GOOD MORNING, WELCOME TO THE
FINAL TALK OF THE BIOWULF
SERIES.
TO THE INTERMURAL RESEARCHERS.
TODAY WE ARE HONORED TO HAVE
DOCTOR MARIA TERESA LANDI SHE
RECEIVED HER MEDICAL DEGREE
FROM UNIVERSITY OF MILANO IN
ITALY AND TRAINED AT SANTA RA
INNOCENTED FAEL.
DR. LANDI IS CURRENTLY THE
SENIOR INVESTIGATOR IN THE
DIVISION OF CANCER EPIDEMIOLOGY.
DR. LANDI'S LAB IN BIOWULF HAS
USED OVER A MILLION HOURS IN
LAST YEAR ALONE.
AND SMFT TOOLS THAT THEY USE
FOR THE RESEARCH ARE SOME
TOOLS, AS WELL AS CUSTOM MADE
TOOLS OF THEIR OWN DESIGN AMONG
MANY OTHERS.
DR. LANDI'S TALK TODAY IS
TITLED THE MUTAGENIC FORCES
SHAPING THE GENOMIC LANDSCAPE
OF LUNG CANCER.
WELCOME DOCTOR.
>> THANK YOU, THANK YOU FOR THE
INVITATION, I'M VERY GRATEFUL
FOR THE POSSIBILITIED AND I'M
VERY GRATEFUL FOR THE WORK OF
THE BIOWULF TEAM AND IN FACT,
HOW SHOULD I MOVE IT?
WHAT HAPPENED?
SORRY FOR THE INTERRUPTION, AS
I WAS SAYING, ALL THAT RESEARCH
THAT I WILL PRESENT HERE ARE
THANKS TO THE BIOWULF TEAM, ALL
THE SOFTWARE AND HELP AND THE
SUPPORT, THE SPACE PROVIDED FOR
THE ANALYSIS AND SO ON.
SO WHY LUNG CANCER?
LUNG CANCER IS VERY IMPORTANT
BECAUSE IT IS STILL OUT OF 16
INDIVIDUALS IN THE U.S. AND IT
IS MORE COMMON IN MEN THAN IN
WOMEN AND THERE ARE SOME
DIFFERENCES WITH A HIGHER RATES
IN AFRICAN AMERICANS AND WHITE
POPULATION.
IN THE MORTALITY IS EXTREMELY
HIGH.
LUNG CANCER IS THE NUMBER ONE
CAUSE OF DEATH WITH OVER 20
PERCENT OF ALL CANCER DEATHS
AND IT IS HIGHER THAN THE
PANCREATIC AND BREAST CANCER
AND PROSTATE CANCER.
THERE IS ALSO A DECREASE IN
INCIDENTS IN MEN AND WOMEN BUT
WITH THE DECREASING OF THE
SMOKING PREVALENCE, PROPORTION
ATELY THERE IS AN INCREASE OF
LUNG CANCER IN MANY SMOKERS.
LUNG CANCER IN MANY SMOKERS IS
DEFINED FOR THE SUBJECTS THAT
SMOKE LESS THAN 1100 CIGARETTES
IN THEIR LIFETIME AND ACCOUNT
FOR 20 PERCENT WORLDWIDE.
BUT IF YOU FOCUS IN POPULATION
IN WOMEN IT REQUEST GO AS HIGH
AS 55 PERCENT.
SXL BY IT SELF, IT'S THE 5th
CAUSE OF CANCER DEATH AND
ALMOST EXCLUSIVELY OF LUNG
CANCERGENE CANCER.
LOOKING AT FACTORS IN LUNG
CANCER SMOKERS AND SOME, TAB CO
SMOKING MORE RECENTLY HAVE
POLLUTION AND LUNG DISEASES.
THE LARGE MAJORITY OF THE
CAUSES OF THE LUNG CANCER ARE
STILL UNKNOWN BECAUSE A LARGE
MAJORITY OF THE CASES CANNOT BE
EXPLAINED BECAUSE OF THE
NO-RISK FACTORS AND THAT'S THE
REASON WHY WE DESIGNED THE
STUDY THAT AIMS TO STUDY THE
LUNG CANCER IN SMOKER USING
GENOMIC DATA AND TODAY I'LL
FOCUS ON THE MUTIZATION THAT I
WILL EXPLAIN.
CURRENTLY FOR A LUNG STUDY WE
COLLECTED OVER 2000 SPECIMENS
FROM 37 REGIONS ACROSS THE FIVE
CONTINENTS AND WE HAVE
CONDUCTED A WHOLE GENO
SEQUENCING, MICRO AND IMAGING
ANALYSIS AND CLINICAL DATA.
IN COMPARISON, I JUST WANTED TO
SHOW YOU THE NUMBER OF STUDIES
ACROSS THE WHOLE GENO AND AUTO
SEQUENCING AND YOU CAN SEE THE
CASES ARE MUCH MUCH SMALLER
THAN OUR STUDY.
OUR STUDY IS POST TO REIDENTIFY
OF LUNG CANCER AND TRYING TO
UNDERSTAND BETTER HOW THE
CANCER DEVELOPED.
SOY MENTIONED THAT I WOULD
DESCRIBE LIMITATION MUTIZATION
AL SIGNATURES.
THIS IS TO IDENTIFY PA TERNS OF
MAOUIZATIONS THAT USING SOME
ALGORITHMS WE CAN TRACE BACK TO
THE POTENTIAL PROCESS THAT'S
LEAD TO THE DEVELOPMENT OF THE
TUMOR.
SO USING GENERAL DATA TO
UNDERSTAND THE CAUSES.
WE KNOW THAT WE ACCUMULATE
MUTATIONS IN EVERY SET OF OUR
BODY TO THE POINT IN WHICH WE
HAVE THE POTENTIAL OF THE
CANCER.
WE KNOW THERE ARE SIX TYPE OF
CLASSES,.
SO WE ACCUMULATE MAOUIZATIONS
DURING THE ENTIRE LIFETIME A
SMALL NUMBER OF MUTATION FOR
EXAMPLE A LOT OF C2 MAOUIZATION.
THEN IT CAN BE EXPOSED TO A
STRONG FACTOR FOR EXAMPLE,
START TOBACCO SMOKING AND FOR A
SHORT PERIOD OF TIME ACCUMULATE
A LARGE NUMBER OF MUTATIONS AND
MAYBE EXPOSED TO OTHER, YOU
KNOW, AIR POLLUTIONS OR
ASBESTOS AND OTHER CAUSES.
SO AT THE TIME OF THE BIOPSY,
WE HAVE A GENO THAT IS A MIX OF
ALL OF THIS PROCESS THAT LEAD
TO THIS.
SO THE IDEA IS TO STUDY ALL OF
THIS CANCER GENO USING
MATHEMATICAL ALGORITHM AND GO
BACK AND TRY TO UNDERSTAND ALL
OF THESE CAUSES.
SO FOR EXAMPLE, IN THE PAST, WE
KNEW ALREADY THAT SKIN CANCER
IS LINKED TO UV LIGHT EXPOSURE
AND UV LIGHT EXPOSURE HAS A
SPECIFIC PATTERN TYPES.
SOL WHEN WE FIND THESE TYPE OF
MUTATIONS, WE UNDERSTAND THAT
THE TUMORS WAS CAUSED OR
POTENTIAL ASSOCIATED TO UV
LIGHT EXPOSURE.
FOR EXAMPLE, IN THE STUDY OF
LUNG CANCER, WE IDENTIFIED TWO
CASES THAT HAD STRONG PATTERNS
OF THIS SIGNATURE SBS-7 THAT IS
ASSOCIATED WITH UV LIGHT AND WE
WERE PUZZLED BECAUSE THESE WERE
LUNG CANCER CASES.
WE WENT BACK TO ALL THE
CLINICAL CHARTS AND IDENTIFIED
THE REASONS FOR THESE BECAUSE
KNEES WERE NOT PRIMARILY LUNG
CANCER CASES BUT CAR SIN NO MA
OF THE SKIN.
WE KNOW ALSO LUNG CANCER
ASSOCIATED WITH TOBACCO
SMOKING, WE HAVE THIS SINGLE
PATTERN SB4 WITH MONTH TRANS
VERSIONS IN THIS WAY.
AND BASED ON THESE TYPES OF
MUTATIONS, THERE WERE STUDIES
THAT WE WERE ABLE TO QUANTIFY
FOR EACH CELL WITH A NUMBER OF
MUTATIONS THAT ARE ASSOCIATED
IN SMOKING TOBACCO AT LEAST A
TACK --A PACK PER DAY AND GOES
TO 6 IN LUNG AND THE LIVER.
SXL IF YOU CONSIDER WE HAVE 33
CELLS CAN YOU IMAGINE WITH
MUTATION ACCUMULATION.
IN ADDITION, WE ACCUMULATE
MUTATIONS ALSO FOR INDULGENCE
REASONS.
FOR EXAMPLE, YOU MAY HAVE
FAILED THE GENETIC PAIR AND
HERE I LISTED THE MAJOR
PATHWAY, YOU CAN HAVE NUCLEAR
TYPE DECISION REPAIR AND MAYBE
OTHER DEFECTS THAT CAUSES A
SERIES OF SIGNATURE LIKE THOSE
THAT I SHOWED TO YOU THAT WHEN
WE IDENTIFY WE CAN SAY, AHA,
HERE THERE IS A REASON FOR THE
DEVELOPMENT OF THESE TUMORS.
SO THE MOST COMMON PATTERN ARE
HERE HERE, WE HAVE INDULGENCE
FACTORS, FOR EXAMPLE,
ACTIVITIES THAT ARE
CHARACTERIZED BY THESE TEAM.
THIS IS APPLE BACK IS VERY
IMPORTANT OF THE IMMUNITY AND
DEFENSE US AGAINST VIRUS AS A
BI PRODUCT CREATES A LOT OF
MUTATIONS AND IDENTIFIED IN 75
PERCENT OF LUNG CANCER TYPES
THAT HAS THIS PATTERN BACK.
WE ALSO HAVE THE MUTATION
SIGNATURE ASSOCIATED WITH
SPECIFIC CANCER TREATMENT, FOR
EXAMPLE, THE SIGNATURE SBS31 IS
ASSOCIATED WITH PATTERN.
OR A SERIES OF EXPOSURES LIKE
THE SBS4 ASSOCIATED TO TOBACCO
SMOKING.
IN ADDITION, WE HAVE DOUBLE
BASIN CONSTITUTIONS IN THERE
ARE SMALL IN SOCIAL
POPULATIONS, VARIANCES EVEN
INSTITUTIONS MORE RECENTLY.
AND WE CAN USE THESE MUTATION
SIGNATURE ALSO TO HAVE INSIDE
OF DIFFERENT PROCESS THAT
ACCUMULATE DIFFERENT TYPE OF
CANCERS BECAUSE OF THE SAME
PROCESSES.
FOR EXAMPLE, HERE IS THE PAN
CANCER ANALYSIS WHERE DIFFERENT
CANCER DEFINE DIFFERENT CANCER
TYPES.
SXL HERE IS THE DIFFERENT
COLORS THAT DEFINE THE MUTATION
SIGNATURES.
SO FOR EXAMPLE, IF WE FOCUS
HERE ASSOCIATED WITH SBS3, THAT
IT'S ASSOCIATED WITH HOMOGLOBAL
DEFICIENTCIE AND WE SEE THAT
THE BREAST AND CARCINOMA HAS
THE SAME, AND HERE WE HAVE OUR
SBS4 THAT IS ASSOCIATED WITH
BOTH LUNG AND CARCINOMA.
SO IN GENERAL MUTATION
SIGNATURE USE THE DIFFERENT IN
THE LATEST YEARS NOT ONLY TO
UNDERSTAND BUT ALSO MUTATION OF
PROPERTY AND EVEN CLINICAL
PUBLICATIONS.
AND IF YOU LOOK AT THE
PUBLICATIONS, THEY INCREASE
EXPONENTIALLY.
SO NOW FOR THE SHERLOCK LUNG
HUD', IN ALMOST 900 SAMPLES IN
FOUR CONTINENTS AND 23 REGIONS
AND CARCINOMA, FOR THIS SECTOR
ANALYSIS IN FOCUSING ON
EUROPEAN ANCESTRY, THE LARGE
MAJORITY IS EXPECTED AT FEMALES
AND FOR APPROXIMATELY HALF, WE
ALSO HAD DETAIL INFORMATION OF
SECOND-HAND SMOKING EXPOSURE.
SO SINCE WE HAD THE DIFFERENT
GEOGRAPHICAL ORIGINS, WE TESTED
WHETHER THERE WERE DIFFERENCES,
NUMBER ALTERATIONS OR STRUCTURE
VARIANTS.
AND WE SAW THAT CASES FROM
SERBIA, AND WE SAW THAT THE
SAMPLES FROM NEW YORK HAD THE
LOWER NUMBER.
WE UNDERSTOOD THAT THIS IS
LIKELY LIKELY TO THE FACT THAT
WE COLLECTED MORE CARCENOL THAT
IS MORE AGGRESSIVE--OF LOWER
NUMBER OF SIGNATURES ALL ACROSS
THE DIFFERENT TYPES.
WE ALSO CHECKED IN A MAJOR
DRIVER GENES AND T B-52 IN
CARCINOID, VERY STRONGLY.
SO HERE ARE THE PATTERNS OF THE
MUTATION SIGNATURES 8 HAVE BEEN
SIDED FOR THE FIRST TIME IN
LUNG CANCER.
SXL WHEN WE COMPARED THE E
STATION TO EUROPEAN, WE SAW THE
DISTRIBUTION WAS SIMILAR.
THE SBS22 WAS IN SECTIONS OF
TAIWAN.
WE SAW THAT SIGNATURE IS
ASSOCIATED WITH THE EXPOSURE TO
A RISTOLOGIC ACID THAT IS
LINKED TO A HERB USED IN THE
AREA THAT IS PREVIOUSLY
IDENTIFIED WITH OTHER CANCER
TYPE, LIVER CANCER, KIDNEY
CANCER, SYMPTOM CANCER BUT THIS
IS THE FIRST TIME THAT WE SEE
ANY EVIDENCE IN SUBJECTS WITH A
LUNG CANCER AMONG SMOKERS.
BUT ALTHOUGH THIS IS OUR
SIGNATURE DUE TO ASSOCIATION
WITH EXPOSURES FROM OUTSIDE,
THE LARGE MAJORITY OF THE
MUTATION SIGNATURES THAT WE
HAVE IDENTIFIED FROM LUNG
CANCER IS ASSOCIATED WITH,
SIGNATURE 1 AND 5 WITH THE AGE.
SIGNATURE 13 ASSOCIATED WITH
APPLE BACK, SIGNATURE 18 WITH
DNA REPAIR DEFICIENCIES, WE
HAVE UNKNOWN SIGNATURE THAT WAS
PREVIOUSLY IDENTIFIED IN KIDNEY
CANCER WITH THE DEFICIENTS SO
OVERALL MAJORITY ARE ASSOCIATED
WITH MUTATIONS THAT DUE TO
INDULGENCE PROCESSES.
WE WANTED TO TEST SOME OF THE
MORE KNOWN AND IMPORTANT RISK
FACTORS THAT GOT ASSOCIATED
WITH LUNG CANCER TO SEE WHETHER
THEY CONTRIBUTED AS MUTAGENTS
AND A TUMOR THAT ALREADY
RECEIVED A DRIVER INPUT THAN
PROGRESS IN THE EVOLUTION.
SO FIRST WE TESTED A
SECOND-HAND TOBACCO SMOKING.
AS I MENTIONED, WE HAD DATA
FROM ABOUT 400 SUBJECTS, 208
AND OVER 250 HAD VERY VARIABLE
INTENSE EXPOSURE TO SECOND-HAND
TOBACCO SMOKING.
AND WHAT WE SAW THE TUMORS
COMING FROM SECOND-HAND
SMOKING, THERE WAS A SLIGHT
INCREASE OF THE BASE
SUBSTITUTION.
BUT WHEN WE COMPARED, WE FOUND
THAT THIS ASSOCIATION WAS NO
LONGER SIGNATURE.
AND SIMILARLY WE DID NOT SEE
ANY MAJOR DIFFERENCE ACROSS THE
DIFFERENT MUTATION TYPES OR NO
MAJOR ENRICHMENT OF ANY DRIVER
GENE OR ANY ENRICHMENT IN MY
MUTATION SIGNATURE.
SO WE TESTED THE LEVEL OF OUR
ALGORITHM THAT'S CAN DETECT THE
NUMBER OF MUTATIONS IN THE
DIFFERENT CELLS TO SEE WHAT
COULD BE THE LEVEL OF
MUTAGENICY.
SO INJECTING INTO THE ALGORITHM
THAT ARE ASSOCIATED WITH
TYPICAL OF TOBACCO SMOKING.
WE SAW FOR EXAMPLE, IF THE CELL
HAD AT LEAST 5 PERCENT OF
MUTATIONS ASSOCIATED WITH SBS4,
WE WOULD BE IDENTIFY THEN IN
20-25 PERCENT OF THE SAMPLES
WHICH WE DID NOT AT ALL SO. WE
COULD NOT CONCLUDED THAT IF
THERE IS A MUTAGENIC AFFECT,
THIS IS BELOW 5 PERCENT CELLS.
OTHERWISE WE WOULD HAVE BEEN
BEEN DETECTED IN LARGER NUMBER.
WE DID OBSERVE A FACTOR THAT
WHEN YOU LOOK AT THE MUTATION
BETWEEN PASSIVE SMOKING AND NON
PASSIVE SMOKING, THEY WERE
ALMOST IDENTIFY CALL.
WE FOUND THAT THERE WAS A VERY
STRONG DECREASE IN THE TELAMERE
LENGTH, WE KNOW THAT EVERY CELL
REPLICATION, THERE IS A
DECREASE OF THE TELO METERS, SO
IT SUGGEST A LARGER NUMBER
WHICH COULD BE A PROMOTION
EFFECT.
AND THIS TIME, WE FOUND THAT
THIS REMAIN STRONGLY
SIGNIFICANT.
SO OUR CONCLUSION SOUTH SIDE
BASED ON THESE ANALYSIS,
SECOND-LAND TOBACCO IS NOT A
POTENT MUTAGENIC FACTOR BUT IT
COULD HAVE A PROMOTION EFFECT.
WHAT ABOUT AIR POLLUTION?
WE TESTED IN PARTICULARLY A
PARTICULAR MATTER BELOW THE
2.5, THE FOREST FIRES, RECORE
EXHAUST, OTHER INDUSTRIAL
RESOURCES COMMON IN DIFFERENT
AREAS OF THE WORLD.
AND WE USED FOR THIS ANALYSIS A
COMBINED MODEL USING OUR
AEROSOL FROM DIFFERENT LIGHTS
COMBINED WITH TRANSFER IN GRAND
BASE PHOTO O METERS AND WE PUT
IT TOGETHER FROM 1998 TO 2021
AND WE LINKED ALL OF THIS DATA
OF THE POLLUTION TO THE
RESIDENT.
AND WHAT WE OBSERVED THAT WE IN
THE TUMORS, THEY CAME FROM AREA
EXPOSED TO VERY HIGH LEVELS OF
POLLUTION, WE HAVE AN INCREASE
OF SBS AND T ALL THE MUTATION
FACTORS AND VERY STRONG TO
EXPOSURE AFFECT.
SO INCREASING EXPOSURE TO AIR
POLLUTION, WE HAVE INCREASING
MUTATION SIGNATURES AND A
DECREASING TELOMERE LENGTH, AND
WITH WHEN WE SAW AREA OF
POLLUTION, THERE WAS A INCREASE
OF TP53.
SXL THIS TIME ALL THE
ASSOCIATES FOR ALL MUTATION
ASSOCIATION AND TELOMERE LENGTH
REMAIN SIGNATURE.
AND HERE YOU CAN SEE ALL THE
REGRESSION MOTED ELZ WITH
DIFFERENT SIGN HERE, ARE THE
NUMBER OF SAMPLES FROM
DIFFERENT COUNTRIES WHERE WE
COLLECTED INFORMATION OF AIR
POLLUTION AND THIS ARE FOR
SINGLE BASE SUBSTITUTION AND
YOU SEE A SIMILAR PATH AND FOR
INCREASE OF TEROMERE LENGTH.
WE SAW AN ENRICH OF SBS5 WITH
AGE AND SELL DIVISION AND SBS4
THAT IS ASSOCIATED WITH TOBACCO
SMOKING.
WHILE HERE THESE WERE
NON-SMOKER AND EVIDENCE OF AIR
POLLUTION AND ID 3 A SIGNATURE
PREVIOUSLY ASSOCIATED WITH
TOBACCO SMOKING.
AND YET YOU CAN SEE THE NUMBER
OF SAMPLES ARE LIMITED BECAUSE
OF THE DIFFERENT TYPES OF
SIGNATURES BUT THERE IS A VERY
STRONG INCREASE WITH EVERY TYPE
OF SIGNATURE.
AND WE, ESTIMATED FOR EXAMPLE,
THAT ONE UNIT INCREASE OF PM2.5
WE COULD HAVE AN INCREASE AND
SIMILAR FOR THE OTHER MUTATION
SIGNATURES.
AND THIS TIME AGAIN, THE
ASSOCIATION WITH THE MUTATION
SIGNATURES REMAIN STRONG
STATISTICAL SIGNATURE AFTER
ADJUSTING THE FORMULA.
SO OUR CONCLUSION FROM HERE IS
THAT AIR POLLUTION DIFFERENT
FROM SECOND-HAND TOBACCO, MAY
HAVE SIMILAR AFFECT.
AND ALSO SBS5 MUTAGENIC SIGN.
WE ALSO HAD ACCESS THANKS TO A
COLLABORATION WITH DR. CHIN FOR
SPECIFIC AND VERY VERY UNUSUAL
AREA FROM CHINA, XUANWEI, WHERE
THE RATE OF LUNG CANCER IS
AMONG THE HIGHEST IN THE WORLD
AND EVEN THE MORTALITY ARE
ALMOST 5 TIMES OF CHINA'S
HIGHEST.
AND THIS IS DUE TO POOR LIVING
HOUSES WHERE WOMEN USE THIS FOR
HEATING BUT ALSO COOKING AND
CONSTANTLY EXPOSED TO THIS
CONBUSTABLE.
SO WE COMPARED THEM WITH
ANOTHER TYPE OF SAMPLE FROM A
DIFFERENT AREA OF CHINA WHERE
THEY USE A DIFFERENT TYPE OF
COAL.
AND HERE FOR ALL THE PRESENT
AND WE SAW THAT IN THE SUBJECT
WITH XUANWEI THERE WERE
DIFFERENT TYPES OF SIGNATURES
INCLUDING THE SBS4 THAT WAS
PREVIOUSLY ASSOCIATED WITH
TOBACCO SMOKING.
AND WHEN WE COMPARE FROM THOSE
OF THE FACTORS, WE SAW THAT WE
HAVE SIMILAR PATTERNS WITH THE
INCREASE OF ALL DSPS-4 AS IN
THOSE EXPOSED.
BUT IF ANY, THE COMBUSTIBLE WAS
HIGH.
SO CLEARLY THERE IS AN EVIDENCE
THAT INDOOR POLLUTION IS ALSO
VERY STRONG MUTAGENIC AFFECT.
SO AT THIS POINT, MY TAKE-HOME
MESSAGE IN THE LARGEST LUNG
CANCER TODAY AND WE CAN DO THIS
BECAUSE WE ARE AT AGE, WE SAW
THAT MUTATIONS WERE MORE COMMON
FROM EUROPEAN ANCESTRY.
BUT THERE ARE SOME EXPOSURES TO
CARCINOGEN, OR AIR POLLUTION
FROM ACROSS DIFFERENT AREAS OF
THE WORLD.
I WANT TO NOW SHOW YOU HOW EVEN
THE USE OF MUTATION SIGNATURE
CAN BE IMPORTANT TO STUDY THE
EVOLUTION OF LUNG CANCER AND I
WILL FOCUS ON THE MOST COMMON
TYPE OF LUNG CANCER.
AND FOR THIS ANALYSIS, I ZOOMED
INTO A SERIES OF SAMPLE THAT
HAD TO HAVE A HIGH OF--THE AND
PURITY AND OTHER FACTORS IN THE
SAMPLE CONTAINED AMPLE TO
FIGHT--AND THIS IS THE SAMPLE
FOR THIS ANALYSIS INCLUDING 108
STATIONS, 104 EUROPEAN WITH NON
SMOKERS BUT ALSO WITH THIS
ANALYSIS WE INCLUDED 120
SMOKERS FOR COMPARISON BECAUSE
IT'S IMPORTANT TO COMPARE FOR
THE DIFFERENT EVOLUTION BECAUSE
WE KNOW IT COULD BE DIFFERENT.
FOR THOSE THAT ARE NOT FAMILIAR
WITH THE HOW WE ESTIMATED TO
REVOLUTION, I WANTED TO USE
THIS CARTOON TO TRY TO EXPLAIN.
AS I MENTIONED AT THE
BEGINNING, WE ACCUMULATE
MUTATION FROM THE BEGINNING
FROM THE AFFECT TO CANCER.
SO SOME MUTATIONS ACCUMULATE
AND ALL THE CELLS CARRY THE
MUTATIONS ACCUMULATED WITH THEM
THE SAME MUTATIONS.
SO WE CALL THE LONG EXPANSION
WHEN EVERY CELLS INCLUDES 100
PERCENT OF THE MUTATION THAT'S
THEY'VE ACCUMULATED.
UNTIL WHAT WE CALL THE MOST
RESENT COMMON ANCESTOR OR IF
YOU WERE ABLE TO DIAGNOSE THE
CANCER AT THIS TIME, ALL THE
CELLS WOULD CARRY THIS MUTATION
AND BASED ON ALTERATION AND
MUTATIONS WE COULD ALSO
DISTINGUISH WHETHER THE
MUTATION ARE VERY EARLY AT THE
BEGINNING OR LATE BUT STILL
CLOSE, STILL PRESENT IN ALL THE
CELLS.
FROM THE TIME OF THE MOST
RESENT COMMON ANCESTOR, THERE
IS A SUB CLONEAL.
SO AT THE TIME OF DIAGNOSIS, IF
YOU DO A CANCER GENO ANALYSIS,
YOU SEE A DIFFERENT PORTIONS OF
CELLS CARRYING DIFFERENT TYPES
OF MUTATIONS.
SO THIS IS DIVERSIFICATION AND
DEFINED AS THE LATENCY, THE
TIME THAT IT OCCURED FROM THE
MOST RESENT ANCESTOR TO THE AGE
OF DIAGNOSIS.
NOW BASED ON THIS, WE FIRST OF
ALL, COMPARED SMOKERS VERSUS
NON-SMOKERS AND IN THE
NON-SMOKERS THE GENE WAS
STRONGLY ASSOCIATED WITH THE
NON SMOKERS WHILE INSTEAD--WERE
ASSOCIATED WITH SMOKERS.
AND WHEN WE LOOKED AT MUTATION
OF SIGNATURES, WE FOUND VERY
INTRIGUING RESULTS.
IF YOU SEE THE LINE THAT IN THE
AROUND ONE, YOU CAN SEE BELOW
THE LINE, THERE ARE MOSTLY
CLONAL MUTATIONS.
SO WE WHAT WE NOTICED, LIKE
SBS4 OR SBS100, THERE ARE BOTH
ASSOCIATED WITH TOBACCO
SMOKING, THERE WERE MOSTLY
CLONAL BELOW THIS LINE MEANS
THEY ARE INVOLVED IN THE
MUTATION BECAUSE THEY ARE FROM
THE BEGINNING.
INSTEAD THE MUTATIONS, THE
MUTATION SIGNATURES HAD SOME
CLONEAL SOME EVEN SUB CLONAL
MUTATION.
AND WHEN WE ZOOM TO THE MAJOR
CANCER GENES, WE OBSERVE THE
SIMILAR PATTERNS THAT IT WAS
INTRIGUING.
THEY CORRESPONDED TO THE
EXPOSURE TO TOBACCO SMOKING.
SOL THE EXPOSURE IN THE TOBACCO
SMOKING PARTICIPATED IN THE
INITIATION OF THE TUMOR AND
MANY TIMES THROUGH THE TRIGGER
OF CANCER DRIVING GENE.
IN COMPARISON TO THIS AND IN
CONTRAST TO THIS, DOMINATED BY
SBS5, SBS14 THEY'RE ALL
INDULGENCE THAT MEANS THAT IT'S
EARLY CLONAL SO PARTICIPATE AT
THE BEGINNING OF THE TUMOR, THE
PROCESSES THAT ARE RESPONSIBLE
FOR THIS ARE MOSTLY OF
INDULGENCE ORIGIN.
WHEN WE LOOKED AT THE LATENCY
IS THE TIME FROM MOST RESENT
ASSESS TO THE AGE OF DIAGNOSIS
OF THE TUMOR, WE OBSERVED A
VERY IMPORTANT DIFFERENCES.
THE TUMOR THAT CARRY FI
MUTATIONS, THEY CARRIED LESS
THAN 5 YEARS IN COMPARISON TO
ALL TUMORS THAT ARE NO MUTATION.
WHEN WE COMPARED BY SEX, WE SAW
THAT WOMEN HAVE LONGER LATENCY,
3.3 AND WHEN WE LOOKED AT THE
MUTATION OF SIGNATURES, WE WERE
REALLY SURPRISED BECAUSE WE
IDENTIFIED ONE SIGNATURE ID-2
THAT UNKNOWN ORIGIN UP TO NOW,
THAT HAD VERY VERY RAPID GROWTH
6.2 YEARS IN AVERAGE FASTER
THAN SHORTEN LATENCY IN
COMPARISON TO OTHER TUMORS.
AND THE LARGE MAJORITY OF THE
ID-2 THERE IS A SMALL DELETION,
A DELETION WHERE EARLY CLONE.
SO SOMETHING TRIGGERED THIS
ID-2 FROM THE BEGINNING OF THIS
TUMORS.
AND THERE WERE QUITE COMMON,
THEY WERE BETWEEN 11 AND 17
PERCENT IN NO SMOKERS OF
EUROPEAN AND 35, 36 PERCENT IN
THE SMOKERS.
SO WHAT WE SAW THAT FIRST OF
ALL WHEN WE COMPARED ALL OF
THIS DATA AND ADJUST IT FOR
IMPORTANT, THE LONGER LATENCY
ASSOCIATED WITH THE FEMALE SEX
AND MUTATION REMAIN SIGNATURE
WHICH COULD BE IMPORTANT FOR
EARLY DETECTION BECAUSE IF A
TUMOR GROWS, THERE IS A WINDOW
OF TIME WHERE ONE CAN INTERVENE.
AND ON THE OTHER SIDE, THE
ASSOCIATION WITH ID-2 WAS
CONFIRMED TO BE VERY VERY
STRONGLY AND SIGNIFICANT
ASSOCIATED WITH THE SHORTEN
LATENCY.
WE WANTED TO INVESTIGATE THESE
FACTORS, SUCH A SHORT LATENCY,
THEY ARE VERY AGGRESSIVE TUMORS
SO WE TESTED THE SERIES OF
MARKERS USING OUR OWN
SEQUENCING DATA AND WE SAW THAT
ALL THE MARKERS WERE ENRICHED
WITH THE TUMORS IN COMPARISON
WITH THE NON-TUMORS.
AND HERE YOU CAN SEE THE
ASSOCIATION BETWEEN THE NUMBER
OF ID2 AND THE EXPRESSIONS
MARKERS, AS YOU CAN SEE VERY
VERY STRONGLY CORRELATED.
WE ALSO FOUND THAT TUMORS WITH
ID2 THE STRONGER SOURCE,
AGGRESSIVE TUMORS THAT BECOME
NE CROTIC AND MATATASIS.
WE KNOW THERE ARE A LOT OF
MUTATIONS AND DIFFERENT
ANTIGENS AND THEY CALL IT A NEW
SYSTEM.
WE SAW THAT AMONG ALL THE
MUTATION SIGNATURE THE LOWEST
WAS ID-2 SO IT WAS NOT ABLE TO
BLOCK THIS TUMOR AS THIS COULD
BE ANOTHER CAUSE OF FAST
DEVELOPMENT OF TUMORS IN THE
SHORTER LATENCY.
WE WANTED TO TEST WHETHER WE
COULD EXPLAIN SOME EXPLANATION
WITH ID2 AND TESTED ALL
POSSIBLE GENO MUTATIONS AND WE
FOUND THREE FINDINGS.
WE FOUND THAT THEY WERE
ENRICHED WITH--WHICH ARE BOTH
SIGNS OF VERY STRONG GENO
MAKING STABILITY, IN FACT WE
SAW THAT THE NUMBER OF ID 2
WERE ENRICHED WITH P53 AND WE
SAW WERE INCREASING IN THE
TUMOR WITH ID2 VERSUS THOSE
WITHOUT ID2.
BUT IN A WAY THIS IS EXPECTED
IF YOU HAVE AN AGGRESSIVE TUMOR.
BUT WE WERE PARTICULARLY
INTRIGUED BY THIS ASSOCIATION
WITH THE LINE ONE, FOR THOSE
NOT FAMILIAR WITH THIS.
LINE 1 FOR LONG INTER ONE, THAT
IS TRAS POSABLE ELEMENTS COPY
AND PASTE ACROSS THE GENOMI C
RANDOMLY.
AND WE KNOW THAT THERE IS 70
PERCENT OF OUR GENO THAT IS DUE
TO THIS THAT WITH CUT AND
PASTED ACROSS THE GENO.
FOR GERM LINE, WE MEAN THAT
PRESENT IN EVERY SENSE.
AND WHAT WE SAW IN OUR STUDIES
THAT WE HAVE SOME GERMLINE
MASTER, SO THERE ARE SOME AREAS
OF THE GENO, THERE WERE
STRONGLY ENRICHED WITH THIS
LINE1 ACTIVATIONS BUT OVERALL,
THEY WERE QUITE FREQUENT AND
OVER 70 PERCENT OF THEM WERE OF
GERMLINE ORIGIN.
SO THE LINE 1, WOULD
PARTICIPATE IN 70 PERCENT OF
THE CASES TO THE INITIATION OF
A TUMOR BECAUSE THEY WERE
PRESENT ALREADY FROM THE
BEGINNING.
THIS IS JUST AN EXAMPLE IN THE
MULTIPLE TUMORS WHEN YOU HAVE A
GERMLINE, LINE 1 AND 22Q AND
HERE ARE THE ALL THE RANDOM
PIECE THAT'S ARE CUT AND PASTE
AND YOU CAN FIND WHEN YOU
SEQUENCE THE GENO ALL OVER THE
PLACE.
WE THEN TESTED THESE TUMORS
WITH LINE 1 TO SEE IF WE
CONFIRMED THAT IT WAS VERY
STRONGLY ASSOCIATED BUT WE ALSO
SAW THERE WAS INCREASED WITH
ANOTHER ID SIGNATURE ID 1 AND
ID 2 WERE VERY VERY STRONGLY
CORRELATED.
SO WITHOUT THIS ID 1 AND ID 2,
THEY'RE BOTH MONO POLLTIN FIVE
T, TTTTT, WHILE ID 2 IS A
HOMOPOLIN, NOW THESE TTTTT-TYPE
OF MOTIVE HIGHLY RESEMBLES THE
ACTIVITY.
IN FACT WE KNOW THAT THE LINE 1
HAS TWO MAJOR READING FRAME.
THE OPERATING FRAME ONE IS THE
ONE THAT IS ASSOCIATED WITH
BINDING.
BUT THE RF2, THE OPEN LEADING
FRAME 2 IS THE ONE INVOLVED
WITH INDOCLEAS, THE COPY AND
PASTE.
AND THIS HAS BINDING TO TTTTT.
SO WHAT WE UNDERSTOOD IS THAT
WHEN LINE 1 IS ACTIVATED MAY
LINK THIS HOPE FRAME, THE LINE
1 IS ACTIVATED AND CREATE A
SERIES OF DAMAGES IN THE GENO
AND IT POTENTIALLY ALTERATIONS.
IN THE ID 1 AND ID 2 ARE SIMPLE
MARKERS OF THIS ACCUMULATION OF
THIS INSERTIONS OF TTTTT.
NOW TYPICALLY SINCE LINE 1 IS
SO DANGEROUS BECAUSE IF IT'S
ACTIVATED, IT CREATES ALL OF
THESE BRAKES AND OTHER DAMAGES
IN THE GENE O THEY'RE TYPICALLY
STRONGLY SILENT IN THE CELLS.
AND IT'S A DIFFERENT TYPE OF
--SO WE HYPOTHESIZES THAT IN
THE TUMORS, THERE ARE A LOT OF
HIGH POLL MUTE TATIONS THAT CAN
REACT LATE THE LINE 1.
SO TO TEST THIS HYPOTHESES WE
FOUND THAT OVER 95 PERCENT OF
PROBES WERE HIGH POSSIBLE IN
THE ID 2-POSITIVE TUMORS
CONFIRMING THE FACTORS THAT
THEY ARE LESS SILENCED.
AND WHEN WE LOOKED AT THE
CHROMOSOME FOR THIS LINE 1 AND
WE COMPARED AND TUMOR MUTATION,
WE SAW THAT IN THIS AREA, WE
SAW THAT THE NORMAL TISSUE WAS
MUTILATED IN COMPARISON TO THE
TUMOR, IT WAS LOW.
SXL WHEN WE COMPARE THE TUMORS
WITH AND WITHOUT THE ID 2 IN
SIGNATURE, WE SAW THAT THOSE
ARE ID-SIGNATURE HAD LOWER MUTE
TATION.
WE THEN AND WITH THE SPECIFIC
NOW IF YOU LOOK AT THE
MUTILATION YOU CAN SEE FROM THE
DARK MEANS HIGH POMATAING.
NOW THE NORMAL TISSUE WOW
ALMOST ALL GREEN.
BUT IN THE TUMORS, WE SAW BELOW
THE, THE DARKER ONES ARE THOSE
WITH ID 2.
SO WE CONFIRMED THAT THERE IS A
HYPO SO OUR HYPOTHESES IS THAT
ID2 ONLINE 1 AND FINDING ID2 IS
IMPORTANT MARKER OF TUMORS AND
LINKED TO TP53 BUT ALSO ALSO
ARE THE ACTIVATION OF LINE 1
WHICH IS IMPORTANT BECAUSE
THERE ARE A LOT OF WORKING
LABORATORIES AND NOW TESTING
THE POSSIBILITY TO TARGET DR2
OF LINE 1 .
SO THE TAKE-HOME MESSAGE, THEY
HAVE CLEAR SIGNS FOR ACTORS ALL
ASSOCIATED WITH TOBACCO SMOKING.
AND TUMORS THAT CARRY THIS TYPE
OF MUTATION HAVE A SHORT
LATENCY.
IN CONTRAST IN THE
NEVER-SMOKERS MUTATIONS ARE GFR
AND DOMINATED BY SIGNATURE AND
THEY HAVE LONGER LATENCY
PARTICULARLY IN FEMALE PATIENTS.
WE SAW ALSO THE EX EXPOSURES
FACTORS AS INDICATED BY
EXPOSURE, THEY ARE MOSTLY
CLONAL WHICH MEANS THE TUMOR IS
INITIALED THROUGH THIS PROCESS.
WHILE INSTEAD WITH THE
ASSOCIATE FOLLOW TT TUMOR
ACROSS THE ENTIRE PROGRESSION.
AND AT THE END, WE IDENTIFIED A
IMPORTANT MARKET ID2 OF
REACTIVATION IN THE TUMORS
WHICH COULD BE IMPORTANT FOR
TREATMENT.
AND FINALLY, I WANT TO
ACKNOWLEDGE HERE ALL OF OUR
INVESTIGATORS IN THE TEAM
WITHOUT WHOM I WOULD NOT BE
ABLE TO PRESENT ALL OF THESE
RESULTS ACROSS DIFFERENT
INSTITUTIONS.
AND AGAIN, MANY THANKS TO THE
BIOWULF SUPPORT FOR THIS
ANALYSIS.
AND I'LL BE HAPPY TO ANSWER ANY
QUESTIONS IF THERE ARE IN THE
CHAT, I DON'T KNOW, ANTONIO?
>> YES, THANK YOU FOR A GREAT
TALK.
FOR THE ATTENDEES THAT ARE
WATCHING THE EVENT ON VIDEO
CAST, IF YOU CAN SEND YOUR
QUESTIONS VIA THE SEND-LIVE
FEEDBACK BUTTON, THAT IS RIGHT
ON THE SCREEN, AND THEN I CAN
RELAY YOUR QUESTIONS TO DR.
LANDI.
WE ACTUALLY DO HAVE A FIRST
QUESTION FROM THE VIDEO CAST
AND THIS IS FROM PETER WHO
SAYS, ANY REASON FOR LONE
MUTATION FREQUENTLY CARCINOMA
COMPARED TO OTHER TYPE SUCH AS
LU ID THIS WAS REFERRED TO IN
POWER POINT PAGE 24.
>> YES, CARCINOMA, WE ACTUALLY
THIS IS AN INTERESTING QUESTION.
THE CARCINO TUMORS IS DRIVEN
BY A DIFFERENT TYPE OF DRIVER
GENES WHICH IS ALSO IDENTIFIED
IN SOME FREQUENTLY IN NORMAL
TISSUE FROM THE LUNG
PARTICULARLY IN THE STUDIES
THAT WE'RE CONDUCTING IN THE
AREA.
SO, AND ARE ALSO ASSOCIATED
WITH THE LOWER GENOMIC FEATURES
WHICH I PRESENTED WHICH IS
CALLED--IT MEANS A QUIET TYPE
OF TUMORS.
SO IT'S CLEARLY A DIFFERENT
TYPE, DIFFERENT OR GENERAL
WHICH COULD BE THE CAUSE OF THE
DIFFERENT SLOW GROWTH AND LOW
GENOMIC FEATURES.
BUT THERE ARE MANY MORE STUDIES
THAT ARE NEEDED FOR CARCINOIDS
THAT ARE REQUIRED, YES.
>> OKAY, ANY OTHER QUESTIONS
HERE AMONG THE PEOPLE HERE?
ACTUALLY I DO HAVE A QUESTION,
YOU MENTIONED EARLIER THAT
SECOND-HAND SMOKE DID NOT HAVE
ANY STATISTICALLY SIGNIFICANT
EFFECT AS COMPARED TO THE
NON-SMOKERS.
BUT YOU DID ALSO MENTION THAT
THERE WAS SOME PROMOTION AL
EFFECT, LATER YOU REFERRED TO
THAT PROMOTION AL EFFECT, MAYBE
EXAMPLE IS THE SHORTER LENGTH
OF TELOMERE.
>> YES.
>> IS THERE A WAY EFFORTS IN
HOW THEY INTERACT?
>> SO TO BE VERY FRANK, I MEAN,
WE'VE REALLY TRIED EVERY
POSSIBLE WAY TO SEE IF THERE
WASER A MUTAGENIC AFFECT, WE
KNOW THE SMOKING INCREASE THE
RISK OF LUNG CANCER.
AND THE ASSOCIATION THROUGH A
EPIDEMIOLOGYCAL BUT IF YOU
ASSOCIATED WITH ACTIVE TOBACCO
SMOKING WHICH IS 35-FOLD, THEN
YOU CAN UNDERSTAND THAT WE'RE
TALKING ABOUT A VERY VERY
STRONG DIFFERENCE.
NONETHELESS WE TRIED TO SEE,
AND AS YOU SAID, WE DIDN'T SEE
ANY EVIDENCE OF MUTAGENIC
AFFECT, NOW TO QUANTIFY HOW THE
EFFECT HAPPENS, WE WERE THE
FIRST TO BE SURPRISED ONE COULD
TEST, MAYBE THERE ARE
EXPERIMENTAL MODELS THAT COULD
BE CONDUCTED TO SEE, TO TRY TO
TRACE WHAT HAPPENS IN MICE, I
DON'T KNOW IF, YOU KNOW, THEY
ARE EXPOSED TO IN THE CHAMBER
INSTEAD OF BEING EXPOSED
DIRECTLY TO TOBACCO SMOKING
WHAT HAPPENS IN THE CELLS, BUT
THIS IS INDIRECT WAY FOR US TO
HYPOTHESIZE THAT THERE IS A
DIRECT EFFECT BECAUSE THE
INDICATIONS OF RAPID
SUBDIVISION AND IF THERE ARE NO
MUTATIONS TO EXPLAIN THAT, WE
CAN ONLY THINK, OKAY, THERE IS
SOMETHING ELSE THAT TRIGGERS
THESE TUMORS AND THEN THE
EXPOSURE TO SECOND-HAND TOBACCO
SMOKING PROMOTE THIS EFFECT.
IN THE CASE OF AIR POLLUTION,
WE SAW BOTH.
IN THE PAST THERE WAS A VERY
IMPORTANT PAPER PUBLISHED BUT
WE DID SEE GIVEN THAT WE HAVE A
LARGE SAMPLE SIZE.
SOLT YEAH, THERE ARE
DIFFERENCES THERE.
>> YES, THANK YOU.
AND PERHAPS RELATED TO THAT, TO
LATER, YOU WERE REFERRING TO
ASSIMILATIONS ARE THOSE
SIMULATIONS BASED ON MODELS
THAT ATTEMPT HAVE PREDICTIONS,
HAVE SOME PREDICT I HAVE VALUE?
>> YES, YES, SO WE PRACTICALLY
INJECTED THE TYPE OF MUTATIONS
THAT ARE SAME TYPE THAT ARE
ASSOCIATED WITH SBS4.
AND TO SEE WHAT WAS THE NUMBER
OF MUTATIONS THAT HAD TO BE
PRESENT IN EVERY CELL IN THE
SAMPLES FOR US TO BE ABLE TO
CAPTURE THEM.
SO THAT WE COULD SAY, OKAY, WE
DON'T SEE ANYTHING BUT MAYBE
BECAUSE THE NUMBER OF MUTATIONS
ARE BELOW THE LIMIT OF OUR
ALGORITHM AND WE DID SEE THAT
BASED ON THE SIMULATION, IF YOU
HAVE 5 PERCENT OR MORE, YOU
SHOULD BE ABLE TO DETECT THEM
OR AT LEAST 20-25 PERCENT OF
THE SAMPLES.
AND WE DID NOT SEE ANY.
SO WE COULD NOT CONCLUDED IT
HAS TO BE AT LEAST BELOW THE 5
PERCENT OTHERWISE WE WOULD HAVE
CAPTURED IT.
SO IF IT IS WEAK--BASED ON THIS
AND BASED ON THE SAMPLE SIZE IS
VERY LOW.
>> GREAT, THANKS.
WE DO HAVE A COUPLE OF
QUESTIONS.
>> OH ALSO A QUESTION FROM HERE.
>> YES, GO AHEAD.
>> THANK YOU.
VERY NICE TALK.
SO I'M JUST CURIOUS THE
PATIENTS FROM EUROPEAN ANCESTRY
AND EASTERN AISHA, THEY ARE
SUBJECT TO THE SAME RISK
FACTORS, OR BUT JUST CURIOUS
WHY THEY HAVE DIFFERENT GENO
MUTATIONS, AND THE REST ARE HFR.
ARE THERE ANY DIFFERENCE IN THE
RISK FACTOR EXPOSURE?
LIKE YOU KNOW, SOME DIFFERENCE
ON THEIR FOOD OR OTHER RISK
FACTORS?
DO YOU HAVE ANY COMMENTS ON
THAT?
>> THIS IS A MULTI MILLION
DOLLARS QUESTION.
I MEAN, WE REALLY DO NOT KNOW.
WE CAN TELL YOU THIS, YES, WE
FOUND FOR EXAMPLE, ONLY IN
TAIWAN WE SEE EXPOSURE, THEY
HAD THIS MEDICINAL IN SOME
AREAS OF CHINA AND EUROPE.
I CAN TELL YOU THAT JGFR, ONLY
DOUBLE MUTATIONS ONLY IN THE
SAMPLES.
AND THERE ARE A SERIES OF
HYPOTHESIS, WE EVEN THOUGH OF
A--GENE.
WE KNOW THAT EUROPE THERE IS 81
AND 82, 81 IS WHERE IT CHANGES
WITH THE OXYGEN AND THEY GO
OVER DIFFERENT.
AND THE 82 ARE LARGER NUMBER OF
CELLS AND WHEN THE MUTATION, IF
THERE IS AN EXPOSURE, AND
TOUCHES THE 82, THEY MAY EVOLVE
BUT WITH--TYPE OF MUTATIONS AND
EVOLVE MORE RAPIDLY.
IF THEY TOUCH THE 81, THERE IS
HYPOTHESIS THAT IT TRIGGERS
MORE OF A TYPE OF MUTATION AND
SLOWER GROWTH.
AND 82 THEN HAVE TO BEGIN THE
EVOLUTION.
AND IN THIS PATTERN, THERE
COULD BE THE EXPLANATION OF
DIFFERENT GENES AND DIFFERENT
LATENCY.
BUT WE NEED A MUCH MORE WORK TO
VERIFY THIS HYPOTHESES.
THANK YOU.
>> WE DO HAVE A COUPLE OF
QUESTIONS FROM THE VIDEO CAST
THAT JUST CAME IN.
WE HAVE A QUESTION FROM IVAN,
THE QUESTION IS DO YOU THINK
YOUR RESULTS WILL ALLOW FOR
EARLIER DETECTION OF LATENT
TUMORS?
WHAT TREATMENT OPPORTUNITIES
COULD THERE BE FOR EARLY
DETECTION OF LATENT TUMORS?
>> YEAH, I MEAN, THAT IS AN
IMPORTANT QUESTION.
WE WERE SO, THE IDEA IS IF IT
IS TRUE AND CONFIRMED AND THE
SECOND TIME WE SEE IT, THERE IS
A LONGER LATENCY IN THE TUMORS
THAT HAVE A SPECIFIC MUTATION,
FOR EXAMPLE IN JFR, WE HAVE
SEEN SIX YEARS LONGER LATENCY
ON AVERAGE AND WE KNOW
THAT--JFR IS EARLY CLONAL THAT
MEANS FROM THE BEGINNING.
THE GOAL IS TO TEST THE TUMORS
TO POTENTIAL IDENTIFY WHEN IT
IS AT THE BEGINNING, EARLY
DETECTION AND WHEN YOU CAN
TARGET IMMEDIATELY WITH GFR
INHIBITOR.
THE MAJOR PROBLEM WITH LUNG
CANCER AND SMOKERS, THERE ARE
NO CURRENT SCREENING CAPACITY
FOR EARLY DETECTION.
THESE TUMORS, THAT'S WHY ALL OF
OUR EFFORT TO DO THIS, BECAUSE
YOU KNOW, SINCE THERE IS
FACTORS ARE SO MOSTLY UNKNOWN,
OR OF INDULGENCE OR GENERAL,
--ORIGIN.
THERE IS TWO STUDIES ON GOING
IN EAST ASIA IN THE U.S., AND
THIS IS BASED ON FEMALES, WITH
EAST ASIAN ORIGIN AGE OF 35 TO
75 SOMETHING LIKE THIS, IN TWO
PILOT CLINICAL TRIALS FOR EARLY
DETECTION SCREENING TRIALS IN
NEW YORK AND IN SAN FRANCISCO,
THEY ARE ON GOING.
AND THEY ARE SEEN A LOT OF
TUMORS AS COMPARABLE TO THE
SCREENING EFFORTS IN HEAVY
SMOKERS.
THE PROBLEM IS, TO BE
ABSOLUTELY SURE, THAT IT'S
CONVENIENT TO LOOK AND TO
TARGET THIS TYPE OF POPULATION,
YOU HAVE TO LOOK AT THE
MORTALITY RATE, OTHERWISE THERE
IS THE RISK OF LEAD TIME BIAS
AND WE'RE NOT SURE IF THERE
REALLY IS THAT YOU IDENTIFY
EARLIER BUT NOTHING CHANGES IN
TERMS OF SURVIVAL.
SO THERE IS MUCH MORE THAT
NEEDS TO BE DONE.
BUT THIS IS VERY VERY IMPORTANT
QUESTION BECAUSE IT'S
ULTIMATELY THE GOAL FOR WHICH
WE ARE DOING THIS STUDY.
YEAH.
>> THANK YOU.
WE HAVE ANOTHER QUESTION ON
FROM THE VIDEO CAST FROM ANDRE
WHO SAYS I'M A CLINICAL FELLOW
FROM NCI DEVELOPMENTAL
THERAPEUTICS CLINICS.
IS THAT GENES HYPO METH
INNOCENT LATED--BE AGENTS?
>> SO I WANTED TO CLARIFY.
TP53 MUTATIONS WERE ENRICHED IN
THE TUMORS WITH THE ID2, THEY
WERE NOT HYPO MUTE TATION, IT
WAS TP53 WERE ENRICHED IN THOSE
TUMORS THAT HAD ID 1 OR ID 2.
TP53 IS COMMON IN MANY MANY
MANY MANY MANY CANCER TYPES IS
NUMBER ONE AND UNFORTUNATELY,
CURRENTLY THERE IS NO TARGET,
NO WAY TO BLOCK THE TP53, I
MEAN, I THINK THAT IF
RESEARCHER CAN LEAD TO
IDENTIFICATION AWAY TO BLOCK
THE TP53, IT WOULD BE AN
INCREDIBLE RESULTS.
BUT IT'S VERY DIFFICULT BECAUSE
TP53 IS DOUBLE FUNCTIONS, IT
COULD BE GOOD, IT COULD BE BAD,
IT COULD BE DEPRESSER, IT'S A
MULTI FUNCTIONS SO THERE IS NO
REAL CURRENT THERAPEUTIC WAY TO
ADDRESS THE TUMORS THAT ARE
MUTATED WITH TP53 AS WE CAN DO
WITH HFR UNFORTUNATELY, YEAH.
THAT'S WHY THE IDENTIFICATIONS
OF LINE 1 REACTIVATE THESE
TUMORS SINCE THERE IS A FOR THE
ORF2 OF THE LINE 1 CAN BE
IMPORTANT.
BECAUSE IN A DIFFERENT WAY, YOU
CAN TARGET TP53.
THERE ARE OTHER EFFORTS NOW
TRYING TO, USING SYNTHETIC OR
OTHER APPROACHES BUT THERE IS
NO DIRECT AFFECT ON THAT GENE.
>> THANK YOU, ANY OTHER
QUESTIONS EITHER HERE IN THE
ROOM OR ON THE VIDEO CAST?
LAST CHANCE.
IF NOT, WELL THANK YOU, THANK
YOU DR. LANDI FOR A VERY VERY
INTERESTING TALK.
>> THANK YOU.
>> THANKS, EVERYBODY WHO
ATTENDED HERE IN PERSON OR IN
THE VIDEO CAST.
THANK YOU.
>> THANK YOU.