONTINENTS AND WE HAVE 96 00:05:08,081 --> 00:05:13,119 CONDUCTED A WHOLE GENO 97 00:05:13,119 --> 00:05:16,823 SEQUENCING, MICRO AND IMAGING 98 00:05:16,823 --> 00:05:20,460 ANALYSIS AND CLINICAL DATA. 99 00:05:20,460 --> 00:05:22,128 IN COMPARISON, I JUST WANTED TO 100 00:05:22,128 --> 00:05:24,431 SHOW YOU THE NUMBER OF STUDIES 101 00:05:24,431 --> 00:05:32,472 ACROSS THE WHOLE GENO AND AUTO 102 00:05:32,472 --> 00:05:34,240 SEQUENCING AND YOU CAN SEE THE 103 00:05:34,240 --> 00:05:36,109 CASES ARE MUCH MUCH SMALLER 104 00:05:36,109 --> 00:05:37,744 THAN OUR STUDY. 105 00:05:37,744 --> 00:05:42,549 OUR STUDY IS POST TO REIDENTIFY 106 00:05:42,549 --> 00:05:44,451 OF LUNG CANCER AND TRYING TO 107 00:05:44,451 --> 00:05:45,452 UNDERSTAND BETTER HOW THE 108 00:05:45,452 --> 00:05:46,419 CANCER DEVELOPED. 109 00:05:46,419 --> 00:05:57,030 SOY MENTIONED THAT I WOULD 110 00:05:57,030 --> 00:05:57,831 DESCRIBE LIMITATION MUTIZATION 111 00:05:57,831 --> 00:05:59,265 AL SIGNATURES. 112 00:05:59,265 --> 00:06:05,271 THIS IS TO IDENTIFY PA TERNS OF 113 00:06:05,271 --> 00:06:08,241 MAOUIZATIONS THAT USING SOME 114 00:06:08,241 --> 00:06:11,010 ALGORITHMS WE CAN TRACE BACK TO 115 00:06:11,010 --> 00:06:12,412 THE POTENTIAL PROCESS THAT'S 116 00:06:12,412 --> 00:06:13,246 LEAD TO THE DEVELOPMENT OF THE 117 00:06:13,246 --> 00:06:17,217 TUMOR. 118 00:06:17,217 --> 00:06:19,285 SO USING GENERAL DATA TO 119 00:06:19,285 --> 00:06:20,453 UNDERSTAND THE CAUSES. 120 00:06:20,453 --> 00:06:24,791 WE KNOW THAT WE ACCUMULATE 121 00:06:24,791 --> 00:06:26,893 MUTATIONS IN EVERY SET OF OUR 122 00:06:26,893 --> 00:06:32,465 BODY TO THE POINT IN WHICH WE 123 00:06:32,465 --> 00:06:33,399 HAVE THE POTENTIAL OF THE 124 00:06:33,399 --> 00:06:34,434 CANCER. 125 00:06:34,434 --> 00:06:40,006 WE KNOW THERE ARE SIX TYPE OF 126 00:06:40,006 --> 00:06:40,640 CLASSES,. 127 00:06:40,640 --> 00:06:43,610 SO WE ACCUMULATE MAOUIZATIONS 128 00:06:43,610 --> 00:06:46,412 DURING THE ENTIRE LIFETIME A 129 00:06:46,412 --> 00:06:47,080 SMALL NUMBER OF MUTATION FOR 130 00:06:47,080 --> 00:06:51,684 EXAMPLE A LOT OF C2 MAOUIZATION. 131 00:06:51,684 --> 00:06:55,355 THEN IT CAN BE EXPOSED TO A 132 00:06:55,355 --> 00:06:57,624 STRONG FACTOR FOR EXAMPLE, 133 00:06:57,624 --> 00:07:00,426 START TOBACCO SMOKING AND FOR A 134 00:07:00,426 --> 00:07:03,363 SHORT PERIOD OF TIME ACCUMULATE 135 00:07:03,363 --> 00:07:05,899 A LARGE NUMBER OF MUTATIONS AND 136 00:07:05,899 --> 00:07:08,001 MAYBE EXPOSED TO OTHER, YOU 137 00:07:08,001 --> 00:07:17,143 KNOW, AIR POLLUTIONS OR 138 00:07:17,143 --> 00:07:18,444 ASBESTOS AND OTHER CAUSES. 139 00:07:18,444 --> 00:07:21,514 SO AT THE TIME OF THE BIOPSY, 140 00:07:21,514 --> 00:07:24,951 WE HAVE A GENO THAT IS A MIX OF 141 00:07:24,951 --> 00:07:26,452 ALL OF THIS PROCESS THAT LEAD 142 00:07:26,452 --> 00:07:27,053 TO THIS. 143 00:07:27,053 --> 00:07:30,957 SO THE IDEA IS TO STUDY ALL OF 144 00:07:30,957 --> 00:07:33,726 THIS CANCER GENO USING 145 00:07:33,726 --> 00:07:36,229 MATHEMATICAL ALGORITHM AND GO 146 00:07:36,229 --> 00:07:37,664 BACK AND TRY TO UNDERSTAND ALL 147 00:07:37,664 --> 00:07:38,364 OF THESE CAUSES. 148 00:07:38,364 --> 00:07:41,100 SO FOR EXAMPLE, IN THE PAST, WE 149 00:07:41,100 --> 00:07:43,836 KNEW ALREADY THAT SKIN CANCER 150 00:07:43,836 --> 00:07:47,707 IS LINKED TO UV LIGHT EXPOSURE 151 00:07:47,707 --> 00:07:53,680 AND UV LIGHT EXPOSURE HAS A 152 00:07:53,680 --> 00:07:54,681 SPECIFIC PATTERN TYPES. 153 00:07:54,681 --> 00:07:58,851 SOL WHEN WE FIND THESE TYPE OF 154 00:07:58,851 --> 00:08:00,620 MUTATIONS, WE UNDERSTAND THAT 155 00:08:00,620 --> 00:08:02,855 THE TUMORS WAS CAUSED OR 156 00:08:02,855 --> 00:08:05,225 POTENTIAL ASSOCIATED TO UV 157 00:08:05,225 --> 00:08:06,326 LIGHT EXPOSURE. 158 00:08:06,326 --> 00:08:08,194 FOR EXAMPLE, IN THE STUDY OF 159 00:08:08,194 --> 00:08:10,029 LUNG CANCER, WE IDENTIFIED TWO 160 00:08:10,029 --> 00:08:11,664 CASES THAT HAD STRONG PATTERNS 161 00:08:11,664 --> 00:08:15,969 OF THIS SIGNATURE SBS-7 THAT IS 162 00:08:15,969 --> 00:08:19,372 ASSOCIATED WITH UV LIGHT AND WE 163 00:08:19,372 --> 00:08:21,674 WERE PUZZLED BECAUSE THESE WERE 164 00:08:21,674 --> 00:08:22,942 LUNG CANCER CASES. 165 00:08:22,942 --> 00:08:24,877 WE WENT BACK TO ALL THE 166 00:08:24,877 --> 00:08:26,279 CLINICAL CHARTS AND IDENTIFIED 167 00:08:26,279 --> 00:08:28,314 THE REASONS FOR THESE BECAUSE 168 00:08:28,314 --> 00:08:31,784 KNEES WERE NOT PRIMARILY LUNG 169 00:08:31,784 --> 00:08:38,391 CANCER CASES BUT CAR SIN NO MA 170 00:08:38,391 --> 00:08:39,792 OF THE SKIN. 171 00:08:39,792 --> 00:08:42,061 WE KNOW ALSO LUNG CANCER 172 00:08:42,061 --> 00:08:43,029 ASSOCIATED WITH TOBACCO 173 00:08:43,029 --> 00:08:48,268 SMOKING, WE HAVE THIS SINGLE 174 00:08:48,268 --> 00:08:50,370 PATTERN SB4 WITH MONTH TRANS 175 00:08:50,370 --> 00:08:51,537 VERSIONS IN THIS WAY. 176 00:08:51,537 --> 00:08:55,475 AND BASED ON THESE TYPES OF 177 00:08:55,475 --> 00:08:56,175 MUTATIONS, THERE WERE STUDIES 178 00:08:56,175 --> 00:08:58,244 THAT WE WERE ABLE TO QUANTIFY 179 00:08:58,244 --> 00:09:00,780 FOR EACH CELL WITH A NUMBER OF 180 00:09:00,780 --> 00:09:02,682 MUTATIONS THAT ARE ASSOCIATED 181 00:09:02,682 --> 00:09:04,751 IN SMOKING TOBACCO AT LEAST A 182 00:09:04,751 --> 00:09:12,992 TACK --A PACK PER DAY AND GOES 183 00:09:12,992 --> 00:09:15,662 TO 6 IN LUNG AND THE LIVER. 184 00:09:15,662 --> 00:09:20,833 SXL IF YOU CONSIDER WE HAVE 33 185 00:09:20,833 --> 00:09:23,202 CELLS CAN YOU IMAGINE WITH 186 00:09:23,202 --> 00:09:26,639 MUTATION ACCUMULATION. 187 00:09:26,639 --> 00:09:28,941 IN ADDITION, WE ACCUMULATE 188 00:09:28,941 --> 00:09:31,944 MUTATIONS ALSO FOR INDULGENCE 189 00:09:31,944 --> 00:09:32,845 REASONS. 190 00:09:32,845 --> 00:09:35,148 FOR EXAMPLE, YOU MAY HAVE 191 00:09:35,148 --> 00:09:36,316 FAILED THE GENETIC PAIR AND 192 00:09:36,316 --> 00:09:38,384 HERE I LISTED THE MAJOR 193 00:09:38,384 --> 00:09:42,021 PATHWAY, YOU CAN HAVE NUCLEAR 194 00:09:42,021 --> 00:09:45,258 TYPE DECISION REPAIR AND MAYBE 195 00:09:45,258 --> 00:09:47,560 OTHER DEFECTS THAT CAUSES A 196 00:09:47,560 --> 00:09:48,728 SERIES OF SIGNATURE LIKE THOSE 197 00:09:48,728 --> 00:09:51,331 THAT I SHOWED TO YOU THAT WHEN 198 00:09:51,331 --> 00:09:54,000 WE IDENTIFY WE CAN SAY, AHA, 199 00:09:54,000 --> 00:09:56,969 HERE THERE IS A REASON FOR THE 200 00:09:56,969 --> 00:09:59,305 DEVELOPMENT OF THESE TUMORS. 201 00:09:59,305 --> 00:10:02,675 SO THE MOST COMMON PATTERN ARE 202 00:10:02,675 --> 00:10:07,046 HERE HERE, WE HAVE INDULGENCE 203 00:10:07,046 --> 00:10:08,848 FACTORS, FOR EXAMPLE, 204 00:10:08,848 --> 00:10:11,617 ACTIVITIES THAT ARE 205 00:10:11,617 --> 00:10:13,019 CHARACTERIZED BY THESE TEAM. 206 00:10:13,019 --> 00:10:16,422 THIS IS APPLE BACK IS VERY 207 00:10:16,422 --> 00:10:18,991 IMPORTANT OF THE IMMUNITY AND 208 00:10:18,991 --> 00:10:24,697 DEFENSE US AGAINST VIRUS AS A 209 00:10:24,697 --> 00:10:28,134 BI PRODUCT CREATES A LOT OF 210 00:10:28,134 --> 00:10:31,337 MUTATIONS AND IDENTIFIED IN 75 211 00:10:31,337 --> 00:10:33,206 PERCENT OF LUNG CANCER TYPES 212 00:10:33,206 --> 00:10:35,541 THAT HAS THIS PATTERN BACK. 213 00:10:35,541 --> 00:10:37,844 WE ALSO HAVE THE MUTATION 214 00:10:37,844 --> 00:10:40,346 SIGNATURE ASSOCIATED WITH 215 00:10:40,346 --> 00:10:41,748 SPECIFIC CANCER TREATMENT, FOR 216 00:10:41,748 --> 00:10:48,388 EXAMPLE, THE SIGNATURE SBS31 IS 217 00:10:48,388 --> 00:10:49,655 ASSOCIATED WITH PATTERN. 218 00:10:49,655 --> 00:10:53,693 OR A SERIES OF EXPOSURES LIKE 219 00:10:53,693 --> 00:10:56,662 THE SBS4 ASSOCIATED TO TOBACCO 220 00:10:56,662 --> 00:10:58,097 SMOKING. 221 00:10:58,097 --> 00:11:00,600 IN ADDITION, WE HAVE DOUBLE 222 00:11:00,600 --> 00:11:02,435 BASIN CONSTITUTIONS IN THERE 223 00:11:02,435 --> 00:11:07,473 ARE SMALL IN SOCIAL 224 00:11:07,473 --> 00:11:09,342 POPULATIONS, VARIANCES EVEN 225 00:11:09,342 --> 00:11:10,243 INSTITUTIONS MORE RECENTLY. 226 00:11:10,243 --> 00:11:13,446 AND WE CAN USE THESE MUTATION 227 00:11:13,446 --> 00:11:15,982 SIGNATURE ALSO TO HAVE INSIDE 228 00:11:15,982 --> 00:11:17,583 OF DIFFERENT PROCESS THAT 229 00:11:17,583 --> 00:11:19,485 ACCUMULATE DIFFERENT TYPE OF 230 00:11:19,485 --> 00:11:22,321 CANCERS BECAUSE OF THE SAME 231 00:11:22,321 --> 00:11:23,055 PROCESSES. 232 00:11:23,055 --> 00:11:27,393 FOR EXAMPLE, HERE IS THE PAN 233 00:11:27,393 --> 00:11:29,462 CANCER ANALYSIS WHERE DIFFERENT 234 00:11:29,462 --> 00:11:30,696 CANCER DEFINE DIFFERENT CANCER 235 00:11:30,696 --> 00:11:30,897 TYPES. 236 00:11:30,897 --> 00:11:32,965 SXL HERE IS THE DIFFERENT 237 00:11:32,965 --> 00:11:35,268 COLORS THAT DEFINE THE MUTATION 238 00:11:35,268 --> 00:11:35,968 SIGNATURES. 239 00:11:35,968 --> 00:11:38,838 SO FOR EXAMPLE, IF WE FOCUS 240 00:11:38,838 --> 00:11:42,775 HERE ASSOCIATED WITH SBS3, THAT 241 00:11:42,775 --> 00:11:52,418 IT'S ASSOCIATED WITH HOMOGLOBAL 242 00:11:52,418 --> 00:11:55,188 DEFICIENTCIE AND WE SEE THAT 243 00:11:55,188 --> 00:11:59,725 THE BREAST AND CARCINOMA HAS 244 00:11:59,725 --> 00:12:02,762 THE SAME, AND HERE WE HAVE OUR 245 00:12:02,762 --> 00:12:05,765 SBS4 THAT IS ASSOCIATED WITH 246 00:12:05,765 --> 00:12:09,435 BOTH LUNG AND CARCINOMA. 247 00:12:09,435 --> 00:12:12,605 SO IN GENERAL MUTATION 248 00:12:12,605 --> 00:12:15,641 SIGNATURE USE THE DIFFERENT IN 249 00:12:15,641 --> 00:12:17,443 THE LATEST YEARS NOT ONLY TO 250 00:12:17,443 --> 00:12:19,045 UNDERSTAND BUT ALSO MUTATION OF 251 00:12:19,045 --> 00:12:23,182 PROPERTY AND EVEN CLINICAL 252 00:12:23,182 --> 00:12:23,850 PUBLICATIONS. 253 00:12:23,850 --> 00:12:29,856 AND IF YOU LOOK AT THE 254 00:12:29,856 --> 00:12:31,691 PUBLICATIONS, THEY INCREASE 255 00:12:31,691 --> 00:12:32,625 EXPONENTIALLY. 256 00:12:32,625 --> 00:12:42,468 SO NOW FOR THE SHERLOCK LUNG 257 00:12:42,468 --> 00:12:46,439 HUD', IN ALMOST 900 SAMPLES IN 258 00:12:46,439 --> 00:12:52,378 FOUR CONTINENTS AND 23 REGIONS 259 00:12:52,378 --> 00:12:55,615 AND CARCINOMA, FOR THIS SECTOR 260 00:12:55,615 --> 00:12:57,683 ANALYSIS IN FOCUSING ON 261 00:12:57,683 --> 00:12:59,318 EUROPEAN ANCESTRY, THE LARGE 262 00:12:59,318 --> 00:13:02,722 MAJORITY IS EXPECTED AT FEMALES 263 00:13:02,722 --> 00:13:06,158 AND FOR APPROXIMATELY HALF, WE 264 00:13:06,158 --> 00:13:09,595 ALSO HAD DETAIL INFORMATION OF 265 00:13:09,595 --> 00:13:11,464 SECOND-HAND SMOKING EXPOSURE. 266 00:13:11,464 --> 00:13:14,200 SO SINCE WE HAD THE DIFFERENT 267 00:13:14,200 --> 00:13:16,936 GEOGRAPHICAL ORIGINS, WE TESTED 268 00:13:16,936 --> 00:13:22,241 WHETHER THERE WERE DIFFERENCES, 269 00:13:22,241 --> 00:13:23,876 NUMBER ALTERATIONS OR STRUCTURE 270 00:13:23,876 --> 00:13:25,978 VARIANTS. 271 00:13:25,978 --> 00:13:35,388 AND WE SAW THAT CASES FROM 272 00:13:35,388 --> 00:13:37,957 SERBIA, AND WE SAW THAT THE 273 00:13:37,957 --> 00:13:39,358 SAMPLES FROM NEW YORK HAD THE 274 00:13:39,358 --> 00:13:40,893 LOWER NUMBER. 275 00:13:40,893 --> 00:13:43,462 WE UNDERSTOOD THAT THIS IS 276 00:13:43,462 --> 00:13:49,769 LIKELY LIKELY TO THE FACT THAT 277 00:13:49,769 --> 00:14:00,313 WE COLLECTED MORE CARCENOL THAT 278 00:14:04,750 --> 00:14:06,519 IS MORE AGGRESSIVE--OF LOWER 279 00:14:06,519 --> 00:14:08,154 NUMBER OF SIGNATURES ALL ACROSS 280 00:14:08,154 --> 00:14:09,789 THE DIFFERENT TYPES. 281 00:14:09,789 --> 00:14:15,094 WE ALSO CHECKED IN A MAJOR 282 00:14:15,094 --> 00:14:25,571 DRIVER GENES AND T B-52 IN 283 00:14:29,342 --> 00:14:33,346 CARCINOID, VERY STRONGLY. 284 00:14:33,346 --> 00:14:38,618 SO HERE ARE THE PATTERNS OF THE 285 00:14:38,618 --> 00:14:39,785 MUTATION SIGNATURES 8 HAVE BEEN 286 00:14:39,785 --> 00:14:41,721 SIDED FOR THE FIRST TIME IN 287 00:14:41,721 --> 00:14:42,822 LUNG CANCER. 288 00:14:42,822 --> 00:14:46,492 SXL WHEN WE COMPARED THE E 289 00:14:46,492 --> 00:14:48,361 STATION TO EUROPEAN, WE SAW THE 290 00:14:48,361 --> 00:14:58,804 DISTRIBUTION WAS SIMILAR. 291 00:14:59,171 --> 00:15:04,076 THE SBS22 WAS IN SECTIONS OF 292 00:15:04,076 --> 00:15:04,343 TAIWAN. 293 00:15:04,343 --> 00:15:05,978 WE SAW THAT SIGNATURE IS 294 00:15:05,978 --> 00:15:13,119 ASSOCIATED WITH THE EXPOSURE TO 295 00:15:13,119 --> 00:15:14,720 A RISTOLOGIC ACID THAT IS 296 00:15:14,720 --> 00:15:16,355 LINKED TO A HERB USED IN THE 297 00:15:16,355 --> 00:15:18,157 AREA THAT IS PREVIOUSLY 298 00:15:18,157 --> 00:15:20,693 IDENTIFIED WITH OTHER CANCER 299 00:15:20,693 --> 00:15:23,696 TYPE, LIVER CANCER, KIDNEY 300 00:15:23,696 --> 00:15:24,630 CANCER, SYMPTOM CANCER BUT THIS 301 00:15:24,630 --> 00:15:26,932 IS THE FIRST TIME THAT WE SEE 302 00:15:26,932 --> 00:15:30,569 ANY EVIDENCE IN SUBJECTS WITH A 303 00:15:30,569 --> 00:15:32,471 LUNG CANCER AMONG SMOKERS. 304 00:15:32,471 --> 00:15:34,507 BUT ALTHOUGH THIS IS OUR 305 00:15:34,507 --> 00:15:36,542 SIGNATURE DUE TO ASSOCIATION 306 00:15:36,542 --> 00:15:40,880 WITH EXPOSURES FROM OUTSIDE, 307 00:15:40,880 --> 00:15:44,283 THE LARGE MAJORITY OF THE 308 00:15:44,283 --> 00:15:45,918 MUTATION SIGNATURES THAT WE 309 00:15:45,918 --> 00:15:49,388 HAVE IDENTIFIED FROM LUNG 310 00:15:49,388 --> 00:15:52,391 CANCER IS ASSOCIATED WITH, 311 00:15:52,391 --> 00:15:56,729 SIGNATURE 1 AND 5 WITH THE AGE. 312 00:15:56,729 --> 00:15:58,831 SIGNATURE 13 ASSOCIATED WITH 313 00:15:58,831 --> 00:16:02,535 APPLE BACK, SIGNATURE 18 WITH 314 00:16:02,535 --> 00:16:04,804 DNA REPAIR DEFICIENCIES, WE 315 00:16:04,804 --> 00:16:06,906 HAVE UNKNOWN SIGNATURE THAT WAS 316 00:16:06,906 --> 00:16:09,642 PREVIOUSLY IDENTIFIED IN KIDNEY 317 00:16:09,642 --> 00:16:15,414 CANCER WITH THE DEFICIENTS SO 318 00:16:15,414 --> 00:16:16,782 OVERALL MAJORITY ARE ASSOCIATED 319 00:16:16,782 --> 00:16:20,052 WITH MUTATIONS THAT DUE TO 320 00:16:20,052 --> 00:16:21,587 INDULGENCE PROCESSES. 321 00:16:21,587 --> 00:16:24,557 WE WANTED TO TEST SOME OF THE 322 00:16:24,557 --> 00:16:28,227 MORE KNOWN AND IMPORTANT RISK 323 00:16:28,227 --> 00:16:30,296 FACTORS THAT GOT ASSOCIATED 324 00:16:30,296 --> 00:16:33,766 WITH LUNG CANCER TO SEE WHETHER 325 00:16:33,766 --> 00:16:42,942 THEY CONTRIBUTED AS MUTAGENTS 326 00:16:42,942 --> 00:16:45,444 AND A TUMOR THAT ALREADY 327 00:16:45,444 --> 00:16:46,846 RECEIVED A DRIVER INPUT THAN 328 00:16:46,846 --> 00:16:48,447 PROGRESS IN THE EVOLUTION. 329 00:16:48,447 --> 00:16:54,620 SO FIRST WE TESTED A 330 00:16:54,620 --> 00:16:55,788 SECOND-HAND TOBACCO SMOKING. 331 00:16:55,788 --> 00:16:58,124 AS I MENTIONED, WE HAD DATA 332 00:16:58,124 --> 00:17:01,994 FROM ABOUT 400 SUBJECTS, 208 333 00:17:01,994 --> 00:17:07,700 AND OVER 250 HAD VERY VARIABLE 334 00:17:07,700 --> 00:17:10,836 INTENSE EXPOSURE TO SECOND-HAND 335 00:17:10,836 --> 00:17:11,604 TOBACCO SMOKING. 336 00:17:11,604 --> 00:17:15,474 AND WHAT WE SAW THE TUMORS 337 00:17:15,474 --> 00:17:16,242 COMING FROM SECOND-HAND 338 00:17:16,242 --> 00:17:18,711 SMOKING, THERE WAS A SLIGHT 339 00:17:18,711 --> 00:17:24,617 INCREASE OF THE BASE 340 00:17:24,617 --> 00:17:26,986 SUBSTITUTION. 341 00:17:26,986 --> 00:17:29,789 BUT WHEN WE COMPARED, WE FOUND 342 00:17:29,789 --> 00:17:31,023 THAT THIS ASSOCIATION WAS NO 343 00:17:31,023 --> 00:17:33,492 LONGER SIGNATURE. 344 00:17:33,492 --> 00:17:35,594 AND SIMILARLY WE DID NOT SEE 345 00:17:35,594 --> 00:17:38,497 ANY MAJOR DIFFERENCE ACROSS THE 346 00:17:38,497 --> 00:17:42,601 DIFFERENT MUTATION TYPES OR NO 347 00:17:42,601 --> 00:17:45,571 MAJOR ENRICHMENT OF ANY DRIVER 348 00:17:45,571 --> 00:17:49,108 GENE OR ANY ENRICHMENT IN MY 349 00:17:49,108 --> 00:17:50,876 MUTATION SIGNATURE. 350 00:17:50,876 --> 00:17:53,879 SO WE TESTED THE LEVEL OF OUR 351 00:17:53,879 --> 00:17:55,948 ALGORITHM THAT'S CAN DETECT THE 352 00:17:55,948 --> 00:17:57,349 NUMBER OF MUTATIONS IN THE 353 00:17:57,349 --> 00:17:58,951 DIFFERENT CELLS TO SEE WHAT 354 00:17:58,951 --> 00:18:09,328 COULD BE THE LEVEL OF 355 00:18:10,129 --> 00:18:11,730 MUTAGENICY. 356 00:18:11,730 --> 00:18:17,870 SO INJECTING INTO THE ALGORITHM 357 00:18:17,870 --> 00:18:19,738 THAT ARE ASSOCIATED WITH 358 00:18:19,738 --> 00:18:20,673 TYPICAL OF TOBACCO SMOKING. 359 00:18:20,673 --> 00:18:22,741 WE SAW FOR EXAMPLE, IF THE CELL 360 00:18:22,741 --> 00:18:25,277 HAD AT LEAST 5 PERCENT OF 361 00:18:25,277 --> 00:18:28,047 MUTATIONS ASSOCIATED WITH SBS4, 362 00:18:28,047 --> 00:18:31,317 WE WOULD BE IDENTIFY THEN IN 363 00:18:31,317 --> 00:18:33,252 20-25 PERCENT OF THE SAMPLES 364 00:18:33,252 --> 00:18:35,421 WHICH WE DID NOT AT ALL SO. WE 365 00:18:35,421 --> 00:18:37,957 COULD NOT CONCLUDED THAT IF 366 00:18:37,957 --> 00:18:46,165 THERE IS A MUTAGENIC AFFECT, 367 00:18:46,165 --> 00:18:50,803 THIS IS BELOW 5 PERCENT CELLS. 368 00:18:50,803 --> 00:18:52,404 OTHERWISE WE WOULD HAVE BEEN 369 00:18:52,404 --> 00:18:55,174 BEEN DETECTED IN LARGER NUMBER. 370 00:18:55,174 --> 00:18:58,143 WE DID OBSERVE A FACTOR THAT 371 00:18:58,143 --> 00:19:01,814 WHEN YOU LOOK AT THE MUTATION 372 00:19:01,814 --> 00:19:04,650 BETWEEN PASSIVE SMOKING AND NON 373 00:19:04,650 --> 00:19:07,553 PASSIVE SMOKING, THEY WERE 374 00:19:07,553 --> 00:19:08,487 ALMOST IDENTIFY CALL. 375 00:19:08,487 --> 00:19:10,689 WE FOUND THAT THERE WAS A VERY 376 00:19:10,689 --> 00:19:16,996 STRONG DECREASE IN THE TELAMERE 377 00:19:16,996 --> 00:19:20,432 LENGTH, WE KNOW THAT EVERY CELL 378 00:19:20,432 --> 00:19:24,036 REPLICATION, THERE IS A 379 00:19:24,036 --> 00:19:30,910 DECREASE OF THE TELO METERS, SO 380 00:19:30,910 --> 00:19:32,544 IT SUGGEST A LARGER NUMBER 381 00:19:32,544 --> 00:19:38,017 WHICH COULD BE A PROMOTION 382 00:19:38,017 --> 00:19:38,984 EFFECT. 383 00:19:38,984 --> 00:19:43,822 AND THIS TIME, WE FOUND THAT 384 00:19:43,822 --> 00:19:44,790 THIS REMAIN STRONGLY 385 00:19:44,790 --> 00:19:45,691 SIGNIFICANT. 386 00:19:45,691 --> 00:19:46,859 SO OUR CONCLUSION SOUTH SIDE 387 00:19:46,859 --> 00:19:51,664 BASED ON THESE ANALYSIS, 388 00:19:51,664 --> 00:19:58,804 SECOND-LAND TOBACCO IS NOT A 389 00:19:58,804 --> 00:20:00,039 POTENT MUTAGENIC FACTOR BUT IT 390 00:20:00,039 --> 00:20:03,542 COULD HAVE A PROMOTION EFFECT. 391 00:20:03,542 --> 00:20:05,644 WHAT ABOUT AIR POLLUTION? 392 00:20:05,644 --> 00:20:09,815 WE TESTED IN PARTICULARLY A 393 00:20:09,815 --> 00:20:12,117 PARTICULAR MATTER BELOW THE 394 00:20:12,117 --> 00:20:16,722 2.5, THE FOREST FIRES, RECORE 395 00:20:16,722 --> 00:20:18,557 EXHAUST, OTHER INDUSTRIAL 396 00:20:18,557 --> 00:20:19,458 RESOURCES COMMON IN DIFFERENT 397 00:20:19,458 --> 00:20:20,859 AREAS OF THE WORLD. 398 00:20:20,859 --> 00:20:24,063 AND WE USED FOR THIS ANALYSIS A 399 00:20:24,063 --> 00:20:27,967 COMBINED MODEL USING OUR 400 00:20:27,967 --> 00:20:30,703 AEROSOL FROM DIFFERENT LIGHTS 401 00:20:30,703 --> 00:20:33,005 COMBINED WITH TRANSFER IN GRAND 402 00:20:33,005 --> 00:20:36,408 BASE PHOTO O METERS AND WE PUT 403 00:20:36,408 --> 00:20:41,013 IT TOGETHER FROM 1998 TO 2021 404 00:20:41,013 --> 00:20:44,717 AND WE LINKED ALL OF THIS DATA 405 00:20:44,717 --> 00:20:46,652 OF THE POLLUTION TO THE 406 00:20:46,652 --> 00:20:47,920 RESIDENT. 407 00:20:47,920 --> 00:20:51,790 AND WHAT WE OBSERVED THAT WE IN 408 00:20:51,790 --> 00:20:54,126 THE TUMORS, THEY CAME FROM AREA 409 00:20:54,126 --> 00:20:56,662 EXPOSED TO VERY HIGH LEVELS OF 410 00:20:56,662 --> 00:20:58,964 POLLUTION, WE HAVE AN INCREASE 411 00:20:58,964 --> 00:21:07,840 OF SBS AND T ALL THE MUTATION 412 00:21:07,840 --> 00:21:09,541 FACTORS AND VERY STRONG TO 413 00:21:09,541 --> 00:21:12,444 EXPOSURE AFFECT. 414 00:21:12,444 --> 00:21:14,380 SO INCREASING EXPOSURE TO AIR 415 00:21:14,380 --> 00:21:16,615 POLLUTION, WE HAVE INCREASING 416 00:21:16,615 --> 00:21:24,356 MUTATION SIGNATURES AND A 417 00:21:24,356 --> 00:21:25,057 DECREASING TELOMERE LENGTH, AND 418 00:21:25,057 --> 00:21:26,692 WITH WHEN WE SAW AREA OF 419 00:21:26,692 --> 00:21:31,930 POLLUTION, THERE WAS A INCREASE 420 00:21:31,930 --> 00:21:32,464 OF TP53. 421 00:21:32,464 --> 00:21:34,299 SXL THIS TIME ALL THE 422 00:21:34,299 --> 00:21:39,805 ASSOCIATES FOR ALL MUTATION 423 00:21:39,805 --> 00:21:42,441 ASSOCIATION AND TELOMERE LENGTH 424 00:21:42,441 --> 00:21:43,509 REMAIN SIGNATURE. 425 00:21:43,509 --> 00:21:48,047 AND HERE YOU CAN SEE ALL THE 426 00:21:48,047 --> 00:21:49,882 REGRESSION MOTED ELZ WITH 427 00:21:49,882 --> 00:21:51,517 DIFFERENT SIGN HERE, ARE THE 428 00:21:51,517 --> 00:21:52,684 NUMBER OF SAMPLES FROM 429 00:21:52,684 --> 00:21:54,753 DIFFERENT COUNTRIES WHERE WE 430 00:21:54,753 --> 00:21:55,921 COLLECTED INFORMATION OF AIR 431 00:21:55,921 --> 00:21:59,091 POLLUTION AND THIS ARE FOR 432 00:21:59,091 --> 00:22:00,025 SINGLE BASE SUBSTITUTION AND 433 00:22:00,025 --> 00:22:07,599 YOU SEE A SIMILAR PATH AND FOR 434 00:22:07,599 --> 00:22:15,541 INCREASE OF TEROMERE LENGTH. 435 00:22:15,541 --> 00:22:21,747 WE SAW AN ENRICH OF SBS5 WITH 436 00:22:21,747 --> 00:22:26,151 AGE AND SELL DIVISION AND SBS4 437 00:22:26,151 --> 00:22:27,986 THAT IS ASSOCIATED WITH TOBACCO 438 00:22:27,986 --> 00:22:29,621 SMOKING. 439 00:22:29,621 --> 00:22:32,858 WHILE HERE THESE WERE 440 00:22:32,858 --> 00:22:36,061 NON-SMOKER AND EVIDENCE OF AIR 441 00:22:36,061 --> 00:22:39,731 POLLUTION AND ID 3 A SIGNATURE 442 00:22:39,731 --> 00:22:41,667 PREVIOUSLY ASSOCIATED WITH 443 00:22:41,667 --> 00:22:42,734 TOBACCO SMOKING. 444 00:22:42,734 --> 00:22:45,003 AND YET YOU CAN SEE THE NUMBER 445 00:22:45,003 --> 00:22:46,839 OF SAMPLES ARE LIMITED BECAUSE 446 00:22:46,839 --> 00:22:48,540 OF THE DIFFERENT TYPES OF 447 00:22:48,540 --> 00:22:51,443 SIGNATURES BUT THERE IS A VERY 448 00:22:51,443 --> 00:22:53,846 STRONG INCREASE WITH EVERY TYPE 449 00:22:53,846 --> 00:22:56,048 OF SIGNATURE. 450 00:22:56,048 --> 00:22:57,883 AND WE, ESTIMATED FOR EXAMPLE, 451 00:22:57,883 --> 00:23:03,589 THAT ONE UNIT INCREASE OF PM2.5 452 00:23:03,589 --> 00:23:06,191 WE COULD HAVE AN INCREASE AND 453 00:23:06,191 --> 00:23:10,963 SIMILAR FOR THE OTHER MUTATION 454 00:23:10,963 --> 00:23:11,263 SIGNATURES. 455 00:23:11,263 --> 00:23:12,131 AND THIS TIME AGAIN, THE 456 00:23:12,131 --> 00:23:14,867 ASSOCIATION WITH THE MUTATION 457 00:23:14,867 --> 00:23:16,902 SIGNATURES REMAIN STRONG 458 00:23:16,902 --> 00:23:20,139 STATISTICAL SIGNATURE AFTER 459 00:23:20,139 --> 00:23:21,507 ADJUSTING THE FORMULA. 460 00:23:21,507 --> 00:23:24,276 SO OUR CONCLUSION FROM HERE IS 461 00:23:24,276 --> 00:23:30,883 THAT AIR POLLUTION DIFFERENT 462 00:23:30,883 --> 00:23:34,753 FROM SECOND-HAND TOBACCO, MAY 463 00:23:34,753 --> 00:23:39,825 HAVE SIMILAR AFFECT. 464 00:23:39,825 --> 00:23:48,100 AND ALSO SBS5 MUTAGENIC SIGN. 465 00:23:48,100 --> 00:23:51,336 WE ALSO HAD ACCESS THANKS TO A 466 00:23:51,336 --> 00:23:56,542 COLLABORATION WITH DR. CHIN FOR 467 00:23:56,542 --> 00:23:59,945 SPECIFIC AND VERY VERY UNUSUAL 468 00:23:59,945 --> 00:24:03,815 AREA FROM CHINA, XUANWEI, WHERE 469 00:24:03,815 --> 00:24:06,351 THE RATE OF LUNG CANCER IS 470 00:24:06,351 --> 00:24:07,719 AMONG THE HIGHEST IN THE WORLD 471 00:24:07,719 --> 00:24:11,156 AND EVEN THE MORTALITY ARE 472 00:24:11,156 --> 00:24:21,667 ALMOST 5 TIMES OF CHINA'S 473 00:24:21,667 --> 00:24:22,201 HIGHEST. 474 00:24:22,201 --> 00:24:27,439 AND THIS IS DUE TO POOR LIVING 475 00:24:27,439 --> 00:24:29,942 HOUSES WHERE WOMEN USE THIS FOR 476 00:24:29,942 --> 00:24:32,711 HEATING BUT ALSO COOKING AND 477 00:24:32,711 --> 00:24:41,253 CONSTANTLY EXPOSED TO THIS 478 00:24:41,253 --> 00:24:42,554 CONBUSTABLE. 479 00:24:42,554 --> 00:24:45,090 SO WE COMPARED THEM WITH 480 00:24:45,090 --> 00:24:48,493 ANOTHER TYPE OF SAMPLE FROM A 481 00:24:48,493 --> 00:24:51,063 DIFFERENT AREA OF CHINA WHERE 482 00:24:51,063 --> 00:24:54,866 THEY USE A DIFFERENT TYPE OF 483 00:24:54,866 --> 00:24:56,568 COAL. 484 00:24:56,568 --> 00:25:00,239 AND HERE FOR ALL THE PRESENT 485 00:25:00,239 --> 00:25:07,746 AND WE SAW THAT IN THE SUBJECT 486 00:25:07,746 --> 00:25:09,181 WITH XUANWEI THERE WERE 487 00:25:09,181 --> 00:25:11,750 DIFFERENT TYPES OF SIGNATURES 488 00:25:11,750 --> 00:25:14,052 INCLUDING THE SBS4 THAT WAS 489 00:25:14,052 --> 00:25:15,754 PREVIOUSLY ASSOCIATED WITH 490 00:25:15,754 --> 00:25:16,822 TOBACCO SMOKING. 491 00:25:16,822 --> 00:25:20,025 AND WHEN WE COMPARE FROM THOSE 492 00:25:20,025 --> 00:25:23,695 OF THE FACTORS, WE SAW THAT WE 493 00:25:23,695 --> 00:25:26,431 HAVE SIMILAR PATTERNS WITH THE 494 00:25:26,431 --> 00:25:31,136 INCREASE OF ALL DSPS-4 AS IN 495 00:25:31,136 --> 00:25:33,572 THOSE EXPOSED. 496 00:25:33,572 --> 00:25:37,476 BUT IF ANY, THE COMBUSTIBLE WAS 497 00:25:37,476 --> 00:25:38,844 HIGH. 498 00:25:38,844 --> 00:25:41,146 SO CLEARLY THERE IS AN EVIDENCE 499 00:25:41,146 --> 00:25:45,250 THAT INDOOR POLLUTION IS ALSO 500 00:25:45,250 --> 00:25:46,652 VERY STRONG MUTAGENIC AFFECT. 501 00:25:46,652 --> 00:25:49,855 SO AT THIS POINT, MY TAKE-HOME 502 00:25:49,855 --> 00:25:51,957 MESSAGE IN THE LARGEST LUNG 503 00:25:51,957 --> 00:25:54,493 CANCER TODAY AND WE CAN DO THIS 504 00:25:54,493 --> 00:25:59,765 BECAUSE WE ARE AT AGE, WE SAW 505 00:25:59,765 --> 00:26:02,734 THAT MUTATIONS WERE MORE COMMON 506 00:26:02,734 --> 00:26:12,844 FROM EUROPEAN ANCESTRY. 507 00:26:12,844 --> 00:26:23,388 BUT THERE ARE SOME EXPOSURES TO 508 00:26:23,655 --> 00:26:25,490 CARCINOGEN, OR AIR POLLUTION 509 00:26:25,490 --> 00:26:26,258 FROM ACROSS DIFFERENT AREAS OF 510 00:26:26,258 --> 00:26:27,559 THE WORLD. 511 00:26:27,559 --> 00:26:31,496 I WANT TO NOW SHOW YOU HOW EVEN 512 00:26:31,496 --> 00:26:35,100 THE USE OF MUTATION SIGNATURE 513 00:26:35,100 --> 00:26:37,002 CAN BE IMPORTANT TO STUDY THE 514 00:26:37,002 --> 00:26:42,240 EVOLUTION OF LUNG CANCER AND I 515 00:26:42,240 --> 00:26:44,810 WILL FOCUS ON THE MOST COMMON 516 00:26:44,810 --> 00:26:46,845 TYPE OF LUNG CANCER. 517 00:26:46,845 --> 00:26:50,349 AND FOR THIS ANALYSIS, I ZOOMED 518 00:26:50,349 --> 00:26:52,417 INTO A SERIES OF SAMPLE THAT 519 00:26:52,417 --> 00:26:58,357 HAD TO HAVE A HIGH OF--THE AND 520 00:26:58,357 --> 00:27:04,563 PURITY AND OTHER FACTORS IN THE 521 00:27:04,563 --> 00:27:06,832 SAMPLE CONTAINED AMPLE TO 522 00:27:06,832 --> 00:27:10,769 FIGHT--AND THIS IS THE SAMPLE 523 00:27:10,769 --> 00:27:14,506 FOR THIS ANALYSIS INCLUDING 108 524 00:27:14,506 --> 00:27:16,541 STATIONS, 104 EUROPEAN WITH NON 525 00:27:16,541 --> 00:27:18,610 SMOKERS BUT ALSO WITH THIS 526 00:27:18,610 --> 00:27:21,847 ANALYSIS WE INCLUDED 120 527 00:27:21,847 --> 00:27:23,415 SMOKERS FOR COMPARISON BECAUSE 528 00:27:23,415 --> 00:27:24,616 IT'S IMPORTANT TO COMPARE FOR 529 00:27:24,616 --> 00:27:26,418 THE DIFFERENT EVOLUTION BECAUSE 530 00:27:26,418 --> 00:27:28,220 WE KNOW IT COULD BE DIFFERENT. 531 00:27:28,220 --> 00:27:30,088 FOR THOSE THAT ARE NOT FAMILIAR 532 00:27:30,088 --> 00:27:36,228 WITH THE HOW WE ESTIMATED TO 533 00:27:36,228 --> 00:27:38,530 REVOLUTION, I WANTED TO USE 534 00:27:38,530 --> 00:27:40,632 THIS CARTOON TO TRY TO EXPLAIN. 535 00:27:40,632 --> 00:27:42,033 AS I MENTIONED AT THE 536 00:27:42,033 --> 00:27:43,869 BEGINNING, WE ACCUMULATE 537 00:27:43,869 --> 00:27:47,038 MUTATION FROM THE BEGINNING 538 00:27:47,038 --> 00:27:50,675 FROM THE AFFECT TO CANCER. 539 00:27:50,675 --> 00:27:52,310 SO SOME MUTATIONS ACCUMULATE 540 00:27:52,310 --> 00:27:55,981 AND ALL THE CELLS CARRY THE 541 00:27:55,981 --> 00:27:57,616 MUTATIONS ACCUMULATED WITH THEM 542 00:27:57,616 --> 00:27:59,851 THE SAME MUTATIONS. 543 00:27:59,851 --> 00:28:04,890 SO WE CALL THE LONG EXPANSION 544 00:28:04,890 --> 00:28:06,758 WHEN EVERY CELLS INCLUDES 100 545 00:28:06,758 --> 00:28:09,861 PERCENT OF THE MUTATION THAT'S 546 00:28:09,861 --> 00:28:10,962 THEY'VE ACCUMULATED. 547 00:28:10,962 --> 00:28:14,599 UNTIL WHAT WE CALL THE MOST 548 00:28:14,599 --> 00:28:17,335 RESENT COMMON ANCESTOR OR IF 549 00:28:17,335 --> 00:28:19,638 YOU WERE ABLE TO DIAGNOSE THE 550 00:28:19,638 --> 00:28:21,740 CANCER AT THIS TIME, ALL THE 551 00:28:21,740 --> 00:28:23,809 CELLS WOULD CARRY THIS MUTATION 552 00:28:23,809 --> 00:28:27,012 AND BASED ON ALTERATION AND 553 00:28:27,012 --> 00:28:29,314 MUTATIONS WE COULD ALSO 554 00:28:29,314 --> 00:28:30,248 DISTINGUISH WHETHER THE 555 00:28:30,248 --> 00:28:32,284 MUTATION ARE VERY EARLY AT THE 556 00:28:32,284 --> 00:28:34,352 BEGINNING OR LATE BUT STILL 557 00:28:34,352 --> 00:28:36,321 CLOSE, STILL PRESENT IN ALL THE 558 00:28:36,321 --> 00:28:37,122 CELLS. 559 00:28:37,122 --> 00:28:40,058 FROM THE TIME OF THE MOST 560 00:28:40,058 --> 00:28:42,828 RESENT COMMON ANCESTOR, THERE 561 00:28:42,828 --> 00:28:46,064 IS A SUB CLONEAL. 562 00:28:46,064 --> 00:28:48,366 SO AT THE TIME OF DIAGNOSIS, IF 563 00:28:48,366 --> 00:28:52,037 YOU DO A CANCER GENO ANALYSIS, 564 00:28:52,037 --> 00:28:54,539 YOU SEE A DIFFERENT PORTIONS OF 565 00:28:54,539 --> 00:28:56,007 CELLS CARRYING DIFFERENT TYPES 566 00:28:56,007 --> 00:28:56,608 OF MUTATIONS. 567 00:28:56,608 --> 00:28:59,711 SO THIS IS DIVERSIFICATION AND 568 00:28:59,711 --> 00:29:02,113 DEFINED AS THE LATENCY, THE 569 00:29:02,113 --> 00:29:04,449 TIME THAT IT OCCURED FROM THE 570 00:29:04,449 --> 00:29:08,820 MOST RESENT ANCESTOR TO THE AGE 571 00:29:08,820 --> 00:29:10,388 OF DIAGNOSIS. 572 00:29:10,388 --> 00:29:14,726 NOW BASED ON THIS, WE FIRST OF 573 00:29:14,726 --> 00:29:17,395 ALL, COMPARED SMOKERS VERSUS 574 00:29:17,395 --> 00:29:19,531 NON-SMOKERS AND IN THE 575 00:29:19,531 --> 00:29:21,399 NON-SMOKERS THE GENE WAS 576 00:29:21,399 --> 00:29:23,902 STRONGLY ASSOCIATED WITH THE 577 00:29:23,902 --> 00:29:28,707 NON SMOKERS WHILE INSTEAD--WERE 578 00:29:28,707 --> 00:29:30,108 ASSOCIATED WITH SMOKERS. 579 00:29:30,108 --> 00:29:32,210 AND WHEN WE LOOKED AT MUTATION 580 00:29:32,210 --> 00:29:34,546 OF SIGNATURES, WE FOUND VERY 581 00:29:34,546 --> 00:29:36,281 INTRIGUING RESULTS. 582 00:29:36,281 --> 00:29:39,784 IF YOU SEE THE LINE THAT IN THE 583 00:29:39,784 --> 00:29:42,120 AROUND ONE, YOU CAN SEE BELOW 584 00:29:42,120 --> 00:29:52,597 THE LINE, THERE ARE MOSTLY 585 00:29:53,698 --> 00:29:54,432 CLONAL MUTATIONS. 586 00:29:54,432 --> 00:30:02,908 SO WE WHAT WE NOTICED, LIKE 587 00:30:02,908 --> 00:30:05,911 SBS4 OR SBS100, THERE ARE BOTH 588 00:30:05,911 --> 00:30:07,746 ASSOCIATED WITH TOBACCO 589 00:30:07,746 --> 00:30:10,749 SMOKING, THERE WERE MOSTLY 590 00:30:10,749 --> 00:30:12,584 CLONAL BELOW THIS LINE MEANS 591 00:30:12,584 --> 00:30:14,953 THEY ARE INVOLVED IN THE 592 00:30:14,953 --> 00:30:15,921 MUTATION BECAUSE THEY ARE FROM 593 00:30:15,921 --> 00:30:17,455 THE BEGINNING. 594 00:30:17,455 --> 00:30:21,526 INSTEAD THE MUTATIONS, THE 595 00:30:21,526 --> 00:30:26,064 MUTATION SIGNATURES HAD SOME 596 00:30:26,064 --> 00:30:30,602 CLONEAL SOME EVEN SUB CLONAL 597 00:30:30,602 --> 00:30:32,037 MUTATION. 598 00:30:32,037 --> 00:30:36,207 AND WHEN WE ZOOM TO THE MAJOR 599 00:30:36,207 --> 00:30:38,510 CANCER GENES, WE OBSERVE THE 600 00:30:38,510 --> 00:30:40,245 SIMILAR PATTERNS THAT IT WAS 601 00:30:40,245 --> 00:30:47,385 INTRIGUING. 602 00:30:47,385 --> 00:30:49,921 THEY CORRESPONDED TO THE 603 00:30:49,921 --> 00:30:53,158 EXPOSURE TO TOBACCO SMOKING. 604 00:30:53,158 --> 00:30:55,360 SOL THE EXPOSURE IN THE TOBACCO 605 00:30:55,360 --> 00:30:56,628 SMOKING PARTICIPATED IN THE 606 00:30:56,628 --> 00:30:58,296 INITIATION OF THE TUMOR AND 607 00:30:58,296 --> 00:31:00,532 MANY TIMES THROUGH THE TRIGGER 608 00:31:00,532 --> 00:31:02,400 OF CANCER DRIVING GENE. 609 00:31:02,400 --> 00:31:06,504 IN COMPARISON TO THIS AND IN 610 00:31:06,504 --> 00:31:13,612 CONTRAST TO THIS, DOMINATED BY 611 00:31:13,612 --> 00:31:15,447 SBS5, SBS14 THEY'RE ALL 612 00:31:15,447 --> 00:31:19,818 INDULGENCE THAT MEANS THAT IT'S 613 00:31:19,818 --> 00:31:21,519 EARLY CLONAL SO PARTICIPATE AT 614 00:31:21,519 --> 00:31:24,623 THE BEGINNING OF THE TUMOR, THE 615 00:31:24,623 --> 00:31:25,557 PROCESSES THAT ARE RESPONSIBLE 616 00:31:25,557 --> 00:31:29,294 FOR THIS ARE MOSTLY OF 617 00:31:29,294 --> 00:31:30,161 INDULGENCE ORIGIN. 618 00:31:30,161 --> 00:31:34,299 WHEN WE LOOKED AT THE LATENCY 619 00:31:34,299 --> 00:31:37,302 IS THE TIME FROM MOST RESENT 620 00:31:37,302 --> 00:31:40,505 ASSESS TO THE AGE OF DIAGNOSIS 621 00:31:40,505 --> 00:31:42,641 OF THE TUMOR, WE OBSERVED A 622 00:31:42,641 --> 00:31:43,775 VERY IMPORTANT DIFFERENCES. 623 00:31:43,775 --> 00:31:54,185 THE TUMOR THAT CARRY FI 624 00:31:57,789 --> 00:31:58,757 MUTATIONS, THEY CARRIED LESS 625 00:31:58,757 --> 00:32:02,794 THAN 5 YEARS IN COMPARISON TO 626 00:32:02,794 --> 00:32:05,563 ALL TUMORS THAT ARE NO MUTATION. 627 00:32:05,563 --> 00:32:07,866 WHEN WE COMPARED BY SEX, WE SAW 628 00:32:07,866 --> 00:32:10,835 THAT WOMEN HAVE LONGER LATENCY, 629 00:32:10,835 --> 00:32:13,838 3.3 AND WHEN WE LOOKED AT THE 630 00:32:13,838 --> 00:32:15,674 MUTATION OF SIGNATURES, WE WERE 631 00:32:15,674 --> 00:32:17,509 REALLY SURPRISED BECAUSE WE 632 00:32:17,509 --> 00:32:20,945 IDENTIFIED ONE SIGNATURE ID-2 633 00:32:20,945 --> 00:32:23,481 THAT UNKNOWN ORIGIN UP TO NOW, 634 00:32:23,481 --> 00:32:29,454 THAT HAD VERY VERY RAPID GROWTH 635 00:32:29,454 --> 00:32:34,693 6.2 YEARS IN AVERAGE FASTER 636 00:32:34,693 --> 00:32:36,995 THAN SHORTEN LATENCY IN 637 00:32:36,995 --> 00:32:38,596 COMPARISON TO OTHER TUMORS. 638 00:32:38,596 --> 00:32:41,132 AND THE LARGE MAJORITY OF THE 639 00:32:41,132 --> 00:32:45,704 ID-2 THERE IS A SMALL DELETION, 640 00:32:45,704 --> 00:32:48,239 A DELETION WHERE EARLY CLONE. 641 00:32:48,239 --> 00:32:50,108 SO SOMETHING TRIGGERED THIS 642 00:32:50,108 --> 00:32:52,077 ID-2 FROM THE BEGINNING OF THIS 643 00:32:52,077 --> 00:32:53,111 TUMORS. 644 00:32:53,111 --> 00:32:54,713 AND THERE WERE QUITE COMMON, 645 00:32:54,713 --> 00:32:57,682 THEY WERE BETWEEN 11 AND 17 646 00:32:57,682 --> 00:33:02,287 PERCENT IN NO SMOKERS OF 647 00:33:02,287 --> 00:33:04,889 EUROPEAN AND 35, 36 PERCENT IN 648 00:33:04,889 --> 00:33:07,092 THE SMOKERS. 649 00:33:07,092 --> 00:33:09,394 SO WHAT WE SAW THAT FIRST OF 650 00:33:09,394 --> 00:33:11,096 ALL WHEN WE COMPARED ALL OF 651 00:33:11,096 --> 00:33:17,168 THIS DATA AND ADJUST IT FOR 652 00:33:17,168 --> 00:33:19,003 IMPORTANT, THE LONGER LATENCY 653 00:33:19,003 --> 00:33:23,108 ASSOCIATED WITH THE FEMALE SEX 654 00:33:23,108 --> 00:33:24,275 AND MUTATION REMAIN SIGNATURE 655 00:33:24,275 --> 00:33:26,111 WHICH COULD BE IMPORTANT FOR 656 00:33:26,111 --> 00:33:28,012 EARLY DETECTION BECAUSE IF A 657 00:33:28,012 --> 00:33:29,581 TUMOR GROWS, THERE IS A WINDOW 658 00:33:29,581 --> 00:33:32,350 OF TIME WHERE ONE CAN INTERVENE. 659 00:33:32,350 --> 00:33:35,153 AND ON THE OTHER SIDE, THE 660 00:33:35,153 --> 00:33:36,054 ASSOCIATION WITH ID-2 WAS 661 00:33:36,054 --> 00:33:40,158 CONFIRMED TO BE VERY VERY 662 00:33:40,158 --> 00:33:40,692 STRONGLY AND SIGNIFICANT 663 00:33:40,692 --> 00:33:44,929 ASSOCIATED WITH THE SHORTEN 664 00:33:44,929 --> 00:33:46,798 LATENCY. 665 00:33:46,798 --> 00:33:49,100 WE WANTED TO INVESTIGATE THESE 666 00:33:49,100 --> 00:33:50,969 FACTORS, SUCH A SHORT LATENCY, 667 00:33:50,969 --> 00:33:54,405 THEY ARE VERY AGGRESSIVE TUMORS 668 00:33:54,405 --> 00:33:57,642 SO WE TESTED THE SERIES OF 669 00:33:57,642 --> 00:34:00,612 MARKERS USING OUR OWN 670 00:34:00,612 --> 00:34:02,680 SEQUENCING DATA AND WE SAW THAT 671 00:34:02,680 --> 00:34:04,516 ALL THE MARKERS WERE ENRICHED 672 00:34:04,516 --> 00:34:07,519 WITH THE TUMORS IN COMPARISON 673 00:34:07,519 --> 00:34:08,453 WITH THE NON-TUMORS. 674 00:34:08,453 --> 00:34:10,255 AND HERE YOU CAN SEE THE 675 00:34:10,255 --> 00:34:15,493 ASSOCIATION BETWEEN THE NUMBER 676 00:34:15,493 --> 00:34:17,562 OF ID2 AND THE EXPRESSIONS 677 00:34:17,562 --> 00:34:21,032 MARKERS, AS YOU CAN SEE VERY 678 00:34:21,032 --> 00:34:22,600 VERY STRONGLY CORRELATED. 679 00:34:22,600 --> 00:34:26,771 WE ALSO FOUND THAT TUMORS WITH 680 00:34:26,771 --> 00:34:30,875 ID2 THE STRONGER SOURCE, 681 00:34:30,875 --> 00:34:32,577 AGGRESSIVE TUMORS THAT BECOME 682 00:34:32,577 --> 00:34:42,987 NE CROTIC AND MATATASIS. 683 00:34:46,291 --> 00:34:50,562 WE KNOW THERE ARE A LOT OF 684 00:34:50,562 --> 00:34:52,197 MUTATIONS AND DIFFERENT 685 00:34:52,197 --> 00:34:53,531 ANTIGENS AND THEY CALL IT A NEW 686 00:34:53,531 --> 00:34:54,332 SYSTEM. 687 00:34:54,332 --> 00:34:58,369 WE SAW THAT AMONG ALL THE 688 00:34:58,369 --> 00:35:02,106 MUTATION SIGNATURE THE LOWEST 689 00:35:02,106 --> 00:35:04,609 WAS ID-2 SO IT WAS NOT ABLE TO 690 00:35:04,609 --> 00:35:06,444 BLOCK THIS TUMOR AS THIS COULD 691 00:35:06,444 --> 00:35:08,746 BE ANOTHER CAUSE OF FAST 692 00:35:08,746 --> 00:35:11,783 DEVELOPMENT OF TUMORS IN THE 693 00:35:11,783 --> 00:35:12,884 SHORTER LATENCY. 694 00:35:12,884 --> 00:35:15,887 WE WANTED TO TEST WHETHER WE 695 00:35:15,887 --> 00:35:17,956 COULD EXPLAIN SOME EXPLANATION 696 00:35:17,956 --> 00:35:22,493 WITH ID2 AND TESTED ALL 697 00:35:22,493 --> 00:35:25,496 POSSIBLE GENO MUTATIONS AND WE 698 00:35:25,496 --> 00:35:26,631 FOUND THREE FINDINGS. 699 00:35:26,631 --> 00:35:31,002 WE FOUND THAT THEY WERE 700 00:35:31,002 --> 00:35:32,403 ENRICHED WITH--WHICH ARE BOTH 701 00:35:32,403 --> 00:35:35,807 SIGNS OF VERY STRONG GENO 702 00:35:35,807 --> 00:35:37,642 MAKING STABILITY, IN FACT WE 703 00:35:37,642 --> 00:35:43,481 SAW THAT THE NUMBER OF ID 2 704 00:35:43,481 --> 00:35:47,719 WERE ENRICHED WITH P53 AND WE 705 00:35:47,719 --> 00:35:50,955 SAW WERE INCREASING IN THE 706 00:35:50,955 --> 00:35:53,157 TUMOR WITH ID2 VERSUS THOSE 707 00:35:53,157 --> 00:35:54,225 WITHOUT ID2. 708 00:35:54,225 --> 00:35:57,161 BUT IN A WAY THIS IS EXPECTED 709 00:35:57,161 --> 00:36:01,099 IF YOU HAVE AN AGGRESSIVE TUMOR. 710 00:36:01,099 --> 00:36:02,500 BUT WE WERE PARTICULARLY 711 00:36:02,500 --> 00:36:04,769 INTRIGUED BY THIS ASSOCIATION 712 00:36:04,769 --> 00:36:06,638 WITH THE LINE ONE, FOR THOSE 713 00:36:06,638 --> 00:36:08,907 NOT FAMILIAR WITH THIS. 714 00:36:08,907 --> 00:36:14,612 LINE 1 FOR LONG INTER ONE, THAT 715 00:36:14,612 --> 00:36:18,983 IS TRAS POSABLE ELEMENTS COPY 716 00:36:18,983 --> 00:36:25,556 AND PASTE ACROSS THE GENOMI C 717 00:36:25,556 --> 00:36:26,324 RANDOMLY. 718 00:36:26,324 --> 00:36:28,426 AND WE KNOW THAT THERE IS 70 719 00:36:28,426 --> 00:36:30,962 PERCENT OF OUR GENO THAT IS DUE 720 00:36:30,962 --> 00:36:34,599 TO THIS THAT WITH CUT AND 721 00:36:34,599 --> 00:36:38,770 PASTED ACROSS THE GENO. 722 00:36:38,770 --> 00:36:44,242 FOR GERM LINE, WE MEAN THAT 723 00:36:44,242 --> 00:36:46,311 PRESENT IN EVERY SENSE. 724 00:36:46,311 --> 00:36:49,514 AND WHAT WE SAW IN OUR STUDIES 725 00:36:49,514 --> 00:36:55,153 THAT WE HAVE SOME GERMLINE 726 00:36:55,153 --> 00:36:58,423 MASTER, SO THERE ARE SOME AREAS 727 00:36:58,423 --> 00:37:00,291 OF THE GENO, THERE WERE 728 00:37:00,291 --> 00:37:06,230 STRONGLY ENRICHED WITH THIS 729 00:37:06,230 --> 00:37:08,566 LINE1 ACTIVATIONS BUT OVERALL, 730 00:37:08,566 --> 00:37:10,835 THEY WERE QUITE FREQUENT AND 731 00:37:10,835 --> 00:37:14,839 OVER 70 PERCENT OF THEM WERE OF 732 00:37:14,839 --> 00:37:16,407 GERMLINE ORIGIN. 733 00:37:16,407 --> 00:37:19,377 SO THE LINE 1, WOULD 734 00:37:19,377 --> 00:37:20,611 PARTICIPATE IN 70 PERCENT OF 735 00:37:20,611 --> 00:37:23,314 THE CASES TO THE INITIATION OF 736 00:37:23,314 --> 00:37:24,549 A TUMOR BECAUSE THEY WERE 737 00:37:24,549 --> 00:37:25,316 PRESENT ALREADY FROM THE 738 00:37:25,316 --> 00:37:27,185 BEGINNING. 739 00:37:27,185 --> 00:37:31,823 THIS IS JUST AN EXAMPLE IN THE 740 00:37:31,823 --> 00:37:35,193 MULTIPLE TUMORS WHEN YOU HAVE A 741 00:37:35,193 --> 00:37:38,429 GERMLINE, LINE 1 AND 22Q AND 742 00:37:38,429 --> 00:37:41,399 HERE ARE THE ALL THE RANDOM 743 00:37:41,399 --> 00:37:43,034 PIECE THAT'S ARE CUT AND PASTE 744 00:37:43,034 --> 00:37:46,704 AND YOU CAN FIND WHEN YOU 745 00:37:46,704 --> 00:37:47,805 SEQUENCE THE GENO ALL OVER THE 746 00:37:47,805 --> 00:37:49,941 PLACE. 747 00:37:49,941 --> 00:37:51,743 WE THEN TESTED THESE TUMORS 748 00:37:51,743 --> 00:37:53,444 WITH LINE 1 TO SEE IF WE 749 00:37:53,444 --> 00:37:55,213 CONFIRMED THAT IT WAS VERY 750 00:37:55,213 --> 00:37:56,814 STRONGLY ASSOCIATED BUT WE ALSO 751 00:37:56,814 --> 00:38:01,152 SAW THERE WAS INCREASED WITH 752 00:38:01,152 --> 00:38:04,122 ANOTHER ID SIGNATURE ID 1 AND 753 00:38:04,122 --> 00:38:06,224 ID 2 WERE VERY VERY STRONGLY 754 00:38:06,224 --> 00:38:07,592 CORRELATED. 755 00:38:07,592 --> 00:38:14,665 SO WITHOUT THIS ID 1 AND ID 2, 756 00:38:14,665 --> 00:38:20,872 THEY'RE BOTH MONO POLLTIN FIVE 757 00:38:20,872 --> 00:38:27,478 T, TTTTT, WHILE ID 2 IS A 758 00:38:27,478 --> 00:38:32,784 HOMOPOLIN, NOW THESE TTTTT-TYPE 759 00:38:32,784 --> 00:38:35,319 OF MOTIVE HIGHLY RESEMBLES THE 760 00:38:35,319 --> 00:38:36,054 ACTIVITY. 761 00:38:36,054 --> 00:38:39,023 IN FACT WE KNOW THAT THE LINE 1 762 00:38:39,023 --> 00:38:42,326 HAS TWO MAJOR READING FRAME. 763 00:38:42,326 --> 00:38:43,394 THE OPERATING FRAME ONE IS THE 764 00:38:43,394 --> 00:38:45,296 ONE THAT IS ASSOCIATED WITH 765 00:38:45,296 --> 00:38:48,666 BINDING. 766 00:38:48,666 --> 00:38:51,402 BUT THE RF2, THE OPEN LEADING 767 00:38:51,402 --> 00:38:56,207 FRAME 2 IS THE ONE INVOLVED 768 00:38:56,207 --> 00:39:03,981 WITH INDOCLEAS, THE COPY AND 769 00:39:03,981 --> 00:39:05,416 PASTE. 770 00:39:05,416 --> 00:39:09,420 AND THIS HAS BINDING TO TTTTT. 771 00:39:09,420 --> 00:39:11,389 SO WHAT WE UNDERSTOOD IS THAT 772 00:39:11,389 --> 00:39:17,261 WHEN LINE 1 IS ACTIVATED MAY 773 00:39:17,261 --> 00:39:19,597 LINK THIS HOPE FRAME, THE LINE 774 00:39:19,597 --> 00:39:22,166 1 IS ACTIVATED AND CREATE A 775 00:39:22,166 --> 00:39:24,268 SERIES OF DAMAGES IN THE GENO 776 00:39:24,268 --> 00:39:27,705 AND IT POTENTIALLY ALTERATIONS. 777 00:39:27,705 --> 00:39:32,076 IN THE ID 1 AND ID 2 ARE SIMPLE 778 00:39:32,076 --> 00:39:36,214 MARKERS OF THIS ACCUMULATION OF 779 00:39:36,214 --> 00:39:39,584 THIS INSERTIONS OF TTTTT. 780 00:39:39,584 --> 00:39:43,321 NOW TYPICALLY SINCE LINE 1 IS 781 00:39:43,321 --> 00:39:45,890 SO DANGEROUS BECAUSE IF IT'S 782 00:39:45,890 --> 00:39:47,058 ACTIVATED, IT CREATES ALL OF 783 00:39:47,058 --> 00:39:49,327 THESE BRAKES AND OTHER DAMAGES 784 00:39:49,327 --> 00:39:54,065 IN THE GENE O THEY'RE TYPICALLY 785 00:39:54,065 --> 00:39:57,135 STRONGLY SILENT IN THE CELLS. 786 00:39:57,135 --> 00:40:04,442 AND IT'S A DIFFERENT TYPE OF 787 00:40:04,442 --> 00:40:08,446 --SO WE HYPOTHESIZES THAT IN 788 00:40:08,446 --> 00:40:12,917 THE TUMORS, THERE ARE A LOT OF 789 00:40:12,917 --> 00:40:15,953 HIGH POLL MUTE TATIONS THAT CAN 790 00:40:15,953 --> 00:40:17,989 REACT LATE THE LINE 1. 791 00:40:17,989 --> 00:40:25,296 SO TO TEST THIS HYPOTHESES WE 792 00:40:25,296 --> 00:40:31,903 FOUND THAT OVER 95 PERCENT OF 793 00:40:31,903 --> 00:40:34,238 PROBES WERE HIGH POSSIBLE IN 794 00:40:34,238 --> 00:40:36,574 THE ID 2-POSITIVE TUMORS 795 00:40:36,574 --> 00:40:39,076 CONFIRMING THE FACTORS THAT 796 00:40:39,076 --> 00:40:40,478 THEY ARE LESS SILENCED. 797 00:40:40,478 --> 00:40:44,582 AND WHEN WE LOOKED AT THE 798 00:40:44,582 --> 00:40:47,552 CHROMOSOME FOR THIS LINE 1 AND 799 00:40:47,552 --> 00:40:50,755 WE COMPARED AND TUMOR MUTATION, 800 00:40:50,755 --> 00:40:52,423 WE SAW THAT IN THIS AREA, WE 801 00:40:52,423 --> 00:40:58,329 SAW THAT THE NORMAL TISSUE WAS 802 00:40:58,329 --> 00:40:59,730 MUTILATED IN COMPARISON TO THE 803 00:40:59,730 --> 00:41:01,599 TUMOR, IT WAS LOW. 804 00:41:01,599 --> 00:41:03,901 SXL WHEN WE COMPARE THE TUMORS 805 00:41:03,901 --> 00:41:08,706 WITH AND WITHOUT THE ID 2 IN 806 00:41:08,706 --> 00:41:11,943 SIGNATURE, WE SAW THAT THOSE 807 00:41:11,943 --> 00:41:16,013 ARE ID-SIGNATURE HAD LOWER MUTE 808 00:41:16,013 --> 00:41:18,516 TATION. 809 00:41:18,516 --> 00:41:21,953 WE THEN AND WITH THE SPECIFIC 810 00:41:21,953 --> 00:41:26,224 NOW IF YOU LOOK AT THE 811 00:41:26,224 --> 00:41:29,994 MUTILATION YOU CAN SEE FROM THE 812 00:41:29,994 --> 00:41:37,134 DARK MEANS HIGH POMATAING. 813 00:41:37,134 --> 00:41:41,973 NOW THE NORMAL TISSUE WOW 814 00:41:41,973 --> 00:41:47,678 ALMOST ALL GREEN. 815 00:41:47,678 --> 00:41:50,948 BUT IN THE TUMORS, WE SAW BELOW 816 00:41:50,948 --> 00:41:53,017 THE, THE DARKER ONES ARE THOSE 817 00:41:53,017 --> 00:41:53,751 WITH ID 2. 818 00:41:53,751 --> 00:42:02,360 SO WE CONFIRMED THAT THERE IS A 819 00:42:02,360 --> 00:42:12,903 HYPO SO OUR HYPOTHESES IS THAT 820 00:42:13,938 --> 00:42:19,343 ID2 ONLINE 1 AND FINDING ID2 IS 821 00:42:19,343 --> 00:42:24,615 IMPORTANT MARKER OF TUMORS AND 822 00:42:24,615 --> 00:42:27,385 LINKED TO TP53 BUT ALSO ALSO 823 00:42:27,385 --> 00:42:29,687 ARE THE ACTIVATION OF LINE 1 824 00:42:29,687 --> 00:42:30,588 WHICH IS IMPORTANT BECAUSE 825 00:42:30,588 --> 00:42:33,858 THERE ARE A LOT OF WORKING 826 00:42:33,858 --> 00:42:35,026 LABORATORIES AND NOW TESTING 827 00:42:35,026 --> 00:42:38,896 THE POSSIBILITY TO TARGET DR2 828 00:42:38,896 --> 00:42:49,106 OF LINE 1 . 829 00:42:49,907 --> 00:42:52,410 SO THE TAKE-HOME MESSAGE, THEY 830 00:42:52,410 --> 00:42:57,214 HAVE CLEAR SIGNS FOR ACTORS ALL 831 00:42:57,214 --> 00:42:59,317 ASSOCIATED WITH TOBACCO SMOKING. 832 00:42:59,317 --> 00:43:01,185 AND TUMORS THAT CARRY THIS TYPE 833 00:43:01,185 --> 00:43:02,920 OF MUTATION HAVE A SHORT 834 00:43:02,920 --> 00:43:04,155 LATENCY. 835 00:43:04,155 --> 00:43:09,393 IN CONTRAST IN THE 836 00:43:09,393 --> 00:43:12,430 NEVER-SMOKERS MUTATIONS ARE GFR 837 00:43:12,430 --> 00:43:15,633 AND DOMINATED BY SIGNATURE AND 838 00:43:15,633 --> 00:43:18,402 THEY HAVE LONGER LATENCY 839 00:43:18,402 --> 00:43:19,570 PARTICULARLY IN FEMALE PATIENTS. 840 00:43:19,570 --> 00:43:26,677 WE SAW ALSO THE EX EXPOSURES 841 00:43:26,677 --> 00:43:29,613 FACTORS AS INDICATED BY 842 00:43:29,613 --> 00:43:33,284 EXPOSURE, THEY ARE MOSTLY 843 00:43:33,284 --> 00:43:35,353 CLONAL WHICH MEANS THE TUMOR IS 844 00:43:35,353 --> 00:43:37,455 INITIALED THROUGH THIS PROCESS. 845 00:43:37,455 --> 00:43:39,724 WHILE INSTEAD WITH THE 846 00:43:39,724 --> 00:43:42,259 ASSOCIATE FOLLOW TT TUMOR 847 00:43:42,259 --> 00:43:45,463 ACROSS THE ENTIRE PROGRESSION. 848 00:43:45,463 --> 00:43:49,800 AND AT THE END, WE IDENTIFIED A 849 00:43:49,800 --> 00:43:51,435 IMPORTANT MARKET ID2 OF 850 00:43:51,435 --> 00:43:53,738 REACTIVATION IN THE TUMORS 851 00:43:53,738 --> 00:43:54,872 WHICH COULD BE IMPORTANT FOR 852 00:43:54,872 --> 00:43:55,840 TREATMENT. 853 00:43:55,840 --> 00:43:58,109 AND FINALLY, I WANT TO 854 00:43:58,109 --> 00:44:02,880 ACKNOWLEDGE HERE ALL OF OUR 855 00:44:02,880 --> 00:44:05,383 INVESTIGATORS IN THE TEAM 856 00:44:05,383 --> 00:44:06,784 WITHOUT WHOM I WOULD NOT BE 857 00:44:06,784 --> 00:44:08,419 ABLE TO PRESENT ALL OF THESE 858 00:44:08,419 --> 00:44:09,387 RESULTS ACROSS DIFFERENT 859 00:44:09,387 --> 00:44:10,721 INSTITUTIONS. 860 00:44:10,721 --> 00:44:14,925 AND AGAIN, MANY THANKS TO THE 861 00:44:14,925 --> 00:44:15,960 BIOWULF SUPPORT FOR THIS 862 00:44:15,960 --> 00:44:16,727 ANALYSIS. 863 00:44:16,727 --> 00:44:19,096 AND I'LL BE HAPPY TO ANSWER ANY 864 00:44:19,096 --> 00:44:20,965 QUESTIONS IF THERE ARE IN THE 865 00:44:20,965 --> 00:44:24,301 CHAT, I DON'T KNOW, ANTONIO? 866 00:44:24,301 --> 00:44:25,870 >> YES, THANK YOU FOR A GREAT 867 00:44:25,870 --> 00:44:27,071 TALK. 868 00:44:27,071 --> 00:44:29,140 FOR THE ATTENDEES THAT ARE 869 00:44:29,140 --> 00:44:31,642 WATCHING THE EVENT ON VIDEO 870 00:44:31,642 --> 00:44:34,879 CAST, IF YOU CAN SEND YOUR 871 00:44:34,879 --> 00:44:37,181 QUESTIONS VIA THE SEND-LIVE 872 00:44:37,181 --> 00:44:38,816 FEEDBACK BUTTON, THAT IS RIGHT 873 00:44:38,816 --> 00:44:41,986 ON THE SCREEN, AND THEN I CAN 874 00:44:41,986 --> 00:44:43,954 RELAY YOUR QUESTIONS TO DR. 875 00:44:43,954 --> 00:44:44,989 LANDI. 876 00:44:44,989 --> 00:44:47,725 WE ACTUALLY DO HAVE A FIRST 877 00:44:47,725 --> 00:44:50,428 QUESTION FROM THE VIDEO CAST 878 00:44:50,428 --> 00:44:53,197 AND THIS IS FROM PETER WHO 879 00:44:53,197 --> 00:44:58,235 SAYS, ANY REASON FOR LONE 880 00:44:58,235 --> 00:45:00,337 MUTATION FREQUENTLY CARCINOMA 881 00:45:00,337 --> 00:45:03,574 COMPARED TO OTHER TYPE SUCH AS 882 00:45:03,574 --> 00:45:05,643 LU ID THIS WAS REFERRED TO IN 883 00:45:05,643 --> 00:45:12,016 POWER POINT PAGE 24. 884 00:45:12,016 --> 00:45:15,486 >> YES, CARCINOMA, WE ACTUALLY 885 00:45:15,486 --> 00:45:21,659 THIS IS AN INTERESTING QUESTION. 886 00:45:21,659 --> 00:45:32,203 THE CARCINO TUMORS IS DRIVEN 887 00:45:32,203 --> 00:45:34,271 BY A DIFFERENT TYPE OF DRIVER 888 00:45:34,271 --> 00:45:36,340 GENES WHICH IS ALSO IDENTIFIED 889 00:45:36,340 --> 00:45:38,442 IN SOME FREQUENTLY IN NORMAL 890 00:45:38,442 --> 00:45:39,810 TISSUE FROM THE LUNG 891 00:45:39,810 --> 00:45:43,681 PARTICULARLY IN THE STUDIES 892 00:45:43,681 --> 00:45:47,985 THAT WE'RE CONDUCTING IN THE 893 00:45:47,985 --> 00:45:48,185 AREA. 894 00:45:48,185 --> 00:45:51,288 SO, AND ARE ALSO ASSOCIATED 895 00:45:51,288 --> 00:45:56,360 WITH THE LOWER GENOMIC FEATURES 896 00:45:56,360 --> 00:45:59,096 WHICH I PRESENTED WHICH IS 897 00:45:59,096 --> 00:46:01,699 CALLED--IT MEANS A QUIET TYPE 898 00:46:01,699 --> 00:46:02,967 OF TUMORS. 899 00:46:02,967 --> 00:46:06,637 SO IT'S CLEARLY A DIFFERENT 900 00:46:06,637 --> 00:46:07,538 TYPE, DIFFERENT OR GENERAL 901 00:46:07,538 --> 00:46:10,374 WHICH COULD BE THE CAUSE OF THE 902 00:46:10,374 --> 00:46:14,845 DIFFERENT SLOW GROWTH AND LOW 903 00:46:14,845 --> 00:46:15,479 GENOMIC FEATURES. 904 00:46:15,479 --> 00:46:17,748 BUT THERE ARE MANY MORE STUDIES 905 00:46:17,748 --> 00:46:27,091 THAT ARE NEEDED FOR CARCINOIDS 906 00:46:27,091 --> 00:46:32,997 THAT ARE REQUIRED, YES. 907 00:46:32,997 --> 00:46:34,865 >> OKAY, ANY OTHER QUESTIONS 908 00:46:34,865 --> 00:46:39,904 HERE AMONG THE PEOPLE HERE? 909 00:46:39,904 --> 00:46:41,772 ACTUALLY I DO HAVE A QUESTION, 910 00:46:41,772 --> 00:46:44,875 YOU MENTIONED EARLIER THAT 911 00:46:44,875 --> 00:46:48,913 SECOND-HAND SMOKE DID NOT HAVE 912 00:46:48,913 --> 00:46:51,649 ANY STATISTICALLY SIGNIFICANT 913 00:46:51,649 --> 00:46:56,387 EFFECT AS COMPARED TO THE 914 00:46:56,387 --> 00:46:57,388 NON-SMOKERS. 915 00:46:57,388 --> 00:46:59,223 BUT YOU DID ALSO MENTION THAT 916 00:46:59,223 --> 00:47:02,660 THERE WAS SOME PROMOTION AL 917 00:47:02,660 --> 00:47:05,429 EFFECT, LATER YOU REFERRED TO 918 00:47:05,429 --> 00:47:07,765 THAT PROMOTION AL EFFECT, MAYBE 919 00:47:07,765 --> 00:47:12,903 EXAMPLE IS THE SHORTER LENGTH 920 00:47:12,903 --> 00:47:13,470 OF TELOMERE. 921 00:47:13,470 --> 00:47:14,171 >> YES. 922 00:47:14,171 --> 00:47:17,841 >> IS THERE A WAY EFFORTS IN 923 00:47:17,841 --> 00:47:19,376 HOW THEY INTERACT? 924 00:47:19,376 --> 00:47:24,014 >> SO TO BE VERY FRANK, I MEAN, 925 00:47:24,014 --> 00:47:26,050 WE'VE REALLY TRIED EVERY 926 00:47:26,050 --> 00:47:30,254 POSSIBLE WAY TO SEE IF THERE 927 00:47:30,254 --> 00:47:35,059 WASER A MUTAGENIC AFFECT, WE 928 00:47:35,059 --> 00:47:36,660 KNOW THE SMOKING INCREASE THE 929 00:47:36,660 --> 00:47:37,795 RISK OF LUNG CANCER. 930 00:47:37,795 --> 00:47:48,305 AND THE ASSOCIATION THROUGH A 931 00:47:49,807 --> 00:47:52,209 EPIDEMIOLOGYCAL BUT IF YOU 932 00:47:52,209 --> 00:47:54,511 ASSOCIATED WITH ACTIVE TOBACCO 933 00:47:54,511 --> 00:47:56,947 SMOKING WHICH IS 35-FOLD, THEN 934 00:47:56,947 --> 00:47:58,282 YOU CAN UNDERSTAND THAT WE'RE 935 00:47:58,282 --> 00:48:00,651 TALKING ABOUT A VERY VERY 936 00:48:00,651 --> 00:48:04,922 STRONG DIFFERENCE. 937 00:48:04,922 --> 00:48:06,056 NONETHELESS WE TRIED TO SEE, 938 00:48:06,056 --> 00:48:08,826 AND AS YOU SAID, WE DIDN'T SEE 939 00:48:08,826 --> 00:48:14,798 ANY EVIDENCE OF MUTAGENIC 940 00:48:14,798 --> 00:48:19,937 AFFECT, NOW TO QUANTIFY HOW THE 941 00:48:19,937 --> 00:48:21,472 EFFECT HAPPENS, WE WERE THE 942 00:48:21,472 --> 00:48:23,874 FIRST TO BE SURPRISED ONE COULD 943 00:48:23,874 --> 00:48:25,376 TEST, MAYBE THERE ARE 944 00:48:25,376 --> 00:48:26,777 EXPERIMENTAL MODELS THAT COULD 945 00:48:26,777 --> 00:48:28,679 BE CONDUCTED TO SEE, TO TRY TO 946 00:48:28,679 --> 00:48:30,447 TRACE WHAT HAPPENS IN MICE, I 947 00:48:30,447 --> 00:48:32,750 DON'T KNOW IF, YOU KNOW, THEY 948 00:48:32,750 --> 00:48:35,285 ARE EXPOSED TO IN THE CHAMBER 949 00:48:35,285 --> 00:48:38,288 INSTEAD OF BEING EXPOSED 950 00:48:38,288 --> 00:48:39,356 DIRECTLY TO TOBACCO SMOKING 951 00:48:39,356 --> 00:48:43,560 WHAT HAPPENS IN THE CELLS, BUT 952 00:48:43,560 --> 00:48:51,068 THIS IS INDIRECT WAY FOR US TO 953 00:48:51,068 --> 00:48:54,071 HYPOTHESIZE THAT THERE IS A 954 00:48:54,071 --> 00:48:55,939 DIRECT EFFECT BECAUSE THE 955 00:48:55,939 --> 00:48:57,274 INDICATIONS OF RAPID 956 00:48:57,274 --> 00:48:59,376 SUBDIVISION AND IF THERE ARE NO 957 00:48:59,376 --> 00:49:01,011 MUTATIONS TO EXPLAIN THAT, WE 958 00:49:01,011 --> 00:49:02,613 CAN ONLY THINK, OKAY, THERE IS 959 00:49:02,613 --> 00:49:06,250 SOMETHING ELSE THAT TRIGGERS 960 00:49:06,250 --> 00:49:10,387 THESE TUMORS AND THEN THE 961 00:49:10,387 --> 00:49:17,628 EXPOSURE TO SECOND-HAND TOBACCO 962 00:49:17,628 --> 00:49:18,529 SMOKING PROMOTE THIS EFFECT. 963 00:49:18,529 --> 00:49:20,230 IN THE CASE OF AIR POLLUTION, 964 00:49:20,230 --> 00:49:21,398 WE SAW BOTH. 965 00:49:21,398 --> 00:49:28,272 IN THE PAST THERE WAS A VERY 966 00:49:28,272 --> 00:49:29,406 IMPORTANT PAPER PUBLISHED BUT 967 00:49:29,406 --> 00:49:33,577 WE DID SEE GIVEN THAT WE HAVE A 968 00:49:33,577 --> 00:49:34,545 LARGE SAMPLE SIZE. 969 00:49:34,545 --> 00:49:35,979 SOLT YEAH, THERE ARE 970 00:49:35,979 --> 00:49:38,882 DIFFERENCES THERE. 971 00:49:38,882 --> 00:49:40,951 >> YES, THANK YOU. 972 00:49:40,951 --> 00:49:44,354 AND PERHAPS RELATED TO THAT, TO 973 00:49:44,354 --> 00:49:48,192 LATER, YOU WERE REFERRING TO 974 00:49:48,192 --> 00:49:49,860 ASSIMILATIONS ARE THOSE 975 00:49:49,860 --> 00:49:53,297 SIMULATIONS BASED ON MODELS 976 00:49:53,297 --> 00:49:57,000 THAT ATTEMPT HAVE PREDICTIONS, 977 00:49:57,000 --> 00:49:59,069 HAVE SOME PREDICT I HAVE VALUE? 978 00:49:59,069 --> 00:50:04,308 >> YES, YES, SO WE PRACTICALLY 979 00:50:04,308 --> 00:50:06,610 INJECTED THE TYPE OF MUTATIONS 980 00:50:06,610 --> 00:50:10,080 THAT ARE SAME TYPE THAT ARE 981 00:50:10,080 --> 00:50:11,014 ASSOCIATED WITH SBS4. 982 00:50:11,014 --> 00:50:15,586 AND TO SEE WHAT WAS THE NUMBER 983 00:50:15,586 --> 00:50:18,322 OF MUTATIONS THAT HAD TO BE 984 00:50:18,322 --> 00:50:20,624 PRESENT IN EVERY CELL IN THE 985 00:50:20,624 --> 00:50:22,726 SAMPLES FOR US TO BE ABLE TO 986 00:50:22,726 --> 00:50:23,393 CAPTURE THEM. 987 00:50:23,393 --> 00:50:26,163 SO THAT WE COULD SAY, OKAY, WE 988 00:50:26,163 --> 00:50:27,798 DON'T SEE ANYTHING BUT MAYBE 989 00:50:27,798 --> 00:50:31,702 BECAUSE THE NUMBER OF MUTATIONS 990 00:50:31,702 --> 00:50:35,339 ARE BELOW THE LIMIT OF OUR 991 00:50:35,339 --> 00:50:37,207 ALGORITHM AND WE DID SEE THAT 992 00:50:37,207 --> 00:50:38,809 BASED ON THE SIMULATION, IF YOU 993 00:50:38,809 --> 00:50:40,878 HAVE 5 PERCENT OR MORE, YOU 994 00:50:40,878 --> 00:50:43,614 SHOULD BE ABLE TO DETECT THEM 995 00:50:43,614 --> 00:50:46,450 OR AT LEAST 20-25 PERCENT OF 996 00:50:46,450 --> 00:50:46,850 THE SAMPLES. 997 00:50:46,850 --> 00:50:48,719 AND WE DID NOT SEE ANY. 998 00:50:48,719 --> 00:50:51,221 SO WE COULD NOT CONCLUDED IT 999 00:50:51,221 --> 00:50:55,159 HAS TO BE AT LEAST BELOW THE 5 1000 00:50:55,159 --> 00:50:57,127 PERCENT OTHERWISE WE WOULD HAVE 1001 00:50:57,127 --> 00:50:59,897 CAPTURED IT. 1002 00:50:59,897 --> 00:51:03,901 SO IF IT IS WEAK--BASED ON THIS 1003 00:51:03,901 --> 00:51:06,170 AND BASED ON THE SAMPLE SIZE IS 1004 00:51:06,170 --> 00:51:08,839 VERY LOW. 1005 00:51:08,839 --> 00:51:09,773 >> GREAT, THANKS. 1006 00:51:09,773 --> 00:51:10,874 WE DO HAVE A COUPLE OF 1007 00:51:10,874 --> 00:51:13,644 QUESTIONS. 1008 00:51:13,644 --> 00:51:16,413 >> OH ALSO A QUESTION FROM HERE. 1009 00:51:16,413 --> 00:51:18,715 >> YES, GO AHEAD. 1010 00:51:18,715 --> 00:51:20,584 >> THANK YOU. 1011 00:51:20,584 --> 00:51:22,619 VERY NICE TALK. 1012 00:51:22,619 --> 00:51:28,792 SO I'M JUST CURIOUS THE 1013 00:51:28,792 --> 00:51:32,262 PATIENTS FROM EUROPEAN ANCESTRY 1014 00:51:32,262 --> 00:51:33,664 AND EASTERN AISHA, THEY ARE 1015 00:51:33,664 --> 00:51:38,235 SUBJECT TO THE SAME RISK 1016 00:51:38,235 --> 00:51:40,103 FACTORS, OR BUT JUST CURIOUS 1017 00:51:40,103 --> 00:51:46,910 WHY THEY HAVE DIFFERENT GENO 1018 00:51:46,910 --> 00:51:52,850 MUTATIONS, AND THE REST ARE HFR. 1019 00:51:52,850 --> 00:51:55,385 ARE THERE ANY DIFFERENCE IN THE 1020 00:51:55,385 --> 00:51:56,787 RISK FACTOR EXPOSURE? 1021 00:51:56,787 --> 00:52:02,726 LIKE YOU KNOW, SOME DIFFERENCE 1022 00:52:02,726 --> 00:52:04,795 ON THEIR FOOD OR OTHER RISK 1023 00:52:04,795 --> 00:52:05,295 FACTORS? 1024 00:52:05,295 --> 00:52:08,065 DO YOU HAVE ANY COMMENTS ON 1025 00:52:08,065 --> 00:52:08,332 THAT? 1026 00:52:08,332 --> 00:52:10,067 >> THIS IS A MULTI MILLION 1027 00:52:10,067 --> 00:52:12,236 DOLLARS QUESTION. 1028 00:52:12,236 --> 00:52:14,972 I MEAN, WE REALLY DO NOT KNOW. 1029 00:52:14,972 --> 00:52:17,741 WE CAN TELL YOU THIS, YES, WE 1030 00:52:17,741 --> 00:52:21,211 FOUND FOR EXAMPLE, ONLY IN 1031 00:52:21,211 --> 00:52:23,280 TAIWAN WE SEE EXPOSURE, THEY 1032 00:52:23,280 --> 00:52:30,554 HAD THIS MEDICINAL IN SOME 1033 00:52:30,554 --> 00:52:36,526 AREAS OF CHINA AND EUROPE. 1034 00:52:36,526 --> 00:52:42,733 I CAN TELL YOU THAT JGFR, ONLY 1035 00:52:42,733 --> 00:52:43,800 DOUBLE MUTATIONS ONLY IN THE 1036 00:52:43,800 --> 00:52:45,535 SAMPLES. 1037 00:52:45,535 --> 00:52:49,640 AND THERE ARE A SERIES OF 1038 00:52:49,640 --> 00:52:54,344 HYPOTHESIS, WE EVEN THOUGH OF 1039 00:52:54,344 --> 00:52:55,579 A--GENE. 1040 00:52:55,579 --> 00:53:00,417 WE KNOW THAT EUROPE THERE IS 81 1041 00:53:00,417 --> 00:53:03,887 AND 82, 81 IS WHERE IT CHANGES 1042 00:53:03,887 --> 00:53:05,589 WITH THE OXYGEN AND THEY GO 1043 00:53:05,589 --> 00:53:08,458 OVER DIFFERENT. 1044 00:53:08,458 --> 00:53:11,295 AND THE 82 ARE LARGER NUMBER OF 1045 00:53:11,295 --> 00:53:14,698 CELLS AND WHEN THE MUTATION, IF 1046 00:53:14,698 --> 00:53:17,501 THERE IS AN EXPOSURE, AND 1047 00:53:17,501 --> 00:53:21,605 TOUCHES THE 82, THEY MAY EVOLVE 1048 00:53:21,605 --> 00:53:25,242 BUT WITH--TYPE OF MUTATIONS AND 1049 00:53:25,242 --> 00:53:28,679 EVOLVE MORE RAPIDLY. 1050 00:53:28,679 --> 00:53:34,584 IF THEY TOUCH THE 81, THERE IS 1051 00:53:34,584 --> 00:53:37,354 HYPOTHESIS THAT IT TRIGGERS 1052 00:53:37,354 --> 00:53:42,025 MORE OF A TYPE OF MUTATION AND 1053 00:53:42,025 --> 00:53:44,061 SLOWER GROWTH. 1054 00:53:44,061 --> 00:53:45,929 AND 82 THEN HAVE TO BEGIN THE 1055 00:53:45,929 --> 00:53:46,830 EVOLUTION. 1056 00:53:46,830 --> 00:53:49,099 AND IN THIS PATTERN, THERE 1057 00:53:49,099 --> 00:53:52,069 COULD BE THE EXPLANATION OF 1058 00:53:52,069 --> 00:53:55,272 DIFFERENT GENES AND DIFFERENT 1059 00:53:55,272 --> 00:53:55,973 LATENCY. 1060 00:53:55,973 --> 00:54:00,377 BUT WE NEED A MUCH MORE WORK TO 1061 00:54:00,377 --> 00:54:03,113 VERIFY THIS HYPOTHESES. 1062 00:54:03,113 --> 00:54:07,918 THANK YOU. 1063 00:54:07,918 --> 00:54:09,586 >> WE DO HAVE A COUPLE OF 1064 00:54:09,586 --> 00:54:11,855 QUESTIONS FROM THE VIDEO CAST 1065 00:54:11,855 --> 00:54:13,156 THAT JUST CAME IN. 1066 00:54:13,156 --> 00:54:16,226 WE HAVE A QUESTION FROM IVAN, 1067 00:54:16,226 --> 00:54:18,295 THE QUESTION IS DO YOU THINK 1068 00:54:18,295 --> 00:54:20,831 YOUR RESULTS WILL ALLOW FOR 1069 00:54:20,831 --> 00:54:22,399 EARLIER DETECTION OF LATENT 1070 00:54:22,399 --> 00:54:24,735 TUMORS? 1071 00:54:24,735 --> 00:54:25,602 WHAT TREATMENT OPPORTUNITIES 1072 00:54:25,602 --> 00:54:27,537 COULD THERE BE FOR EARLY 1073 00:54:27,537 --> 00:54:28,939 DETECTION OF LATENT TUMORS? 1074 00:54:28,939 --> 00:54:31,508 >> YEAH, I MEAN, THAT IS AN 1075 00:54:31,508 --> 00:54:33,510 IMPORTANT QUESTION. 1076 00:54:33,510 --> 00:54:38,749 WE WERE SO, THE IDEA IS IF IT 1077 00:54:38,749 --> 00:54:40,384 IS TRUE AND CONFIRMED AND THE 1078 00:54:40,384 --> 00:54:42,719 SECOND TIME WE SEE IT, THERE IS 1079 00:54:42,719 --> 00:54:44,755 A LONGER LATENCY IN THE TUMORS 1080 00:54:44,755 --> 00:54:47,491 THAT HAVE A SPECIFIC MUTATION, 1081 00:54:47,491 --> 00:54:51,128 FOR EXAMPLE IN JFR, WE HAVE 1082 00:54:51,128 --> 00:54:53,497 SEEN SIX YEARS LONGER LATENCY 1083 00:54:53,497 --> 00:54:58,468 ON AVERAGE AND WE KNOW 1084 00:54:58,468 --> 00:55:01,505 THAT--JFR IS EARLY CLONAL THAT 1085 00:55:01,505 --> 00:55:02,639 MEANS FROM THE BEGINNING. 1086 00:55:02,639 --> 00:55:06,109 THE GOAL IS TO TEST THE TUMORS 1087 00:55:06,109 --> 00:55:07,010 TO POTENTIAL IDENTIFY WHEN IT 1088 00:55:07,010 --> 00:55:09,312 IS AT THE BEGINNING, EARLY 1089 00:55:09,312 --> 00:55:13,383 DETECTION AND WHEN YOU CAN 1090 00:55:13,383 --> 00:55:16,353 TARGET IMMEDIATELY WITH GFR 1091 00:55:16,353 --> 00:55:17,821 INHIBITOR. 1092 00:55:17,821 --> 00:55:20,791 THE MAJOR PROBLEM WITH LUNG 1093 00:55:20,791 --> 00:55:23,093 CANCER AND SMOKERS, THERE ARE 1094 00:55:23,093 --> 00:55:24,928 NO CURRENT SCREENING CAPACITY 1095 00:55:24,928 --> 00:55:26,797 FOR EARLY DETECTION. 1096 00:55:26,797 --> 00:55:27,964 THESE TUMORS, THAT'S WHY ALL OF 1097 00:55:27,964 --> 00:55:31,601 OUR EFFORT TO DO THIS, BECAUSE 1098 00:55:31,601 --> 00:55:32,969 YOU KNOW, SINCE THERE IS 1099 00:55:32,969 --> 00:55:37,974 FACTORS ARE SO MOSTLY UNKNOWN, 1100 00:55:37,974 --> 00:55:46,450 OR OF INDULGENCE OR GENERAL, 1101 00:55:46,450 --> 00:55:47,384 --ORIGIN. 1102 00:55:47,384 --> 00:55:50,620 THERE IS TWO STUDIES ON GOING 1103 00:55:50,620 --> 00:55:52,722 IN EAST ASIA IN THE U.S., AND 1104 00:55:52,722 --> 00:55:58,428 THIS IS BASED ON FEMALES, WITH 1105 00:55:58,428 --> 00:56:01,198 EAST ASIAN ORIGIN AGE OF 35 TO 1106 00:56:01,198 --> 00:56:05,335 75 SOMETHING LIKE THIS, IN TWO 1107 00:56:05,335 --> 00:56:09,973 PILOT CLINICAL TRIALS FOR EARLY 1108 00:56:09,973 --> 00:56:10,574 DETECTION SCREENING TRIALS IN 1109 00:56:10,574 --> 00:56:12,375 NEW YORK AND IN SAN FRANCISCO, 1110 00:56:12,375 --> 00:56:14,945 THEY ARE ON GOING. 1111 00:56:14,945 --> 00:56:18,181 AND THEY ARE SEEN A LOT OF 1112 00:56:18,181 --> 00:56:19,349 TUMORS AS COMPARABLE TO THE 1113 00:56:19,349 --> 00:56:20,650 SCREENING EFFORTS IN HEAVY 1114 00:56:20,650 --> 00:56:23,453 SMOKERS. 1115 00:56:23,453 --> 00:56:26,223 THE PROBLEM IS, TO BE 1116 00:56:26,223 --> 00:56:27,824 ABSOLUTELY SURE, THAT IT'S 1117 00:56:27,824 --> 00:56:29,659 CONVENIENT TO LOOK AND TO 1118 00:56:29,659 --> 00:56:30,894 TARGET THIS TYPE OF POPULATION, 1119 00:56:30,894 --> 00:56:33,597 YOU HAVE TO LOOK AT THE 1120 00:56:33,597 --> 00:56:34,731 MORTALITY RATE, OTHERWISE THERE 1121 00:56:34,731 --> 00:56:37,501 IS THE RISK OF LEAD TIME BIAS 1122 00:56:37,501 --> 00:56:40,504 AND WE'RE NOT SURE IF THERE 1123 00:56:40,504 --> 00:56:42,572 REALLY IS THAT YOU IDENTIFY 1124 00:56:42,572 --> 00:56:44,207 EARLIER BUT NOTHING CHANGES IN 1125 00:56:44,207 --> 00:56:44,875 TERMS OF SURVIVAL. 1126 00:56:44,875 --> 00:56:46,476 SO THERE IS MUCH MORE THAT 1127 00:56:46,476 --> 00:56:47,444 NEEDS TO BE DONE. 1128 00:56:47,444 --> 00:56:49,946 BUT THIS IS VERY VERY IMPORTANT 1129 00:56:49,946 --> 00:56:51,114 QUESTION BECAUSE IT'S 1130 00:56:51,114 --> 00:56:51,915 ULTIMATELY THE GOAL FOR WHICH 1131 00:56:51,915 --> 00:56:53,416 WE ARE DOING THIS STUDY. 1132 00:56:53,416 --> 00:56:55,452 YEAH. 1133 00:56:55,452 --> 00:56:56,853 >> THANK YOU. 1134 00:56:56,853 --> 00:56:59,789 WE HAVE ANOTHER QUESTION ON 1135 00:56:59,789 --> 00:57:02,092 FROM THE VIDEO CAST FROM ANDRE 1136 00:57:02,092 --> 00:57:06,897 WHO SAYS I'M A CLINICAL FELLOW 1137 00:57:06,897 --> 00:57:10,767 FROM NCI DEVELOPMENTAL 1138 00:57:10,767 --> 00:57:13,970 THERAPEUTICS CLINICS. 1139 00:57:13,970 --> 00:57:19,543 IS THAT GENES HYPO METH 1140 00:57:19,543 --> 00:57:20,844 INNOCENT LATED--BE AGENTS? 1141 00:57:20,844 --> 00:57:26,883 >> SO I WANTED TO CLARIFY. 1142 00:57:26,883 --> 00:57:30,120 TP53 MUTATIONS WERE ENRICHED IN 1143 00:57:30,120 --> 00:57:32,856 THE TUMORS WITH THE ID2, THEY 1144 00:57:32,856 --> 00:57:37,694 WERE NOT HYPO MUTE TATION, IT 1145 00:57:37,694 --> 00:57:39,563 WAS TP53 WERE ENRICHED IN THOSE 1146 00:57:39,563 --> 00:57:45,068 TUMORS THAT HAD ID 1 OR ID 2. 1147 00:57:45,068 --> 00:57:46,469 TP53 IS COMMON IN MANY MANY 1148 00:57:46,469 --> 00:57:48,738 MANY MANY MANY CANCER TYPES IS 1149 00:57:48,738 --> 00:57:50,473 NUMBER ONE AND UNFORTUNATELY, 1150 00:57:50,473 --> 00:57:54,678 CURRENTLY THERE IS NO TARGET, 1151 00:57:54,678 --> 00:57:58,114 NO WAY TO BLOCK THE TP53, I 1152 00:57:58,114 --> 00:58:03,353 MEAN, I THINK THAT IF 1153 00:58:03,353 --> 00:58:05,855 RESEARCHER CAN LEAD TO 1154 00:58:05,855 --> 00:58:08,658 IDENTIFICATION AWAY TO BLOCK 1155 00:58:08,658 --> 00:58:11,027 THE TP53, IT WOULD BE AN 1156 00:58:11,027 --> 00:58:13,296 INCREDIBLE RESULTS. 1157 00:58:13,296 --> 00:58:16,700 BUT IT'S VERY DIFFICULT BECAUSE 1158 00:58:16,700 --> 00:58:18,068 TP53 IS DOUBLE FUNCTIONS, IT 1159 00:58:18,068 --> 00:58:20,403 COULD BE GOOD, IT COULD BE BAD, 1160 00:58:20,403 --> 00:58:23,607 IT COULD BE DEPRESSER, IT'S A 1161 00:58:23,607 --> 00:58:26,810 MULTI FUNCTIONS SO THERE IS NO 1162 00:58:26,810 --> 00:58:30,046 REAL CURRENT THERAPEUTIC WAY TO 1163 00:58:30,046 --> 00:58:33,049 ADDRESS THE TUMORS THAT ARE 1164 00:58:33,049 --> 00:58:37,621 MUTATED WITH TP53 AS WE CAN DO 1165 00:58:37,621 --> 00:58:39,689 WITH HFR UNFORTUNATELY, YEAH. 1166 00:58:39,689 --> 00:58:42,726 THAT'S WHY THE IDENTIFICATIONS 1167 00:58:42,726 --> 00:58:45,729 OF LINE 1 REACTIVATE THESE 1168 00:58:45,729 --> 00:58:50,433 TUMORS SINCE THERE IS A FOR THE 1169 00:58:50,433 --> 00:58:52,902 ORF2 OF THE LINE 1 CAN BE 1170 00:58:52,902 --> 00:58:53,470 IMPORTANT. 1171 00:58:53,470 --> 00:58:57,374 BECAUSE IN A DIFFERENT WAY, YOU 1172 00:58:57,374 --> 00:58:58,275 CAN TARGET TP53. 1173 00:58:58,275 --> 00:59:01,478 THERE ARE OTHER EFFORTS NOW 1174 00:59:01,478 --> 00:59:06,283 TRYING TO, USING SYNTHETIC OR 1175 00:59:06,283 --> 00:59:07,450 OTHER APPROACHES BUT THERE IS 1176 00:59:07,450 --> 00:59:09,419 NO DIRECT AFFECT ON THAT GENE. 1177 00:59:09,419 --> 00:59:11,154 >> THANK YOU, ANY OTHER 1178 00:59:11,154 --> 00:59:12,322 QUESTIONS EITHER HERE IN THE 1179 00:59:12,322 --> 00:59:15,925 ROOM OR ON THE VIDEO CAST? 1180 00:59:15,925 --> 00:59:20,997 LAST CHANCE. 1181 00:59:20,997 --> 00:59:23,733 IF NOT, WELL THANK YOU, THANK 1182 00:59:23,733 --> 00:59:25,702 YOU DR. LANDI FOR A VERY VERY 1183 00:59:25,702 --> 00:59:26,303 INTERESTING TALK. 1184 00:59:26,303 --> 00:59:28,138 >> THANK YOU. 1185 00:59:28,138 --> 00:59:29,539 >> THANKS, EVERYBODY WHO 1186 00:59:29,539 --> 00:59:31,374 ATTENDED HERE IN PERSON OR IN 1187 00:59:31,374 --> 00:59:31,841 THE VIDEO CAST. 1188 00:59:31,841 --> 00:59:33,209 THANK YOU. 1189 00:59:33,209 --> 00:59:43,453 >> THANK YOU.