GREETINGS.
I'M WIN ARIAS AT THE NATIONAL
INSTITUTES OF HEALTH IN
BETHESDA, MARYLAND.
IT CERTAINLY IS AN EXCITING
PLEASURE TO HAVE ANOTHER SESSION
IN OUR UNIQUE COURSE CALLED
DEMYSTIFYING MEDICINE.
LET ME EXPLAIN.
THIS COURSE HAS BEEN IN
EXISTENCE NOW FOR 22 YEARS AND
IT'S INTENT -- IT'S REALLY A
COURSE IN BRIDGE BUILDING.
IT'S INTENT IS TO BRIDGE THE
EXCITING DEVELOPMENTS IN
BIOLOGY, ENGINEERING AND
COMPUTER SCIENCE WITH MEDICINE.
THE GOAL IS TO EXCITE OUR
HETEROGENEOUS AUDIENCE, WHICH IS
GLOBAL.
THE LOGO IN THE UPPER RIGHT ON
THE SLIDE IS THE CLASSIC
BROOKLYN BRIDGE.
AND LIKE ALWAYS IT REPRESENTS
TWO INDIVIDUALS ON A CATWALK
SHARING THEIR INFORMATION AND
KNOWLEDGE.
IN EFFECT, CONVERTING SILOS AS
SHOWN IN THE BOTTOM RIGHT OF
DETAILED INFORMATION AND OUT OF
IT GENERATING NEW CONCEPTS, NEW
IDEAS AND NEW PATHWAYS FOR THE
ADVANCEMENT OF HUMAN HEALTH.
SO THE COURSE MEETS ON TUESDAY
AFTERNOONS FROM 3:00 TO 5:00
FROM JANUARY UNTIL THE END OF
MAY.
YOU CAN WATCH IT ON THE
VIDEOCAST LINK SHOWN ON THE
SLIDE.
WE ARE NOT GIVING CME CREDITS
TODAY FOR REASONS I DON'T FULLY
UNDERSTAND, BUT YOU ARE
ENCOURAGED, PLEASE, TO SUBMIT
QUESTIONS DURING THE
PRESENTATIONS AND YOU DO THAT BY
CLICKING THE SEND LIVE FEEDBACK
ON THE VIDEOCAST DISPLAY ON YOUR
COMPUTER.
AND THESE QUESTIONS WILL THEN BE
THE BASIS FOR WHAT IS ALWAYS A
LIVELY Q&A AND DISCUSSION THAT
FOLLOWS BOTH PRESENTATIONS.
I BRING YOUR ATTENTION THAT ALL
PREVIOUS SESSION FOR 22 YEARS
ARE ARCHIVED IN THE NIH VIVID --
VIDEOCAST NETWORK.
THE LINK ON THE SLIDE.
IF YOU HAVE DESIRE FOR FURTHER
INFORMATION CONTACT US AT
DEMYSTIFYING MEDICINE@NIH.gov.
TODAY'S SUBJECT IS PRIMARY
CANCER OF THE COLON.
WHICH HAS ATTRACTED AN
INCREASING DEGREE OF ATTENTION
BECAUSE OF ITS SEVERITY,
FREQUENCY, AND ADVANCES MADE AND
BEGINNING TO UNDERSTAND
SOMETHING ABOUT THE BASIS OF
THIS DISEASE, WHICH IS OFTEN
FATAL.
IN FACT USUALLY.
SO SOME OF THE QUESTIONS THAT
POPPED INTO MY MIND ARE
INDICATED ON THE SLIDE.
AND THEY REALLY SERVE AS
INTRODUCTION TO OUR TWO
OUTSTANDING INDIVIDUALS WHO HAVE
BEEN KIND ENOUGH TO MAKE
PRESENTATIONS.
SO THE FIRST IS, IS THE
INCIDENCE OF COLON CANCER
INCREASING?
IF SO, IS IT WORLDWIDE?
IS IT IN ANY PARTICULAR GROUP OF
INDIVIDUALS THAT MAY GIVE SOME
INCLUDE AS TO WHAT IS GOING ON
MECHANISTICALLY?
AND ARE THERE EPIDEMIOLOGIC
CLUES AS TO WHAT COULD BE RISK
FACTORS OR PERHAPS EVEN FACTORS
THAT ARE PROTECTIVE?
NOW, EVERYBODY KNOWS ABOUT
COLONOSCOPY AND TESTING OF BLOOD
IN THE STOOL, ALL DIRECTED TO
EARLY DIAGNOSIS AND IMPROVED
TREATMENT BUT HOW EFFECTIVE ARE
THESE PROCEDURES?
MOST IMPORTANTLY, WHAT PUBLIC
HEALTH GUIDANCE IS CRITICAL?
THIS IS THE BASIC SUBJECT AREA
IN WHICH OUR FIRST SPEAKER,
REBECCA SIEGEL WILL ADDRESS.
THEN THERE'S A GENETIC
RELATIONSHIP TO THE VARIOUS
INHERITABLE CANCER SYNDROME.
IS THE MICROBIOME A CRITICAL
FACTOR?
AFTER ALL, THIS IS THE COLON THE
MAJOR SITE OF THE MICROBIOME.
AND HOW HAVE ADVANCES IN
MOLECULAR BIOLOGY AND GENETICS,
HAVE THEY PROVIDED BETTER
DIAGNOSIS AND TREATMENT?
OF COURSE THE HUGE QUESTION IS
WHAT ARE THE BIG CHALLENGES FOR
BETTER PREVENTION, DETECTION AND
TREATMENT?
AND THIS LATTER PORTION OF MY
QUESTION WAS WHAT WE ADDRESSED
BY SANDY, WHOM I'LL INTRODUCE IN
A MOMENT.
SO, OUR FIRST SPEAKER IS REBECCA
SIEGEL WHO TOOK HER DEGREE IN
GENETICS AT THE UNIVERSITY OF
GEORGIA AND FOLLOWED BY A MASTER
IN PUBLIC HEALTH IN EMORY IN THE
SCHOOL OF PUBLIC HEALTH.
REBECCA IS THE SENIOR SCIENTIFIC
DIRECTOR OF SURVEILLANCE
RESEARCH AT THE AMERICAN CANCER
SOCIETY.
SHE IS A LEADING EPIDEMIOLOGIST
AND EPIDEMIOLOGY IS THE FIRST
STEP IN MEDICINE BEFORE ADVANCES
IN PUBLIC HEALTH TAKE PLACE.
THE RESEARCH FOCUS OF HER WORK
ARE DISPARITIES AND COLON RECTAL
CANCER.
WHO GETS IT?
PARTICULARLY WITH RESPECT TO
AGE.
AND HER EPIDEMIOLOGIC STUDIES
HAVE HAD A BIG EFFECT ON MENTAL
HEALTH POLICY.
THEY'VE CHANGED THE AMERICAN
CANCER SOCIETY FOR SCREENING
GUIDELINES.
WE'LL HEAR MORE ABOUT THIS.
OUR SECOND SPEAKER IS SANFORD
MARKOWITZ WHO TOOK HIS DEGREE IN
CHEMISTRY AND PHYSIC INS HARVARD
AND THEN M.D. AND Ph.D. AT YALE.
SANDY IS A PROFESSOR OF MANY
THINGS.
HE'S A PROFESSOR OF CANCER
GENETICS, OF GENETICS AND
GENOMIC SCIENCES, AND MOLECULAR
AND MICROBIOLOGY AND CO-LEADER
OF THE G.I. GENETICS PROGRAM
PART OF THE COMPREHENSIVE CANCER
CENTER.
ALL OF THIS AT CASE WESTERN
RESERVE UNIVERSITY SCHOOL OF
MEDICINE.
NOW, THIS WORK HAS BEEN
OUTSTANDING AND HIS WORK IS
DIRECTED TOWARDS IDENTIFYING
MOLECULAR ABNORMALITIES IN BOTH
THE SPORADIC TYPE OF COLORECTAL
CANCER AND ALSO IN THE NUMEROUS
INHERITABLE SYNDROMES.
HIS WORK IS DIRECTED TO
IDENTIFYING BOTH POSITIVE AND
NEGATIVE REGULATORY GROWTH
FACTORS AND MORE RECENTLY THE
ROLE OF GENOMIC INSTABILITY.
AND ALL OF THIS HAS HAD A
PROFOUND INFLUENCE ON BETTER
UNDERSTANDING IN OUR CURRENT
STATUS OF POSSIBLE UNDERLYING
MECHANISMS RESPONSIBLE FOR THE
COLORECTAL PROBLEM.
SO, WE WILL BEGIN WITH OUR FIRST
SPEAKER, REBECCA SIEGEL, WILL
YOU PLEASE CARRY ON.
>> THANK YOU SO MUCH, DR. ARIAS.
I AM THRILLED TO BE HERE AND I'M
GOING TO SHARE MY SCREEN -- CAN
YOU SEE THE SLIDES?
OKAY.
ALL RIGHT.
SO THANK YOU SO MUCH FOR THE
INTRODUCTION, DR. ARIAS.
I'M THRILLED TO BE HERE TODAY TO
TALK ABOUT THE CHANGING
LANDSCAPE OF COLORECTAL CANCER
AND HOW THE DISEASE IS BECOMING
MUCH MORE COMMON IN YOUNGER
ADULTS.
SO REALLY BECOMING MORE OF A
HORSE THAN A ZEBRA IN THE EXAM
ROOM.
OUR OBJECTIVES ARE TO LEARN
ABOUT HOW THESE CHANGES IN
COLORECTAL CANCER ARE THE RESULT
OF A STRONG BIRTH COHORT EFFECT
AND SHIFT OUTSIDE THE
U.S. BORDERS AND LOOK AT WHETHER
THIS IS HAPPENING GLOBALLY AS
WELL.
AND THEN WE WILL LOOK AT SOME
POTENTIAL CAUSES AT A VERY HIGH
LEVEL AND OPPORTUNITIES FOR
MITIGATING THE BURDEN WHILE
WE'RE STILL WAITING ON ANSWERS
FOR THOSE SPECIFIC CAUSES.
THE INFORMATION IN THIS FIRST
SECTION IS BASED ON HIGH-QUALITY
POPULATION-BASED CANCER REGISTRY
DATA EITHER FROM NCI, SEER
PROGRAM OR DATA FROM THE
NATIONAL CANCER PROGRAM OF
CANCER REGISTRIES AT CDC.
WE RECEIVED THIS COMBINEDED DATA
SET FROM THE NORTHERN AMERICAN
REGISTRY OF CENTRAL REGISTRIES.
WHICH IS A STANDARD CENTER THAT
ENSURES HIGH QUALITY DATA AT AN
UMBRELLA ORGANIZATION THAT IS
ALSO A CONVENER.
SO ALL OF THESE ORGANIZATIONS
ARE VERY IMPORTANT IN THE WORK
THAT WE DO.
MORTALITY IS A LITTLE MORE
STRAIGHTFORWARD.
IT'S PROVIDED BY THE NATIONAL
CENTER FOR HEALTH STATISTICS AND
ALSO AT CDC BASED ON THE
UNDERLYING CAUSE OF DEATH
RECORDED ON DEATH CERTIFICATES.
FOR ALL 50 STATES AND D.C. AND
OF COURSE WE HAVE THIS DATA
GOING BACK TO BEFORE THE 1930s.
IN ADDITION TO INCIDENTS OF
MORTALITY AND BECAUSE OF THE
TIME REQUIRED TO COLLECT THE
DATA AND DISSEMINATE IT, THE
AMERICAN CANCER SOCIETY ANNUALLY
PRODUCES ESTIMATED CASES IN
DEATHS FOR THE CURRENT YEAR AND
WE DO THIS IN COLLABORATION WITH
STATISTICIANS AT NCI.
SO I DO HAVE ONE SLIDE THAT
INCLUDES OUR ESTIMATES.
THEN WE ALSO USE NCI SOFTWARE TO
CALCULATE RATES AND QUANTIFY
TRENDS.
SO THIS SLIDE SHOWS LONG-TERM
TRENDS IN OVER ALL COLORECTAL
CANCER INCIDENTS AND MORTALITY.
AND COLORECTAL CANCER IS ONE OF
THE CANCERS THAT IS OFTEN TOUTED
AS A SUCCESS STORY ESPECIALLY IN
THE U.S. BECAUSE INCIDENTS AND
DEATH RATES HAVE BEEN DECLINING
FOR DECADES.
THIS IS BECAUSE OF CHANGING
PATTERNS IN RISK FACTORS LIKE
REDUCTIONS IN SMOKING, SMOKING
INCREASES RISK AS WELL AS
INCREASED USE OF
ANTI-INFLAMMATORY DRUGS WHICH
DECREASE RISK.
AND THEN DURING THE 2000s THERE
WAS THE WIDESPREAD UPTAKE OF
COLONOSCOPY SCREENING AND
COLONOSCOPY, AS I'M SURE YOU
KNOW, DETECTS CANCER EARLY BUT
ACTUALLY THE PRIMARY WAY THAT
COLORECT OL CANCER SCREENING
WORKS IS TO PREVENT CANCER.
IT CAUSED A LARGE ACCELERATION
FOR INCIDENTS AND MORTALITY.
IN THE PAST DECADE THERE'S BEEN
DECLINES IN INCIDENTS OF ABOUT
1% A YEAR AND A LITTLE STEEPER
DECLINES IN MORTALITY BECAUSE OF
THE ADDITIONAL CONTRIBUTION OF
ADVANCES IN TREATMENT.
HOWEVER AS WE KNOW FROM -- I
WOU
WOULD ARGUE TO SAY FROM OUR MOST
FAMOUS EPIDEMIOLOGIST THAT
PROGRESS MUST BE EVALUATED WITH
RESPECT TO YOUNGER ADULTS
BECAUSE CANCER OCCURRING IN
YOUNG ADULT IS THE FIRST TO WILL
BEAR INFLUENCE OF CARCINOGENIC
EXPOSURES.
WHEN WE BREAK OUT THE TRENDS AND
INCIDENTS BY AGE, IT BECOMES
IMMEDIATELY CLEAR THAT THE OVER
ALL PROGRESS IS MASKING
INCREASING INCIDENTS IN YOUNG
ADULTS.
INCIDENT RATES HAVE BEEN
INCREASING STEEPLY IN PEOPLE 65
AND OVER BY ABOUT 2.6% PER YEAR
IN THE PAST DECADE.
WHILE DURING THE SAME TIME
PERIOD, THERE WERE INCREASES OF
THE SAME MAGNITUDE IN PEOPLE
UNDER 50.
AND NOW EVEN IN PEOPLE AGE 50 TO
64 WHICH I'LL REFER TO AS MIDDLE
AGE, RATES ARE INCREASING BY
0.4% PER YEAR.
YOU MIGHT SAY THIS DOESN'T SEEM
LIKE A VERY BIG INCREASE AND IT
ISN'T EXCEPT THAT IT'S ON THE
HEELS OF RAPID DECLINES IN THIS
AGE GROUP THAT VERY MUCH MIRROR
THE PATTERNS IN PEOPLE 65 AND
OVER.
SO WHY WOULD YOU HAVE THIS
ABRUPT CHANGE?
THE REASON IS BECAUSE OF A
STRONGER BOTH COHERT EFFECT.
PEOPLE BORN AFTER CIRCA 1950
HAVE ELEVATED RISK OF KOL J JLO
COLORECTAL CANCER AND INCREASES
AND PEOPLE LIKE ME BORN IN THE
1960s ARE ON THE CUSP OF HIGHER
RISK AND I CARRY THE ELEVATED
RISK WITH ME.
THAT'S WHY THE RATES ARE TICKING
UP NOW WHEN THEY WERE JUST
DECLINING VERY RECENTLY.
THESE NEXT TWO SLIDES ARE
SHOWING FROM SLIDES FROM YEARS
AGO.
THEY DO A GOOD JOB AT
ILLUSTRATING THE BIRTH COHORT
WHICH CAN BE A DIFFICULT
CONCEPT.
SO THIS SLIDE SHOWS AND THESE
ARE TRENDS FOR COLON CANCER ON
THE TOP AND COLORECTAL ON THE
BOTTOM BY 10 AGE GROUP 20 TO 54.
THE DOTS ARE OBSERVED RATES AND
THE LINES ARE THE JOINT POINT
TREND.
THE FOCUS SHOULD BE ON THE LINES
AND WHETHER THEY'RE INCREASING
OR DECREASING.
IF PEOPLE IN THEIR 20s, INCIDENT
RATES OF RECTAL CANCER HAVE BEEN
INCREASING SINCE AT LEAST THE
MID '70s.
BUT RATES DIDN'T BEGIN
INCREASING UNTIL 1980 IN PEOPLE
IN THEIR 30s.
1991, IN PEOPLE IN THEIR 40s AND
SO ON.
SO THIS UP TICK MOVES FORWARD IN
TIME WITH INCREASING AGE LIKE A
SLOW MOVING TSUNAMI.
AND THIS IS FROM THE PAPER
SHOWING AGE SPECIFIC INCIDENTS
OF COLON CANCER IN BLUE AND
RECTAL CANCER IN ORANGE AND
GENERATIONS FROM PEOPLE BORN IN
THE LATE 1800s UNTIL 1990.
AND THIS IS RELATIVE RISK SO
IT'S THE RISK OF THESE
GENERATIONS COMPARED TO PEOPLE
BORN IN 1949 WHO HAVE THE LOWEST
RISK AND YOU CAN SEE THAT
INDICATED BY THE DOTTED LINE
HERE.
IT LOOKS A LITTLE OFF CENTER SO
THAT, THAT LOWEST RISK COHORT
WAS BORN CIRCA 1949.
OFTEN I SAY 1950 BECAUSE PEOPLE
CAN REMEMBER THAT EASIER BUT
THAT'S WHY THE DOTTED LINE LOOKS
A LITTLE OFF THERE BECAUSE THE
MEDIAN BIRTH YEAR FOR THE COHORT
IS 1949.
SO EVERY GENERATION SUBSEQUENT
TO 1949 HAS A LITTLE BIT HIGHER
RISK SO PEOPLE BORN IN 1990 HAVE
TWICE THE RISK OF COLON CANCER
AND FOUR TIMES THE RISK OF
RECTAL CANCER COMPARED TO PEOPLE
BORN IN 1949.
ANOTHER THING THAT YOU CAN
NOTICE HERE IN THE FIRST LINE I
TALKED ABOUT CHANGING PATTERNS
IN RISK FACTORS THAT REDUCED
RISK.
AND YOU CAN SEE THAT IN THE
FIRST HALF OF THE FIGURE WHERE
RISK WAS DECLINING UNTIL THE
1949 BIRTH COHORT.
SO WHAT DOES THIS MEAN?
WELL, WHEN YOU HAVE A VERY
STRONG BIRTH COHORT EFFECT LIKE
THIS, IT TELLS YOU THAT THE
CHANGING RISK IS BECAUSE OF
EXPOSURES.
AND THERE'S BEEN EITHER AN
INTRODUCTION OF A NEW
CARCINOGENIC EXPOSURE IN 1949
WITH SUBSEQUENT GENERATIONS
HAVING ACCUMULATIVE INCREASED
RISK OR COULD BE A DECLINE IN
THE PROTECTIVE FACTOR LIKE WE
SAW WITH THE EARLIER SLIDE.
SO REDUCTIONS IN SMOKE AND
INCREASED USE OF
ANTI-INFLAMMATORY DRUGS MAY HAVE
DIFFERENT EFFECTS BUT BOTH WORK
TO RECREASING RISK.
HERE WE HAVE DECREASING HISPANIC
BUT DON'T KNOW WHY.
BACK TO OUR CONTEMPORARY DATA
AND WE HAVE INCREASED RATES IN
YOUNGER ADULTS THE MEDIAN AGE OF
COLORECTAL CANCER HAS DROPPED IN
JUST TWO DECADES.
AND WE'RE ALSO SEEING THIS PLAY
OUT THE SHIFT TO ANNUAL AGE
DIAGNOSIS AND THESE ARE OUR
ESTIMATED CASES FOR 2025.
WE'RE EXPECTING A LITTLE OVER
154,000 CASES OF COLORECTAL
CANCER WILL BE DIAGNOSED IN THE
U.S.
OF THESE, 44% WILL BE DIAGNOSED
IN PEOPLE IN THEIR EARLY 60s OR
YOUNGER.
THIS IS UP FROM 27% FROM 1995.
ADDITIONALLY, 21,000 OF THESE
NEW DIAGNOSES WILL BE PEOPLE IN
THEIR 40s OR YOUNGER.
EQUIVALENT OF 58 DIAGNOSES EACH
DAY WHICH IS QUITE A LARGE
NUMBER FOR A CANCER THAT ONLY
VERY RECENTLY WAS CONSIDERED AN
OLD PERSON'S DISEASE.
THERE'S SOME INTERESTING RACIAL
AND ETHNIC VARIATION IN THE
EARLY ONSET TRENDS.
THIS FIGURE SHOWS INCIDENT RATES
FOR THE FIVE BROADLY DEFINEDED
RACIAL AND ETHNIC GROUPS FOR
WHICH WE HAVE CANCER DATA.
AND FOR EXAMPLE IN THE BLACK
POPULATION, WHICH IS SHOWN IN
ORANGE, RATES HAVE BEEN STEADY
UNTIL JUST RECENTLY.
SO ONLY BEGAN TO INCREASE IN THE
LAST COUPLE OF YEARS.
WHEREAS IN THE WHITE SHOWN IN
BLUE, RATES HAVE BEEN STEADILY
INCREASING SINCE THE MID '90s.
AND THEN NATIVE AMERICANS, SO
THIS IS AMERICAN INDIAN AND
ALASKAN NATIVE HAVE HAD THE
STEADIEST INCREASE SINCE 1998.
THEIR RATES SURPASSED THE BLACK
POPULATION TO HAVE THE HIGHEST
EARLY ONSET RATES BY FAR.
ANOTHER INTERESTING
CHARACTERISTIC OF THE TREND I
ALREADY TOUCHED ON EARLIER IS
THE PROPONDERANCE OF RECTAL
TUMORS WELL IN THE DISTAL COLON.
I INCLUDE THE DIAGRAM HERE IN
CASE YOU MAYBE HAVE FORGOT STEN
YOUR ANATOMY AND SEEING THEM 2%
PER YEAR WITH THE SMALL INCREASE
OF PROXIMAL TUMORS OF .3% PER
YEAR.
AND BECAUSE OF THE STRONG BOTH
COHORT EFFECT THESE CANCER
SUBSITES ARE ALSO DRIVING THE
INCREASE FOR MIDDLE AGE PEOPLE.
EVEN IN PEOPLE 65 AND OLDER,
RECTAL CANCER HAS BECOME THE
SECOND MOST COMMON AMONG THESE
CANCERS.
SO SOMETHING THAT'S REALLY
INTERESTING TO ME IS THAT THIS
BIRTH COHORT EFFECT HAS
COMPLETELY REVERSED A TREND THAT
WAS HAPPENING 15 YEARS AGO.
THERE WAS CONCERN ABOUT THIS
TREND TOWARD MORE PROXIMAL COLON
CANCERS.
THE REASON THAT WAS CONCERNING
IS BECAUSE PROXIMAL CANCERS ARE
MORE DIFFICULT TO PREVENT
THROUGH SCREENING AND HARDER TO
TREAT.
SURVIVAL RATES ARE LOWER.
BUT THIS BOTH COHORT EFFECT HAS
REVERSED THIS TREND.
THIS IS -- THIS PLOT IS SHOWING
A RATIO OF RECTAL CANCER VERSUS
COLON CANCER OVER TIME IN MEN
AND WOMEN.
TODAY, THERE ARE ABOUT SIX
RECTAL CANCERS FOR EVERY 10
COLON CANCERS DIAGNOSED.
AND THE REASON THAT THIS IS
SURPRISING IS BECAUSE THE RECTUM
ACCOUNTS FOR 10% OF THE TOTAL
LARGE INTESTINE AND BECAUSE THIS
IS ALL AGES, THERE'S AN WHY --
AN IMPACT AT SCREENING AND WORKS
TO PREVENTING TUMORS IN THE
RECTUM BECAUSE OF THEIR
LOCATION.
ANOTHER MORE CONCERNING
CHARACTERISTIC OF THE EARLY
ONSET TREND IS THE PREPONDERANCE
OF ADVANCED STAGE DISEASE.
THIS SHOWS INCIDENT RATES BY
STAGE AT DIAGNOSIS.
THESE ARE SUMMARY STAGE BECAUSE
WE CAN'T LOOK AT AAJC STABLING
WHICH IS MORE CLINICALLY
RELEVANT BECAUSE OF IMPROVEMENTS
IN STAGING OVER TIME.
BUT THESE BASICALLY ALIGN WITH
THE HAJC STAGING.
THEY JUST HAVE BROADER
CATEGORIES.
SO THERE'S BEEN AN INCREASE IN
INCIDENTS FOR BOTH REGIONAL AND
DISTANT STAGE DISEASE OF 3% PER
YEAR.
IT'S A VERY STEEP INCREASE YEAR
OVER YEAR IN RATES.
AND THERE'S LOCALIZED STATE
DISEASE HAS REMAINED FLAT.
THIS IS PARTLY BECAUSE THIS
POPULATION HAS NOT HISTORICALLY
BEEN SCREENED.
SO LOCALIZED DISEASE IS USUALLY
ASYMPTOMATIC.
BUT IT'S ALSO BECAUSE OF
AVOIDABLE DELAYS IN DIAGNOSIS.
THE MOST COMMON BEING A DELAY IN
THE TIMING BETWEEN THE ONSET OF
SYMPTOMS AND THE INITIAL MEDICAL
CONTACT.
BUT ALSO A CONTRIBUTOR TO THESE
DELAYS IN DIAGNOSIS IS THE
DIAGNOSIS RECTAL BLEEDING IS THE
MOST COMMON SYMPTOM IN YOUNG
PATIENTS AND THEY'LL OFTEN BE
DIAGNOSED WITH HEMORRHOIDS WHICH
IS THE HORSE, AND NOT THE ZEBRA.
INSTEAD OF BEING FOLLOWED UP FOR
CANCER BECAUSE THEY'RE YOUNG AND
CANCER ISN'T EXPECTED.
EARLY ONSET CANCERS DON'T APPEAR
TO BE MORE AGGRESSIVE THOUGH.
YOU MIGHT COME TO THAT
CONCLUSION AND A LOT OF PEOPLE
DID INITIALLY BUT THERE'S BEEN
SEVERAL STUDIES AND STUDIES
INDICATE EARLY ONSET DISEASE IS
REALLY DRIVEN BY SPORADIC
CANCERS MEANING CANCERS THAT
DON'T HAVE GENETIC
PREDISPOSITION AND ALSO THEY'RE
BIO LOGICALLY VERY SIMILAR EARLY
ONSET AND LATER ONSET DISEASE.
SO THE INCREASING TREND IN
PEOPLE IN MIDDLE AGE, AS YOU'D
EXPECT, OR MAYBE NOT EXPECT
BECAUSE THESE ARE SCREENING AGE
BUT INDEED THE INCREASE IS
CONFINED TO REGIONAL AND DISTANT
STAGE AND THE MOST COMMON
DIAGNOSIS FOR COLORECTAL CANCER
OVER ALL ALL AGES COMBINED NOW
IS STAGE 3.
I HAVE TO TELL YOU WHEN I
REALIZED THIS I WAS SHOCKED
BECAUSE FOR OTHER SCREENABLE
CANCERS LIKE BREAST AND CERVIX,
STAGE 1 IS MOST COMMON.
SO THIS IS SURPRISING.
THIS BAR CHART SHOWS STAGE
DISTRIBUTION IN THE MOST RECENT
FIVE YEARS OF DATA AND NOT
SURPRISINGLY PEOPLE UNDER 50, SO
SHOWN IN THE BLUE BARS, ARE
LEAST LIKELY TO BE DIAGNOSED
WITH LOCALIZED STAGE.
ONLY 1 IN 4 OF THESE PATIENTS
ARE DIAGNOSED EARLY VERSUS 1 IN
3 PEOPLE 50 AND OLDER.
HOWEVER, YOUNG PATIENTS DO TEND
TO HAVE HIGHER SURVIVAL RATES
BECAUSE THEY'RE USUALLY HEALTHY
AND TREATED AGGRESSIVELY WHICH
IS SOMEWHAT CONTROVERSIAL.
NEVERTHELESS, DEATH RATES IN
PEOPLE UNDER 55 ARE INCREASING
AFTER MANY DECADES OF DECLINES.
THESE FIGURES SHOW TRENDS IN
DEATH RATES IN PEOPLE YOUNGER
THAN 55 OVER ALL AND BY RACE.
AND THE REASON THERE'S ONLY
BLACK AND WHITE RACE HERE IS
BECAUSE WHEN WE LOOK AT
HISTORICAL MORTALITY DATA WE
ONLY HAVE THESE THREE RACE
STRATIFICATIONS.
THESE PATTERNS ARE SIMILAR TO
WHAT WE SEE FOR INCIDENTS.
THE INCREASE IN DEATH RATES IN
WHITE PEOPLE IS STEEPER THAN THE
OVER ALL INCREASE AND WE'RE
STILL SEEING DECLINES IN THE
DEATH RATE IN THE BLACK
POPULATION UNDER 55.
THIS IS A LITTLE BIT DATED
BECAUSE THIS IS OUR FIRST STUDY
SHOWING THE INCREASE IN EARLY
ONSET DEATH RATES BUT THE
PATTERNS ARE STILL HOLDING
THOUGH THE INCREASE IN THE WHITE
POPULATION IS A LITTLE BIT
STEEPER NOW ALMOST 2% PER YEAR
INCREASE IN DEATH RATES.
AND THE DECREASE IN THE YOUNG
BLACK POPULATION HAS SLOWED TO
ABOUT .6%.
SO, AS A RESULT, COLORECTAL
CANCER HAS BECOME THE MOST
COMMON CAUSE OF CANCER DEATH IN
MEN UNDER 50 AND THE SECOND MOST
COMMON CAUSE OF CANCER DEATH IN
WOMEN UNDER 50 AFTER BREAST
CANCER, WHICH STILL HAS MANY
MORE DEATHS ABOUT 2,000 MORE
DEATHS THAN COLORECTAL CANCER.
THIS IS ALSO THOUGH AS I'M SURE
YOU'LL NOTICE BECAUSE OF STEEP
DECLINES IN LUNG CANCER DEATHS,
SHOWN IN GREEN, BECAUSE THERE'S
SUCCESSFUL TA BOBACCO CONTROL.
YOU MIGHT NOTICE IN THE FIGURES,
COLON CANCER IS SHOWN IN BLUE
AND DEATHS -- THE NUMBER OF
DEATHS FROM COLORECTAL CANCER
STARTED INCREASING IN 1990 AND
SHOWS INCONSISTENT FROM WHAT YOU
SAID OF INCREASES STARTING IN
THE 2000s.
BECAUSE THE POPULATION IS AGING
AND GROWING, THERE HAS TO BE A
VERY LARGE RATE OF DECREASE IN
ORDER FOR THERE NOT TO BE AN
INCREASE IN THE NUMBER OF CANCER
DEATHS.
SO THIS IS TRUE FOR CASES AS
WELL.
THIS IS WHY WE HAVE DECREASING
OVER ALL CANCER INCIDENTS YEAR
OVER YEAR SINCE 1981 BUT THE
NUMBER OF CANCER DEATHS
CONTINUES TO INCREASE OVER THE
YEAR.
WE STARTED LOOKING AT INCREASES
RATES IN 2009.
WE WONDERED WHETHER THIS WAS A
GLOBAL PHENOMENON OR CONFINED TO
THE U.S.
SO WE COLLABORATED WITH
RESEARCHERS AT TO LOOK AT THE
CI5 DATA INCLUDING MANY
COUNTRIES, 43 IN THIS ANALYSIS,
THOUGH I WILL SAY MOST
LOW-INCOME COUNTRIES ARE NOT
INCLUDED AND MANY MANY MIDDLE
INCOME COUNTRIES ARE ALSO NOT
INCLUDED BECAUSE THEY DON'T HAVE
THE RESOURCES TO COLLECT CANCER
INFORMATION.
WE DID THIS STUDY PUBLISHED IN
2019 WE IDENTIFIED EIGHT
COUNTRIES IN ADDITION TO THE
U.S. WHERE THERE WAS INCREASING
EARLY ONSET DISEASE ALONGSIDE
STABLE OR DECLINING RATES IN
PEOPLE 50 AND OLDER.
AND THEN JUST A COUPLE MONTHS
AGO WE PUBLISHED AN UPDATE OF
THE ANALYSIS.
WE WERE ABLE TO ADD SIX MORE
COUNTRIES PLUS THE
U.S. TERRITORY OF PUERTO RICO
AND ALSO FIVE ADDITIONAL YEARS
OF DATA.
THIS WAS ALSO COLLABORATION WITH
RESEARCHERS AT IARC.
SO IN THIS ANALYSIS WE
IDENTIFIED 12 COUNTRIES IN
ADDITION TO THE U.S. THAT
EXHIBITED THIS UNIQUE INCREASE
IN EARLY ONSET DISEASE AS WELL
AS THE TERRITORY OF PUERTO RICO.
AND YOU MAY HAVE NOTICED IN THE
LAST SLIDE WE WERE ONLY ABLE TO
ANALYZE THE U.K. IN THE LAST
STUDY BUT IN THE CURRENT STUDY
WERE WERE ABLE TO BREAK OUT
ENGLAND AND SCOTLAND SO I HAVE
NOTED SCOTLAND AS A NEW FINDING
BECAUSE WHEN YOU LOOK AT DATA
FOR THE U.K. OVER ALL IT'S
DRIVEN BY ENGLAND.
SO THESE FIGURES ARE EXAMPLES OF
SOME OF THE STEEPEST INCREASES
WE FOUND IN THE NEW STUDY.
INCREASES OF 3% TO 4% PER YEAR.
AND THE COUNTRIES ON THE LEFT
ARE COUNTRIES THAT WE IDENTIFIED
IN THE LAST STUDY SO THEY'RE NOT
NEW WITH THE EXCEPTION OF PUERTO
RICO.
PUERTO RICO WAS NOT ABLE TO BE
ANALYZED LAST TIME BECAUSE AS
YOU'LL NOTICE FROM THE SHORT
LINES, WE ONLY HAD ENOUGH
LONGITUDINAL DATA RECENTLY IN
ORDER TO ANALYZE TRENDS.
THESE FIGURES SHOW TRENDS IN
YOUNG ADULTS -- 50 IN RED AND 50
AND OLDER IN BLUE.
WE HAVE THE AVERAGE ANNUAL
PERCENT CHANGE IN THE LAST
DECADE SHOWN UNDERNEATH.
INTERESTINGLY THE STEEP INCREASE
IN PUERTO RICO -- PUERTO RICO IS
99% HISPANIC.
IT'S IN LINE WITH RECENT TRENDS
AMONG HISPANIC PEOPLE ALTHOUGH
IT'S ONLY IN THE MORE RECENT
FIVE YEARS OR SO THAT RATES HAVE
REALLY TAKEN OFF HIGHER.
THEY WERE MORE STABLE.
IT WILL BE INTERESTING TO FOLLOW
THIS TREND IN PUERTO RICO.
AND THIS SLIDE SHOWS NEWLY
IDENTIFIED COUNTRIES.
SO, WE FOUND THIS TREND IN
ISRAEL, ARGENTINA, NORWAY AND
FRANCE.
SOME OF THESE COUNTRIES WE
WEREN'T ABLE TO USE 100%
POPULATION COVERAGE AND THAT'S
THE ASTERISK IN ARGENTINA SO
THIS IS SUB NATIONAL DATA.
ALL THE COUNTRIES HAD STEEP
INCREASES OF 2% TO 3.5% PER YEAR
FOR EARLY ONSET DISEASE.
AND THE REASON THE AVERAGE
ANNUAL PERCENT CHANGE IS MISSING
FROM ARGENTINA, NORWAY AND
FRANCE IS BECAUSE RATES IN 50
AND OLDER ARE STABLE.
IN SEVERAL COUNTRIES RATES WERE
INCREASING IN BOTH AGE GROUPS
UNDER 50 AND 50 AND OLDER.
BUT THE INCREASE IN THE YOUNGER
ADULTS OF WAS MUCH STEEPER.
THESE ARE TWO OF THE MORE
EXTREME SAMPLES IN SWEDEN AND
CHILE.
COLORECTAL CANCER IS A PROXY FOR
GLOBAL DEVELOPMENT ON THE
ECONOMIC SCALE BECAUSE LOW AND
MIDDLE INCOME COUNTRIES THAT ARE
DEVELOPING AND ADOPTING THOSE
RISK FACTORS LIKE GAINING
WEIGHT, EATING MORE RED MEAT,
SMOKING, THEY'RE ASSOCIATED WITH
A MORE WESTERN LIFESTYLE.
SO, IT'S VERY COMMON FOR THESE
COUNTRIES TO HAVE INCREASING
INCIDENCE RATES THOUGH IT
DOESN'T APPLY TO SWEDEN AND
CHILE BUT COLORECTAL CANCER IS A
PROXY FOR GLOBAL DEVELOPMENT AND
PEER COUNTRIES AND RATES WHERE
OLDER ADULT DECLINING BUT DON'T
SEE AN INCREASE IN EARLY ONSET
THESE.
WE SAW THIS PATTERN IN SPAIN,
ITALY AND AUSTRIA.
IT WILL BE INTERESTING TO WATCH
THE COUNTRIES AND SEE IF THE
STABLE RATES HOLD OR ULTIMATE HI
INCREASE BECAUSE THE TIMING DOES
DEFER IN SOME OF THE COUNTRIES.
WE'LL LOOK AT POTENTIAL CAUSES
AND MITIGATING THE RISING
BURDEN.
THE FIRST QUESTION EVERYONE ASKS
IS WHY IS THIS HAPPENING?
THE FIRST PLACE TO LOOK IS
ESTABLISHED RISK FACTORS FOR THE
DISEASE AND THIS SHOWS WELL
ESTABLISHED RISK FACTORS FOR
COLORECTAL CANCER.
ON THE FIRST HALF ARE FACTORS
THAT INCREASE RISK AND THEN
THERE'S A COUPLE PROTECTIVE
FACTORS AND THEY'RE SHOWN WITH
THEIR RELATIVE RISK ESTIMATE AS
WELL AS POPULATION PREVALENCE
TRENDS.
SO THE FIRST THING THAT EVERYONE
THINKS ABOUT IS WE USED TO SEE
EPIDEMIC AND KNOW IT'S BEEN
INCREASING SINCE THE 1970s WITH
CUMULATIVE EXCESS BODY WEIGHT
AMONG YOUNGER GENERATIONS.
THIS IS CERTAINLY SOMETHING TO
LOOK INTO AS WELL AS OUR MORE
SEDENTARY LIFESTYLE.
PHYSICAL ACTIVITY OR LACK IT
THEREOF ASSOCIATED WITH COLON
CANCER BUT NOT ASSOCIATED WITH
RECTAL CANCER.
AT LEAST IN STUDIES OF OLDER
COHORTS AND THAT'S SOMETHING I
WANTED TO POINT OUT IN THE
TABLE.
ALL THESE ESTABLISHED RISK
FACTORS ARE BASED ON DISEASE IN
OLDER ADULTS.
AND SO THEY MAY OR MAY NOT BE
ASSOCIATED WITH EARLY ONSET
DISEASE.
A GROUP AT THE UNIVERSITY OF
WASHINGTON PUBLISHED BETWEEN
ESTABLISHED RISK FACTORS AND
EARLY ONSET COLORECTAL CANCER
USING THE NURSES HEALTH STUDY TO
DATE.
IN THIS STUDY THEY WERE LOOKING
AT WHETHER OBESITY WAS
ASSOCIATED WITH AN INCREASED
RISK.
THIS COHORT IS ONLY WOMEN.
SO THIS FINDING IS COMBINED TO
WOMEN.
BUT THEY FOUND A 20% HIGHER RISK
WITH EVERY FIVE UNITS OF BMI.
THIS IS CONSISTENT WITH THE
ASSOCIATION FOR OLDER ADULTS.
HOWEVER, IT'S IMPORTANT TO
REALIZE OBESITY AT LEAST IN
OLDER ADULTS IS MUCH MORE
STRONGLY ASSOCIATED WITH COLON
CANCER THAN WITH RECTAL CANCER.
SO, IF EXCESS BODY WEIGHT WAS
THE SOLE CAUSE OF THE INCREASE,
YOU'D EXPECT IT TO BE DRIVEN BY
COLON CANCER AND NOT RECTAL
CANCER, WHICH IS THE PATTERN
WE'RE SEEING.
AND THEY'RE LOOKING AT WHETHER
SEDENTARY LIFESTYLE IN TERMS OF
TV VIEWING WAS ASSOCIATED WITH
EXCESS RISK.
TV VIEWING IS THE SEDENTARY
BEHAVIOR MOST STRONGLY
ASSOCIATED WITH HARMS TO HEALTH.
AND THEY FOUND THE HIGHER
ELEVATED RISK.
69% INCREASED RISK FOR WOMEN WHO
WATCHED MORE THAN 14 HOURS OF TV
PER WEEK COMPARED TO WOMEN WHO
WERE WATCHING 7 OR FEWER HOURS
OF TV.
AGAIN, IMPORTANT TO REALIZE IN
OLDER ADULTS THIS WOULD NOT BE
ASSOCIATED WITH RECTAL CANCER.
SO, IT DOESN'T APPEAR AS THOUGH
OUR ESTABLISHED RISK FACTORS CAN
AT LEAST FULLY EXPLAIN WHAT'S
HAPPENING WITH THOSE COHORT
EFFECT AND WHY RATES ARE
INCREASING.
THERE'S BEEN A FLURRY OF
RESEARCH THINKING OUTSIDE THE
BOX LOOKING AT VARIOUS EXPOSURES
FROM ANTIBIOTIC USE TO BREAST
FEEDING TO IN UTERO EXPOSURES,
POLLUTANTS IN OUR FOOD AND
WATER, AS WELL AS MICROPLASTICS.
NOTHING DEFINITIVE HAS BEEN
ESTABLISHED.
THERE'S ALSO A LOT OF WORK WITH
THE GUT MICROBIOME AND HOW THIS
MIGHT INFLUENCE THE COLONIC
MUCOSA WHICH PROTECTS US FROM
DISEASE IN THE COLON.
I THINK WE'RE GOING HEAR MORE
FROM DR. MARKOWITZ ABOUT THIS IN
THE NEXT SECTION.
SO, WHILE WE AWAIT THE MORE
DEFINITIVE CAUSE OF WHAT'S
HAPPENING HERE, WE HAD A RAPIDLY
INCREASING BURDEN OF DISEASE
SHIFTING TO OUR MOST PRODUCTIVE
CITIZENS.
WE ALSO KNOW WE HAD AN EFFECTIVE
SCREENING TEST THAT NOT ONLY
PREVENTS CANCER DEATH BUT ALSO
CAN PREVENT CANCER AT LEAST IN
OLDER ADULTS.
NOTABLY AMONG PEOPLE DIAGNOSED
BEFORE 50, ALMOST HALF ARE IN
PEOPLE IN THEIR LATE 40s.
AND AN ADDITIONAL NEARLY 30% OF
EARLY ONSET PATIENTS HAVE A
FAMILY HISTORY OF THE DISEASE OR
FAMILY HISTORY OF ADENOMAS OR
GENETIC PREDISPOSITION.
AND WE'LL HEAR MORE ABOUT THIS
FROM DR. MARKOWITZ.
PEOPLE IN THIS HIGHER RISK
CATEGORY ARE RECOMMENDED TO
START SCREENING EARLIER THAN
AVERAGE RISK.
SO THE AGE TO BEGIN SCREENING
WAS LOWERED FROM 50 TO 45 YEARS
FOR AVERAGE RISK ADULTS BY THE
AMERICAN CANCER SOCIETY IN 2018
AND THEN BY THE U.S. PREVENTIVE
SERVICES TASK FORCE IN 2021.
BOTH WERE QUALIFIED
RECOMMENDATIONS.
AT THE TIME THERE WAS EMPIRICAL
EVIDENCE TO SHOW SCREENING WOULD
BE EFFECTIVE IN PEOPLE UNDER 50
AND IN FACT THERE WAS A LOT OF
CRITICISM IN 2018 ACS WHEN THEY
FIRST LOWERED THE AGE TO SCREEN.
BUT I'M HAPPY TO REPORT IN THE
YEARS SINCE THERE'S BEEN FAST
ACCUMULATING EVIDENCE THAT
INDEED THE PREVALENCE OF
PRECANCEROUS LESIONS AND CANCER
IS THE SAME IN PEOPLE IN THEIR
LATE 40s AS THOSE IN THEIR EARLY
50s.
THESE ARE TWO OF THE EARLIER
STUDIES THAT REPORTED THIS
FINDING.
AND THEN THIS IS THE MOST RECENT
PAPER.
THIS IS A STUDY OF KAISER B
BENEFICIARIES WHO TESTED
POSITIVE ON THE STOOL TEST, THE
FIT TEST.
THIS WAS LOOKING AT PEOPLE 35 TO
49 THE NEWLY ELIGIBLE SCREENING
GROUP COMPARED TO PEOPLE WHO ARE
50 AND THIS IS COLONOSCOPY
FOLLOW-UP OF A POSITIVE STOOL
TEST.
THEY FOUND INDEED REGARDLESS OF
AGE, THERE WAS THE SAME
PREVALENCE OF ADVANCED ADENOMA
AND SERRATED LESIONS AND CANCER.
ALL THIS REALLY SUPPORTS THE USE
OF SCREENING TO DAMPEN THE
DISEASE BURDEN.
SO, WHERE ARE WE WITH SCREENING?
THESE ARE RECOMMENDED TESTS.
STOOL TESTING AND CT COLONOSCOPY
AND THIS IS ANY RECOMMENDED
TEST.
IT WAS VERY EXCITING TO SEE THE
INCREASE IN THE NEWLY ELIGIBLE
AGE GROUP 20% IN 2023 BUT STILL
FAR BELOW WHERE WE ARE WITH
PEOPLE 65 AND OLDER.
80% OF WHOM ARE CURRENT FOR
SCREENING.
I WANTED TO END ON A POSITIVE
NOTE.
THESE PAPERS ARE FROM A PAPER IN
PRESS RIGHT NOW.
AND THIS IS THAT WE'RE SEEING
EARLY SIGNS OF SCREENING UPTAKE
IN THE 45 TO 49 YEAR AGE GROUP.
THESE ARE INCIDENT RATES JUST
FROM 1998 TO 2021 OVER ALL ON
THE FAR LEFT AND FOR LOCALIZED
STAGE IN THE MIDDLE AND ADVANCED
STAGE DISEASE ON THE RIGHT.
FOR LOCALIZED STAGE DISEASE
THERE WAS A 7% INCREASE FROM
2018 TO 2021.
AND THIS FOLLOWS OF A STIFT
WHICH I SIGNIFICANT DECLINE IN
THE PREVIOUS DECADE OF 1.6% PER
YEAR.
THIS IS A STRONG SIGN THIS IS
THE DIAGNOSIS OF ASYMPTOMATIC
CANCERS BECAUSE OF THE UPTAKE OF
SCREENING.
BECAUSE AS I SAID EARLIER,
LOCALIZED STAGE DISEASE USUALLY
DOES NOT HAVE SYMPTOMS.
BUT IMPORTANT TO REALIZE THERE'S
STILL A VERY STEADY AND STEEP
INCREASE IN ADVANCED STAGE
DISEASE WHICH IS REGIONAL AND
COMBINED.
WE'RE HOPEFUL WITH MORE
SCREENING WE'LL BE ABLE TO
DAMPEN THIS TREND.
SO IN SUMMARY COLORECTAL CANCER
RATES ARE INCREASING IN PEOPLE
BORNE AFTER CIRCA 1950 WITH THE
BUR
BURDEN SHIFTING TO YOUNGER
PEOPLE IN THE RECTUM AND DISTAL
COLON AND ADVANCED STAGE
DISEASE.
I HOPE I'VE CONVINCED EVERYONE
THIS IS NOT AN EARLY ONSET
PROBLEM.
THIS IS A GLOBAL PROBLEM THAT
NEEDS TO BE UNDERSTOOD AND
ADDRESSED.
THIS INCREASE IS HAPPENING
INCREASINGLY ON A GLOBAL SCALE
IN MANY HIGH INCOME COUNTRIES
AROUND THE WORLD.
AND ESTABLISHED RISK FACTORS
DON'T APPEAR TO BE THE SOLE
CAUSE THOUGH CERTAINLY EXCESS
BODY WEIGHT AND OUR MORE
SEDENTARY LIFESTYLE ARE
CONTRIBUTING IN SOME WAY TO THE
INCREASE.
SO WHAT CAN WE DO NOW TO HELP
MITIGATE THIS GROWING BURDEN?
I DO THINK THERE'S A LOT THAT
CAN BE DONE.
ONE IS SCREENING.
WE'VE ALREADY TALKED ABOUT THAT.
IT CAN REALLY MAKE A DIFFERENCE
AND I WOULD POINT TO THE VERY
FIRST SLIDE I SHOWED.
WE SAW ACCELERATED DECREASES IN
BOTH INCIDENTS AND MORTALITY
WHEN THERE WAS WIDESPREAD
COLONOSCOPY UPTAKE IN THE
U.S. OVER ALL SO WE KNOW IT CAN
BE EFFECTIVE.
THERE ARE MANY PEOPLE DIAGNOSED
BEFORE 45.
SO INCREASING THE AWARENESS OF
SYMPTOMS AND JUST THE FACT THAT
DISEASE INCREASE IS INCREASING
IN YOUNGER ADULTS.
RECTAL BLEEDING AND ABDOMINAL
PAIN ARE THE TWO MOST COMMON
SYMPTOMS IN YOUNG ADULTS AND
THIS IS DIFFERENT THAN OLDER
PATIENTS BECAUSE THESE ARE
PREDOMINANTLY RECTAL CANCERS.
THIS IS THE SYMPTOMOLOGY.
AND BE THE ALSO REDUCING THE
STIGMA BECAUSE THAT DELAY IN
PATIENT FOLLOW-UP AT THE CLINIC
WITH THEIR SYMPTOMS IS OFTEN
TIMES BECAUSE OF EMBARRASSMENT.
SO REDUCING STIGMA OF THIS
DISEASE AND THE SYMPTOMS AROUND
IT.
I'D LIKE TO GIVE A BIG BIG THANK
YOU TO CANCER REGISTRARS IN THE
U.S. AND GLOBALLY THAT ALLOW US
TO DO ALL OF THIS WORK AS WELL
AS MY ACS COLLABORATORS.
I THANK YOU SO MUCH FOR YOUR
ATTENTION.
>> THERE'S BEEN A FOCUS ON
GENETIC AND MOLECULAR ASPECTS OF
COLORECTAL CANCER IN THE
INHERITABLE AND SPORADIC FORMS.
SANDY, WOULD YOU PLEASE CARRY
ON.
>> WIN, AM I VISIBLE?
>> YOUR BACKGROUND SCREEN IS
VISIBLE.
YOU'RE NOT IN THAT ROOM ON THE
BEACH.
BUT MAYBE YOU CAN START SHARING.
>> LET'S SEE IF I CAN FIGURE OUT
HOW TO GET MYSELF VISIBLE.
>> OKAY.
THERE YOU ARE.
>> AND YOU CAN HEAR ME?
>> YES, WE CAN HEAR YOU.
AND YOU'RE PROBABLY SEEING NOW
THE MAC PRESENTER MODE.
>> NOT QUITE.
THERE IT IS.
>> OKAY.
WELL, WIN, THANKS VERY MUCH FOR
INVITING ME TO PRESENT IN THIS
CERTAINLY DISTINGUISHED SEMINAR
SERIES WITH A GREAT LEGACY.
REBECCA JUST TALKED ABOUT THE
EPIDEMIOLOGY OF THE ONSET OF
YOUNG COLORECTAL CANCER AND I
CAN PROVIDE THE MOLECULAR
EXPLANATION FOR THE OBSERVATION
BUT NO BODY HAS ONE.
WHAT I'M GOING TO DO IS TALK
ABOUT WHAT'S BEEN LEARNED FROM
THE STUDY OF YOUNG ONSET CO
COLORECTAL CANCER IN FAMILIES IN
THE HOPE IT PROVIDES OPTIMISM
THE PROBLEMS ARE SOLVABLE AND
ALSO REASON TO CONTINUE ON
BECAUSE IT TURNS OUT ANSWERING
THESE TYPES OF QUESTIONS TURNED
OUT TO HAVE BROAD IMPACT BEYOND
JUST IS THE INITIAL POPULATION
THAT'S BEING THE OBJECT OF
STUDY.
I'M GOING TO TALK ABOUT STUDIES
THAT WERE DONE IN YOUNG ONSET
HEREDITARY COLORECTAL CANCER
GOING BACK NOW 20 SOMETHING
YEARS BETWEEN OUR GROUP AND
COLLABORATORS.
THESE ARE MY DISCLOSURES.
I WILL BE TALKING ABOUT
HETEROLO
HETEROLOGIES AND INTERESTS.
LET'S TALK A LITTLE BIT ABOUT
COLORECTAL CANCER FOR A MOMENT.
IT HAS PROGRESSIVE CLINICAL
STAGES.
THE FIRST STAGE IS SHOWN ON THE
LEFT IS NOT CANCER AT ALL.
IT'S A BENIGN PRECURSOR FOR THE
COLORECTAL CANCER IN THE FORM OF
A TUBULAR ADENOMA AND YOU SEE IT
AS A BUMP IN THE WALL OF THE
COLON IN THIS EXAMINATION AND
OVERTIME THESE BENIGN TUMORS CAN
PROGRESS AND BECOME INVASIVE
COLORECTAL CANCERS AS YOU SEE
HERE WHERE THE COLON'S BEEN OPEN
TO EXPOSE THE TUMOR ON THE
INSIDE.
WITH TIME THEY CAN SPREAD BEYOND
THE WALL OF THE COLON.
MOST CHARACTERISTICALLY SPREAD
TO THE LIVER AND METASTATIC
DISEASE WHICH IS LARGELY
INCURRABLE.
HERE YOU SEE A PICTURE OF COLON
CANCER AND PATIENTS EXPOSED IN
THE OPERATING ROOM.
NOW, THROUGH THE EFFORTS OF MANY
LABORATORIES AND PREDOMINANTLY A
LOT OF HAS BEEN LEARNED ABOUT
THE GENES THAT DRIVE THE
DEVELOPMENT OF COLORECTAL
CANCER.
THIS IS A FIGURE FROM A REVIEW
IN THE NEW ENGLAND JOURNAL OF
MEDICINE SEVERAL YEARS AGO.
AND ON THE TOP YOU SEE GENES
THAT ARE INVOLVED IN THESE
PROGRESSIVE STAGES OF COLORECTAL
CANCER.
THE GENES DRIVES THE DEVELOPMENT
OF COLORECTAL CANCER AND THESE
ARE GENES THAT ARE ACTIVATED AND
SOME ARE DEACTIVATED AN YOU SEE
GRAY FACTOR PATHWAYS THE COX 2
THE TARGET OF NON STEROIDAL
INFLAMMATORY DRUGS AND OPPOSING
FACTORS SUCH AS GROWTH FACTOR
DATA.
WHAT I'M GOING TO TELL YOU IS
STUDIES FROM OUR LAB THAT PUT
SEVERAL OF THE GENES AND
PATHWAYS DEPICTED ON THE MAP
INTO OUR UNDERSTANDING OF
COLORECTAL CANCER.
AND THESE STUDIES COMMENCED
THROUGH OUR STUDIES OF
HEREDITARY COLON CANCER OR AS IS
OFTEN KNOWN AND WHAT YOU SEE IS
THE FAMILY SLIDE OF A PATIENT
TWO AND A HALF DECADES AGO.
HE WAS A 33-YEAR-OLD ACCOUNTANT
FROM A CLEVELAND SUBURB AND HAD
COLORECTEL CANCER AND EVEN MORE
AND WHAT IS MORE SURPRISING IS
THE FAMILY HISTORY SIMILAR ONSET
COLORECTAL CANCER KILLED HIS
FATHER AND GRANDFATHER.
MOREOVER, WHEN WE INQUIRED ABOUT
OTHER MEMBERS OF THE FAMILY, WE
FOUND THERE WERE YOUNG ONSET
ENDOMETRIAL AND OVARIAN CANCERS
IN FEMALE MEMBERS OF THIS
KINDRED.
NOW, TODAY THIS IS RECOGNIZED AS
PROTOTYPICAL SYNDROME.
AT THE TIME I FIRST SAW THE
INDIVIDUAL THE SYNDROME WASN'T
YET IN THE MEDICAL TEXTBOOKS AND
SKEPTICALLY VIEWED AS BAD LUCK
THE COOCCURRENCE OF COMMON
CANCERS BUT IF YOU LOOKED HARD
ENOUGH YOU WOULD FIND.
WE RECOGNIZE THIS AS POTENTIALLY
REPRESENTING A NEW GENETIC
SYNDROME AND SO WE HARVESTED THE
PATIENT'S TUMOR AFTER HIS DEMISE
AND SUCCEEDED IN GROWING THAT
POSTHUMOUS SAMPLE IN THE
LABORATORY AND THEN TURNED TO
OTHER PATIENTS WE WERE ABLE TO
IDENTIFY WITH SIMILAR HISTORIES
AND ULTIMATELY WERE ABLE TO
ESTABLISH A SMALL PANEL OF CELL
LINES WE CONTRIBUTED TO THE
EFFORTS FOCUSSED ON GENETIC
INTERROGATION OF THE SYNDROME
AND NO EFFORTS LED TO THE
IDENTIFICATION THAT OUR PATIENT
AND OTHER PATIENTS CONTRIBUTED
TO THE STUDY ALL HAD IN BORN
ERRORS IN A SYSTEM KNOWN AS
SYSTEM DNA MISMATCH REPAIR.
THAT COULD BE SIMPLY THOUGHT OF
AS A DNA SPELL CHECKER.
IT'S A PROTEIN COMPLEX OF FOUR
DIFFERENT SUB UNITS AND IT RUNS
ALONG THE DOUBLE HELIX
REPLICATION AND THOSE CREATE A
SMALL BUBBLE IN THE DOUBLE HELIX
WHERE YOU DON'T HAVE
COMPLEMEN
COMPLEMENTARY BASIS IS OPPOSITE
ONE ANOTHER AND THE PATIENT HAD
BEEN BORN WITH INACTIVATION OF
THE MH2 SUB UNIT OF THE CHECKER
AND MOST PATIENTS HAD A SUB UNIT
OF THE SPELL CHECKER AND THIS
WAS A SYNDROME NOT JUST BAD LUCK
BUT DUE TO FORTUNATE MISCUES.
AND THE MOMENT THIS DISCOVERY
WAS MADE WAS WHAT WOULD THE
CONNECTION BE BETWEEN HAVING A
MUTATION THAT INACTIVATED THE
MISMATCH REPAIR DNA SYSTEM SPELL
CHECKER AND THE COLORECTAL
CANCER?
OUR TEAM HYPOTHESIZED THERE MUST
BE A GENE CRUCIAL TO THE
PREVENTION OF COLORECTAL CANCER
AND HAD SOME SORT OF STRUCTURE
IT WAS CRUCIALLY DEPENDENT ON
THE DNA MISMATCH REPAIR SYSTEM
TO MAINTAIN ITS GENOMIC
INTEGRITY AND WE SUCCEEDED IN
IDENTIFYING SUCH A GENE AND IT
WAS THE TYPE 2 RECEPTOR FOR THE
TGF BETA AND THE TGF BETA TYPE 2
RECEPTORS ARE A SIMPLE TYPE 1
PROTEIN AND INTERMINUS OUTSIDE
THE CELL AND C TERMINUS INSIDE
THE CELL.
WHAT WE NOTED WAS THERE WAS A
VERY UNUSUAL SEQUENCE IN THE
GENE ENCODING THIS RECEPTOR
WHICH WAS 10 REPEATS OF THE SAME
DNA BASE ALL IN A ROW.
AS YOU WOULD IMAGINE IF YOU
TRIED TO SAY AAAAAAAA AND STOP
EXACTLY ON THE 10th A YOU MAY
STUTTER AND THE POLYMERASE HAS
THE SAME PROBLEM.
THERE'S ENORMOUS RELIANCE ON THE
DNA SPELL CHECKER TO CORRECT THE
STUTTERING ACROSS THE RUN THE
DNA POLYMERASE HAS TROUBLE
FAITHFULLY COPYING.
SUCH AS WHEN WE LOOKED AT ALL
THE COLON CANCERS THAT AROSE IN
PATIENTS WITH THE SYNDROME, WE
FOUND THIS GENE HAD BEEN
INACTIVATED IN 100% OF THE
TUMORS AND THE INACTIVATIONS
WERE STUTTERING OF THE DNA
POLYMERASE THAT ADDED OR
SUBTRACTED AN A OR TWO As FROM
THE GENE WHEN IT WAS COPIED.
ALL THESE STUTTERING ERRORS HAVE
THE SAME EFFECT.
THEY CREATED A STOP MUTATION IN
THE GENE AND CREATED A PROTEIN
THAT WAS NOW TRUNCATED AND NO
LONGER ACROSS THE CELL MEMBRANE
AS THEY WERE ABLE TO SIGNAL INTO
THE CELL.
WHAT IS IT TGF BETA DOES AND WHY
WOULD THE BETA RECEPTOR MATTER?
THIS IS WHAT THE HISTOLOGY OF
THE COLON LOOKS LIKE.
HERE YOU HAVE THE BANDS OF
MUSCLE THAT SQUEEZED OR ENABLE
THE COLON TO CONTRACT AND REPEL
THE DIGESTIVE CONTENTS THROUGH
THE GUT.
AND UP HERE SEE THE EPITHELIAL
CELLS THE COLUMNS OF CELLS AND
THIS IS THE INNER LINING OF THE
COLON, THE FECAL STREAM IS UP
HERE ABOVE THESE EPITHELIAL
LINING AND THIS EPITHELIA IS
AMONG THE FASTEST
PROLIFERATING -- AND THE ENTIRE
TISSUE REMOVES ITSELF ON A
WEEKLY BASIS.
SO WHAT HAPPENS IS NEW CELLS ARE
GENERATED AT THE BASE OF THE
COLUMNS AND THEN MATURE CELLS
DIE AND SLOUGHED OFF INTO THE
LUMEN -- AND IT PLAYS A CRUCIAL
ROLE IN THE CONTROL THAT LEADS
TO THE MATURATION AND DEATH OF
THE CELLS AFTER A FEW DAYS'
TIME.
SO HERE WE HAVE A CARTOON COLON
CELL.
HERE IS TGF BETA AND THE
RECEPTOR AND OF COURSE WHAT
HAPPENS IS WHEN THE LIGAND TGF
BETA ENGAGE THE RECEPTOR IT
SENDS A SIGNAL TO THE NUCLEUS OF
THE CELL LEADING TO THE
APOPTOTIC CELL DEATHS AND THE
FINDING OF UBIQUITOUS IN THE
PATIENTS IN THE PATIENTS WITH
THE DEFECTIVE SPELL CHECKER LED
US TO REALIZE THERE WERE SEVERAL
IMPLICATIONS.
FIRST IT SAID THE TGF BETA TYPE
2 RECEPTOR IS A GENE MUTAT
MUTATIONALLY INACTIVATED IN
COLORECTAL CANCER AND THE
SIGNALLING PATHWAY WAS LIKELY A
TUMOR SUPPRESSER FUNCTION.
AND THIRDLY IT ESTABLISHED THESE
MUTATIONS AS PUNITIVE MECHANISMS
THAT CONNECT DEFECTS AND
MISMATCH REPAIR WITH THE
INACTIVATION OF THE TUMOR
SUPPRESSER GENE ENABLING THE
DEVELOPMENT OF COLON CANCERS IN
THE INDIVIDUALS.
SO TO TURN THIS INTO A SIMPLE
CARTOON, ONE CAN THINK OF TGF
BETA AS THE WALL OF APOPTOTIC
CELL DEATH IN THE COLON.
NORMALLY ALL COLON CANCERS ENTER
AN APOPTOTIC CELL DEATH PHASE
BUT THOSE WITH THE SPELL CHECKER
THERE'S A TIME BOMB UNDER THE
TGF BETA WALL OF DEATH AND WHEN
THE TIME BOMB RESULTS IN
MUTATIONS IN THE TGF BETA
RECEPTOR AND NOW YOU BLOW A HOLE
IN THE FUNCTIONAL MECHANISM AND
THE POTENTIAL CANCER CELLS
INSTEAD OF BEING SLOUGHED OFF
INTO THE LUMEN OF THE COLON AND
NOW PERSISTS AND PROGRESS.
SO WE HAVE THE BEGINNING OF A
PATHWAY IN WHICH LESIONS AND DNA
MISMATCH REPAIR TARGET THE TUMOR
SUPPRESSER GENE LEADING TO THE
ONSET OF YOUNG ONSET COLON
CANCERS TYPICALLY BEFORE THE AGE
OF 35 IN THE KINDREDS.
WE FURTHER VALIDATED TGF BETA
RECEPTORS WERE SUPPRESSER GENES
BY OF AND FINDING MUTATIONS AT
OTHER SITES IN THE GENE THAT
DEVELOPED INSPORADIC COLON
CANCERS IN WHICH THE DNA SPELL
CHECKER WAS OKAY AND THE TRACT
WAS NOT MUTATED BUT OTHER
REGIONS THE GENE COULD BE
TARGETED AND TOGETHER WE SHOWED
AN INDIVIDUAL IN THE TGF BETA
RECEPTOR WITH WILD TYPE IN THE
COLORECTAL CANCER IS THE
SIGNALLING PATHWAY WAS STILL
INACTIVATED AND THAT THROUGH
MUTATIONS IN THE SPLAT COMPLEX
CONNECT THE TGF BETA RECEPTORS
WITH THE NUCLEUS AND WHAT WOULD
MATTER SO MUCH THAT THIS PATHWAY
WOULD BE UNDER THIS EXQUISITE
PRESSURE FROM MUTATIONAL
INACTIVATION?
TO ADDRESS THAT QUESTION WE DID
AN EARLY FORM OF WHAT TODAY
WOULD BE CONSIDERED A BIO
INFORMATICS EXPERIMENT AND USED
EXPRESSION MICROARRAYS DEVELOPED
AT THAT TIME TO ASK A BULIAN
ENQUESTION OF HOW MANY WERE
TURNED OFF IN COLORECTAL
CANCERS.
WHILE THERE'S THOUSANDS OF GENES
DOWN REGULATED IN COLON CANCER
WE FOUND THERE WERE ONLY EIGHT
GENES UPREGULATED BY TEN FOLD OR
MORE BY TGF BETA IN THE NORMAL
COLON AND ONLY 25 DOWN REGULATED
BY 10 OR MORE IN COLON CANCER
AND ONLY ONE GENE MET BOTH
CONDITIONS AND THAT WAS 15 PR
PROSTAGLAND AND IT DIDN'T
CONNECT TO CANCER OF ANY KIND IN
MODEL SYSTEMS.
WHEN WE ASKED WHAT IT DID WE
BEGAN TO FORMULATE A HYPOTHESIS
BECAUSE IT TURNED OUT TO ENCODE
AN ENZYME.
THE FUNCTION WAS TO CATALYZE THE
DE INSTRUCTION OF THE
PROSTAGLANDIN 2 AND OXIDIZES TO
THE GROUP ON THE MODEL AND THAT
INACTIVATES THE PGE2 TO ACT AS A
LIGAND AND TO SIGNAL.
AND IT WAS A GROWTH FACTOR IN
THE COLON AND KNOWN TO BE
INCREASED IN COLORECTAL CANCER
BY THE ACTIVATION OF THE COX 2
ENZYME THAT SYNTHESIZES IT AND
RECEPTORS HAD BEEN IDENTIFIED
AND ALL G PROTEIN COUPLED
RECEPTORS AND SHOWED THEY COULD
SIGNAL THROUGH CYCLIN D1 AND
ACTIVATE MIGRATION AND ALL
PHENOTYPES ASSOCIATED WITH
NEOPLASIA.
SO WE HYPOTHESIZED THAT PERHAPS
15PGDH HAD BEEN OVERLOOKED AND
MAY BE ABLE TO DOWN REGULATE THE
PATHWAY AND ENABLE ITS
HOMEOSTATIC CONTROL.
SO TO EXPLORE THAT HYPOTHESIS WE
WERE ABLE TO OBTAIN THE KNOCKOUT
MOUSE JUST MADE BY BETH KOLLERS
LAB AT THE UNIVERSITY OF NORTH
CAROLINA.
SHE GRACIOUSLY SHARED THAT MOUSE
WITH US AND THE MOUSE WAS ON A
C57 BLACK BACKGROUND NOTORIOUSLY
RESISTANT TO THE INDUCTION OF
COLON TUMORS.
INDEED WHEN WE TREATED A WILD
TYPE C57 BLACK 6 MOUSE WE COULD
NOT INDUCE COLON TUMORS.
BUT WHEN WE TREATED THE KNOCKOUT
MOUSE WE FOUND THEY WERE
SUSCEPTIBLE TO THE
CARCINOGENESIS AND YOU CAN SEE
ONE SUCH TUMOR AND WHEN WE DID
THIS EXPERIMENT ACROSS A COHORT
OF MICE, NONE OF THE WILD TYPE
MICE THAT WERE CARCINOGEN
EXPOSED DEVELOPED TUMORS BUT THE
HETTER ZYGOUS MOUSE DEVELOPED
COLON TUMORS WITH TUBULAR
ADENOMAS IN YELLOW WITH HIGH
GRADE DYSPLASIA SHOWN IN RED.
AND WE ASKED WHAT WAS GOING ON
AT THE MICROSCOPIC LEVEL AND IF
WE LOOKED AT CARCINOGEN TREATED
MICE COLONS FROM A WILD TYPE OR
KNOCKOUT MOUSE, WHAT YOU CAN SEE
IS IN THE WILD TYPE MOUSE THERE
IS A LESION.
YOU HAVE THIS LARGE CRYPT BUT
IT'S HISTOLOGICALLY BLAND IN THE
KNOCKOUT MOUSE THERE'S BEEN
PROLIFERATION AND ONE CAN
VISUALIZE THAT BY STAINING THE
LESIONS WITH THE PROLIFIC MARKER
AND THE LARGE CRYPTS ARE
ESPECIALLY SHUT DOWN.
THEY'RE NOT PROLIFERATING
PARTICULARLY RAPIDLY AND IN THE
KNOCKOUT MOUSE YOU SEE THE
PROLIFERATIVE CELLS AND GOING UP
TO THE TO THE OF THE CRYPT WHERE
NORMALLY YOU'D SEE APOPTOTIC
CELL DEATH AND WHAT IS DRIVING
THIS IS THE CYCLIN D1 PATHWAY
YOU CAN VISUALIZE AND SEEING THE
NUCLEAR LOCALIZATION IN THE
KNOCKOUT MOUSE AND ONE CAN
QUANTITATE THIS AND SEE IN THE
WILD TYPE MOUSE AND STIPALED
MOUSE THE ACTIVATION OF CYCLIN
D1 PATHWAY.
SO WHAT WE WERE ABLE TO PUT
TOGETHER WAS A ROUGH OUTLINE OF
WHAT WAS HAPPENING.
IT WAS UNDERSTOOD THAT COX-2 WAS
UPREGULATED AND INCREASED
PROSTAGLANDIN AND THAT WAS
ASSOCIATED WITH THE COLON
ADENOMAS AND WERE ABLE TO SHOW
WHAT IS GOING ON IS IF YOU HAVE
A MUTATED CELL OR INITIATED CELL
IN THE CRYPT OF A COLON, IT'S
OFTEN QUIESCENT BUT THIS GIVES
RISE TO THESE PRECURSOR REGIONS
THE ADENOMAS AND ITS NORMALLY
HAS A PHYSIOLOGIC REGULATOR IN
THE FORM OF 15-PGDH AND
REGULATION OF TGF-BETA AND THERE
WAS UNDER APPRECIATED CROSS TALK
THAT ALLOWED IT TO NEGATIVELY
REGULATE THE CELLS.
WE HAD A SIMPLE STORY.
LOW PGDH IS BAD FOR YOU AND
ALLOWS FOR PROLIFERATION IN THE
COLON.
THE FLY IN THE OINTMENT, IF YOU
WILL, WAS WHEN WE MEASURED
LEVELS OF PGDH IN THE COLON
ACROSS INDIVIDUALS WE FOUND
HETERODISPERSION IN THE
POPULATIONS AND LEVELS ACROSS A
GROUP OF PATIENTS.
I THINK 20 IN NUMBER.
YOU CAN SEE THERE'S NEARLY A
12-POINT RANGE IN THE HUMAN
POPULATION WITH VERY LONG TAIL
OF INDIVIDUALS WITH VERY LOW
LEVELS OF COLONIC PGDH.
WHEN YOU SEE THIS KIND OF
GENETIC SIGNAL IT USUALLY MEANS
YOU'VE MISSED HALF THE STORY AND
THERE IS SOME SELECTIVE
ADVANTAGE FOR INDIVIDUALS WITH
LOW PGDH.
THE QUESTION IS WHAT WOULD THAT
SELECTIVE ADVANTAGE BE?
OF COURSE THROUGH MUCH OF
EVOLUTION THE CONCERN WITH
EVOLUTION IS NOT PROTECTING YOUR
COLON FROM PROLIFERATING IN YOUR
OLD AGE BUT RATHER ENABLING YOU
TO SURVIVE INFECTIONS.
ENABLING YOU TO SURVIVE
INFECTIOUS DIARRHEAS -- AND
REPAIR THE DAMAGE TO THE MUCOSA
AND THOUGHT WE COULD LOOK AT THE
REPAIR OF THE MODEL AND THE
MODEL WE CHOSE WAS ULCERATIVE
COLITIS WHERE MICE ARE FED A
CHEMICAL IN THE DIET, AND YOU
CAN SEE IN THE MOUSE COLONOSCOPY
THE MICE DEVELOPED THE WHITE
ULCERATIONS UNDER THE MICROSCOPE
AND THIS IS AN EPITHELIAL ULCER
WHERE IT'S GONE AND THESE ARE
INFLAMMATORY.
WE FOUND WE COULD WITH DSF
ULCERATE ABOUT 8% OF THE COLON
OF THIS WILD TYPE MOUSE AND THE
KNOCKOUT MOUSE WAS COMPLETELY
RESISTANT.
THERE WERE NO ULCERS WHATSOEVER
IN THE KNOCKOUT MOUSE.
EVEN IN AREAS WHERE THE
EPITHELIUM REMAINED VISIBLY IN
THE COLONO SCOPE IN THE WILD
TYPE THE EPITHELIUM WAS BEING
ERODED UNDERNEATH AND IN THE
KNOCKOUT MOUSE THERE WERE NO
EROSIONS WHATSOEVER AND COULD
QUANTITATE THIS SHOWING THIS
CRYPTITIS OCCURRING UNDERNEATH
THE EPITHELIUM OF THE WILD TYPE
MOUSE AND NEAR COMPLETE
RESISTANCE TO THE LOSS OF CRYPTS
IN THE KNOCKOUT MOUSE.
WHEN WE ASKED WHY WAS THE
KNOCKOUT MOUSE RESISTANT TO THE
ULCERATIONS THESE ARE SHOWN IN
THE FLUORESCENT STRAIN AND THE
RED DOTS ARE THE PROLIFERATING
CELLS AND IF THIS IS A NORMAL
WILD TYPE MOUSE YOU CAN SEE WHEN
THE MOUSE IS FED DSS BY THE
EIGHTH DAY OF EXPOSURE, MOST OF
THE RED DOTS ARE GONE.
MOST THE PROLIFERATING CELLS
HAVE BEEN KILLED OFF.
BUT IF YOU LOOK AT THE KNOCKOUT
MOUSE IT STARTS LOOKING JUST
LIKE THE WILD TYPE MOUSE BUT IN
THE FACE OF THE STRESS IT'S
ACTUALLY ABLE TO UPREGULATE THE
PROLIFERATION AND REPLENISH THE
COLONS AS FAST AS THE CELLS ARE
KILLED OFF AND THEN UNTREATED
THE WILD TYPE MOUSE LOSES
PROLIFERATIVE MOUSE THE KNOCKOUT
MOUSE GAINS THEM.
SO, IT APPEARS UNDER SEVERAL
CONTEXT HAVING LOW ACTIVITY OF
THE DATA SIGNALLING PATHWAY IS
ACTUALLY GOOD FOR YOU BECAUSE IT
ALLOWS YOU TO REPAIR TISSUE
DAMAGE.
WE WONDERED COULD WE DEVELOP A
DRUG THAT WOULD ALLOW US TO SHUT
THIS PATHWAY OFF IN THE CONTEXT
OF DISEASES WHERE YOU MIGHT WANT
TO SHUT IT OFF?
WE USED GENETIC ENGINEERING
TECHNOLOGY AND YOU CAN SEE CELLS
AND VISUALIZE THE LEVEL OF PGDH
BY HOW MUCH LIGHT THE CELLS ARE
GIVING OFF AND USED THAT ASSAY
TO SCREEN A QUARTER OF A MILLION
SMALL MOLECULES WITH
COLLABORATION WITH A TEAM AT THE
UNIVERSITY OF TEXAS SEARCH
WARRANT.
-- SOUTHWESTERN AND OUT OF THAT
SCREEN WE IDENTIFIED THIS
MOLECULE AS SWO33291 WHICH WAS
POTENT IN INHIBITING THE
ENZYMATIC ACTIVITY AND HAD A
BINDING CONSTANT OF LESS THAN
ONE NANOMOLE AR FOR INHIBITING
THE PDGH AND STABLE AND ACTIVE
WHEN INJECTED INTO MICE AND SEE
IT AGAIN THE DISEASE PATTERN OF
A WILD TYPE MOUSE THE DSS AND
THE INDUCTION OF THE ULCERS THE
PREVENTION BY KNOCKING OUT PDGH
AND THE PREVENTION OF THE ULCERS
BY GIVING THE DRUG AND SAME IS
TRUE ALSO FOR THE CRYPTITIS
SCORE.
SO NOW WE HAD A PICTURE THAT
SAID NORMALLY YOU HAVE THE
PROSTAGLANDIN AND PRODUCED BY
COX 1 OR COX 2 AND IN THE
TISSUES THE LEVEL OF PGDH2 IS
REGULATED BY THE COMPLEX.
IF WE DISTRIBUTE THE INHIBITOR
WE CAN NOW BLOCK THAT KETABOLIC
PATHWAY AND POTENTIATES THE
PROLIFERATING CELL.
AND WE NOW HAVE HAD A CHEMICAL
PROBE WE COULD DO CHEMICAL
BIOLOGY AND LOOKED AT HOW
CONSERVED THE PATHWAY WAS.
AND WE FOUND INHIBITING COULD
POTENTIATE REPAIR AFTER INJURY
TO THE LIVER AND COULD
POTENTIATE REPAIR IN THE BONE
MARROW AND IN EXPERIMENTS WE
SHOWED WE COULD MARKEDLY
UPREGULATE THE POPULATION OF THE
HEMATOPOIETIC SYSTEM THROUGH
UPREGULATE THE BONE MARROW AND
TURNING ON THE PRODUCTION OF TWO
STEM CELL CYTOKINES AND XCL12.
HOW IS IT THE MOLECULE IS SO
POTENT?
HOW DID WE GET TO LUCKY?
TWO YEARS AGO WE WERE ABLE TO
SOLVE THE CRYO EM STRUCTURE OF
THE FAMILY OF DRUG ABOUT TO
15PDGH.
THE STUDY SHOWED ITSELF IS A
HOMO DIMER AND THE MOLECULE
BOUND TO THE PROTEIN AND YOU SEE
THE OBVIOUS MYSTERY WHICH IS THE
DRUG IS BURIED DEEP INSIDE THE
PROTEIN.
SO HOW IN THE WORLD DID IT GET
THERE AND GET INSIDE.
WE HAVE A SHIP IN THE BOTTLE
PROBLEM.
IT TURNED OUT TO BE THE GOLD
HELIX CAN MOVE AND FUNCTION AS A
TRAP DOOR TO OPEN AND CLOSE AND
REVEAL THIS HIDDEN POCKET IN
15PDGH.
AND THE TRAP DOOR MECHANISM
TURNS OUT TO BE PHYSIOLOGIC.
THE POCKET IS THE POCKET BY
WHICH PG2 NORMALLY BINDS TO
52PDGH AND WHEN THE DOOR CLOSES
THE MECHANISM BY THE TWO AMINO
ACIDS CAN DESTROY PDG2 AND
THEY'RE WIRING THE DOOR SHUT.
SO WHEN THE TRAP DOOR CLOSES ON
THE DRUG AS YOU SAW IN THE CRYO
EM STRUCTURE IT BINDS TO THE
DOOR AND NOW THE ENZYME IS
INACTIVATED.
SINCE THE INITIAL PUBLICATION,
WE'VE IDENTIFIED THIS PATHWAY IS
CONSERVED AND ENGAGED IN
MULTIPLE AND WHAT WE SEE IN
MODELS OF HUMAN DISEASE
INCLUDING REGULATING THE BONE
MARROW RECOVERY AFTER BONE
MARROW TRANSPLANTATION AND
REGULATING THE RATE OF
DEVELOPMENT OF APLASTIC ANEMIA
AND ENABLING PROTECTION FROM
ISCHEMIC INJURY AND THE
REGULATION OF TISSUE REPAIR
TURNS OUT TO BE DEEPLY CONSERVED
ACROSS MULTIPLE TISSUES IN THE
MOUSE BODY AND HOPEFULLY IN THE
HUMAN AS WELL AND WITH THAT
UNDERSTANDING WE WANTED TO GO
FORWARD AND SEE IF WE COULD
BRING THIS FORWARD FOR POTENTIAL
HUMAN USE.
WE WERE ABLE TO COME UP WITH THE
ACCELERATOR LIFE SCIENCE
PARTNERS FOR A BIO TECH START
UP AND WERE CAPITALIZED BY A
NUMBER OF LARGE PHARMACEUTICAL
COMPANIES AND ABBVIE AND LILY
AND JOHNSON AND JOHNSON AND MUCH
TO OUR SURPRISE IN 2021, AMGEN
CAME KNOCKING ON THE DOOR AND
SAID THEY WERE INTERESTED AND
ACQUIRED THE LICENSE TO THE
COMPOUNDS WE DEVELOPED AND ARE
NOW CARRYING THE TECHNOLOGY
FORWARD CURRENTLY IN PRECLINICAL
DRUG DEVELOPMENT.
SO WE HOPE WE WILL SEE THE
POTENTIAL OF THIS PATHWAY TESTED
IN THE MODELS OF HUMAN DISEASE.
SO, WE WENT FROM THE MISMATCH
REPAIR SYSTEM TO IDENTIFYING
MUTATIONS IN THE BETA RECEPTORS,
IDENTIFYING A PATHWAY THAT
ULTIMATELY CONVERGED ON 15PDGH
AND INHIBIT THE SIGNALLING.
BUT AS THE ANOTHER BIG HUGE
QUESTION, THE GORILLA IN THE
ROOM.
WHILE SHE SYNDROME ACCOUNTS FOR
5% OF THE COLORECTAL CANCERS THE
TGF BETA SIGNALLING PATHWAY AND
THE MNEMONIC MUTATION AND THE
TRACK OF THE RGF BETA 2 WAS
FOUND IN 15% OF COLORECTAL
CANCERS AND FOUND IN NEARLY HALF
THAT AROSE IN THE RIGHT SIDE IN
THE ASCENDING COLON.
WE AND MANY OTHER LABORATORIES
TRIED TO UNDERSTAND HOW THIS
HUMAN HEREDITARY CANCER WAS
BEING PHENOCOPIED BY 15% OF
INDIVIDUALS WHO DEVELOPED
COLORECTAL CANCER?
AND WE LOOKED FOR OTHER MEMBERS
OF THE DNA MISMATCH REPAIR.
WITHOUT SUCCESS.
WE LOOKED FOR SPLICE MUTATIONS.
THE ANSWER TURNED OUT TO BE IN
THE LAST PLACE WE LOOKED.
IT WAS IN THE COLON EPIGENOME.
N
IF THIS IS A SCHEMATIC SHOWING
THE LOCATION OF ONE OF GENES OF
THE DNA SPELL CHECKER HERE IN
THE WILD TYPE INDIVIDUALS YOU
SEE TWO GOOD COPIES OF GENES
BOTH BEING EXPRESSED.
AND IN LYNCH SYNDROME ONE
INHERITS A COPY OF THE HMLH1 AND
WHEN THE COPY IS LOST THE SPELL
CHECKER IS ACTIVATED AND NEOPLAY
SLA -- NEOPLASIA ACTIVATE AND IT
WAS COVERING UP THE PROMOTER OF
THE GENE SO IT COULDN'T BE
TURNED ON.
WHILE EPIGENETIC GENE SILENCING
CAN ACTIVATE GENES IN CANCER AND
IN 1988 THIS WAS ONE OF THE
FIRST SAMPLES OF SILENCING OF
THE GENE AND SO MUCH SURPRISED
BY THE OBSERVATION WE WERE
CONCERNED IT WAS A CORRELATIVE
AND MAY BE A CASE OF TRUE, TRUE
AND UNRELATED.
SO TO TRY TO GET FURTHER
EVIDENCE THE EPIGENETIC GENE
SILENCING COULD BE CAUSING
CANCER WE TURNED TO ANOTHER
HEREDITARY CANCER MODEL OF DI
DIFFUSED GASTRIC CANCER IS
CAUSED BY INHERITANCE OF THE
MUTANT FORM OF THE CDH1 GENE.
AND HERE IS A BIOPSY FROM THE
STOMACH OF AN INDIVIDUAL WHO HAS
INHERITED THE MUTATION.
IT'S BEING STAINED HERE IN THE
NORMAL PART AND YOU SEE THE
BROWN STAIN SHOWING THE PROTEIN
AND HERE IS THIS PATIENT'S
TUMOR.
THESE ARE HORRIBLE TUMORS.
YOU CAN SEE THEIR DIFFUSE CELLS
AND YOU CAN SEE IN THE TUMOR
THERE ARE TWO PRESERVED NORMAL
CYSTS THAT RETAINED EXPRESSION.
IN THE TUMORS IT'S BEEN
ACTIVATED AND WE ASKED HOW THAT
LAND.
IT HAPPENS BY THE DEVELOPMENT OF
A SECOND MUTATION THAT
INACTIVATES THE INHERITED WILD
TYPE ALLELE AND FOUND IT AGAIN
HAPPENS BY METHYLATION THAT
COVERS UP THE PROMOTER OF THE CD
H1 GENE ENCODING CADHERIN AND
IT'S THE SECOND HIT THAT GIVES
RISE TO THE CANCERS IN THESE
INDIVIDUALS WE NOW HAD THAT THE
METHYLATION WASN'T JUST
CORRELATED WITH CANCER BUT COULD
INITIATE IT.
IT LED TO STUDIES IN OUR
LABORATORY ASKING HOW COMMON IT
WAS AND FOUND THE METHYLATION
WAS HUGELY COMMON AND AFFECTED A
HUGE NUMBER OF GENES.
MANY WHICH DOESN'T SEEM TO BE
DIRECTLY INVOLVED IN
CARCINOGENESIS AND SERVED AS
BIOMARKERS USEFUL FOR EARLY
DETECTION OF CANCER.
WE TARGETED THE METHYLATION AND
HAVING A CLUSTER AS SHOWN IN THE
YELLOW BALLS OF IN THE FIRST
EXON AND FOUND IN COLON CANCER
80% OF THE TIME THEY BECAME
METHYLATED AND COULD EASILY
DETECT IT USING METHYLATION
SPECIFIC ASSAY.
WITH THE BIOMARKER IN HAND WE
WONDERED IF WE CAN USE THIS TO
DEVELOP A TEST FOR EARLY
DETECTION OF COLON CANCER.
THIS LED TO ONE OF THE FIRST
EXPERIMENTS.
OF TRYING TO DETECT METHYLATED
DNA AND HERE IS THE FIRST
EXPERIMENT PULLING DNA FROM A
STOOL SO THE COLON CANCER
PATIENTS YOU SEE THE DETECTION
OF THE METHYLATE D DNA IN THE
STOOLS OF COLON CANCER PATIENTS.
AND THERE WAS 84% SENSITIVITY TO
DETECT CURABLE CANCER STAGE 1
AND 2 CANCERS WITH SPECIFICITY
FROM 83% TO 90%.
WE BROUGHT THAT STUDY OUT IN
JNCI.
AND LAUNCHED THIS TEST
COMMERCIALLY IN COLLABORATION
WITH LAB CORP THE MARKETING ARM
AND ESTABLISHED YOU CAN DETECT
COLON CANCER THROUGH DE
METHYLATED DNA AND THIS IS THE
UNDERLYING TECHNOLOGY WHICH
TODAY DRIVES THE SECOND
IMPLEMENTATION OF COLOGUARD
STILL BEING OFFERED DIRECTLY BY
EXACT SCIENCES.
WITH THE UNDERSTANDING THAT
METHYLATED DNA WOULD BE A
BIOMARKER TO ENABLE EARLY
DETECTION OF G.I. CANCERS.
WE WONDERED IF THERE WERE OTHER
G.I. CANCERS TO TAKE ADVANTAGE
OF THE OBSERVATION.
AND ONE IN PARTICULAR WE WERE
INTERESTED UP WAS ESOPHAGEAL
CARCINOMA EAC BECAUSE IT WAS
SHINE ESOPHAGEAL CANCER CA
CARCINOMA WAS THE FASTEST
GROWING TUMOR AND YOU SEE THE IN
INCIDENTS OVER TIME.
IT WAS SELDOM DETECTED EARLY AND
THERE WAS DIFFICULT IN
SWALLOWING AND SURVIVAL WITH THE
CANCER IS ABYSMAL LESS THAN 20%
ON PAR WITH PANCREAS CANCER.
WE WERE AWARE THERE WAS AN
OPPORTUNITY.
AS COLORECTAL CANCERS HAVE THIS
AND THERE'S A PRECURSOR.
THERE'S A LESION CALLED
BARRETT'S ESOPHAGUS AND THOUGHT
TO ARISE IN PATIENTS WITH
EPISODIC HEART BURN AND
RECOGNIZING ALLOWS AN
ENDOSCOPIST TO ABLATE THE
DISEASE AND DETER THE PROGRESS
OF DISEASE.
AND HOW WITH WE GOING TO SAMPLE
THE ESOPHAGUS?
TO DO THAT WE DEVELOPED A FUN
LITTLE DEVICE NOW KNOWN AS
ESOCHECK.
A CAPSULE THE SIZE OF A VITAMIN
AND IT WOULD BALLOON AND THE
BALLOON COULD BE POPPED OUT
WHERE THE ESOPHAGUS ARISES AND
THE AIR CAN BE WITHDRAWN AND
SHRINK THE BALLOON BACK DOWN TO
THE SIZE OF A VITAMIN PILL AND
PAIRED IT BACK AND DID A
CLINICAL TRIAL.
THIS WAS BROUGHT OUT IN SCIENCE
TRANSLATIONAL MEDICINE AND THE
BALLOON AND METHYLATED DNA WAS
SENSITIVE FOR FINDING BARRETT'S
ESOPHAGUS IN INDIVIDUALS WITH
LONG STANDING HEART BURN.
THE ABILITY TO IDENTIFY WAS
RECOGNIZED AS SPECIALLY AN
IMPACTFUL TECHNOLOGY AND THE
YEAR THE PAPER WAS PUBLISHED WAS
HIGHLIGHTED IN THE NCI
DIRECTOR'S ANNUAL REPORT TO
CONGRESS WITH THIS NICE INFO
GRAPHIC.
SO WHAT'S HAPPENED IS WE WERE
ABLE IT BRING IT TO LICENSE.
IN 2009 THE BALLOON DEVICE
RECEIVED FDA APPROVAL AND THE
METHYLATED DNA PANEL RECEIVED
BREAKTHROUGH DEVICE DESIGNATION
AND IN 2022 THE COMBINATION OF
WHAT IS NOW THE ESO CHECK DEVICE
WERE INCORPORATED INTO THE
SCREENING RECOMMENDATIONS INTO
THE GASTROENTEROLOGICAL
ASSOCIATION.
THIS IS NOW AN EMERGING STANDARD
APPROACH FOR SCREENING AND
PREVENTION OF ESOPHAGEAL
CARCINOMA.
SINCE OUR ORIGINAL PAPER IN
SCIENCE TRANSLATIONAL MEDICINE
FOLLOW VALIDATION STUDIES.
AND THOSE ESTABLISHED THE
POSITIVE PREDICTIVE VALUE OF THE
TECHNOLOGY IS ABOUT 30% WHICH IS
BETTER THAN ALMOST ANY OTHER
SCREENING ASSAY IN CLINICAL USE.
SO, STARTING WITH STUDIES OF
LYNCH SYNDROME WE WERE ABLE TO
FROM EARLY ONSET CANCER SYNDROME
OF YOUNG INDIVIDUALS IDENTIFY
GENETIC PATHWAY THAT LED TO
EARLY ONSET COLON CANCER.
STUDIES OF THAT PATHWAY
INTERROGATION OF THE PATHWAY LED
TO THE IDENTIFICATION OF
PROSTAGLANDIN HYDROGENASE FOR
TISSUE REGENERATION AND GIVEN
RISE TO A NEW CANDIDATE DRUG FOR
TREATING ULCERATIVE COLITIS AND
OTHER DISEASES AND LED TO THE
DNA METHYLATION AS A WIDESPREAD
PHENOMENON IN CANCER.
AND ALLOWED US TO GIVE RISE TO
FIRST THE USE OF METHYLATED DNA
IN STOOL AS A BIOMARKER FOR
EARLY CANCER DETECTION AND
METHYLATED DNA EFFORTING IN
ESOPHAGEAL SAMPLES FOR EARLY
DETECTION OF DISEASE.
SO THIS WAS THE WONDERFUL
WONDERFUL TEAM OF INDIVIDUALS
WHO PARTNERED TOGETHER IN THE
PGDH STUDIES.
AND HERE THE TEAM THAT PARTNERED
ON THE STUDIES ON THE ESOPHAGUS
AND WANT TO ACKNOWLEDGE THE
FUNDING SOURCES QUITE
PROMINENTLY FROM THE NIH AND
R-35 AND BETTER NET PROGRAM AS
WELL AS INCUBATOR AWARDS THAT WE
RECEIVED TO DEVELOP THESE
TECHNOLOGIES INCLUDING FROM THE
HARINGTON INSTITUTE AND KECK
SCHOOL OF MEDICINE AND THE
SUPPORT I RECEIVED AS A HOWARD
HUGHES INVESTIGATOR.
THAT BRINGS ME TO THE CONCLUSION
OF THE WORK AND I'M HAPPY TO
PAUSE AND SEE IF I CAN RETURN
THE CONTROL OF THE SYMPOSIUM
BACK TO WIN.
>> YOU'RE BACK.
DR. ARIAS, CAN YOU UNMUTE
YOURSELF?
WE HAD TO MUTE YOU.
IN MUTE YOURSELF, DR. ARIAS, UP
IN THE CORNER THERE.
>> THANK YOU VERY MUCH.
WE'VE HAD A SERIES OF QUESTIONS
AND THANK YOU BOTH FOR VERY
PROVOCATIVE AND INTERESTING
PRESENTATIONS.
SO, LET ME BEGIN ONE A QUESTION
WE HAD SEVERAL TIMES.
AND THAT IS WHETHER COLON CANCER
IN PARTICULAR IS ALWAYS RELATED
TO THE FORMATION OF A POLYP OR
ARE THERE OTHER FORMS THAT FOR
EXAMPLE MIGHT BEGIN WITH AN
ULCERATIVE PHENOTYPE.
IS A POLYP AN ESSENTIAL PART IN
THE DEVELOPMENT OF SPORADIC --
>> THERE ARE NUANCES TO THAT
QUESTION.
SO THE CLASSIC TUBULAR ADENOMA
INITIATED BY THE PATIENTS IS
VERY MUCH A FEATURE OF THE GREAT
PROBABLY ALMOST ALL CANCERS THAT
ARISE IN THE RECTUM AND
DESCENDING AND TRANSVERSE COLON.
IN THE DESCENDING COLON THERE'S
A FEATURE OF SERRATED ADENOMAS
AND THESE ARE FLAT LESIONS AND
INDEED FOR MANY YEARS THEY WERE
NOT APPRECIATED ENDOSCOPICALLY
BECAUSE THEY DON'T HAVE THAT
TYPICAL MUSHROOM APPEARANCE
THROUGH A COLONOSCOPE.
THERE'S MORE CHANGES IN THE
TEXTURE OF THE COATING.
NONETHELESS, WHEN THEY'RE
BIOPSIED THEY ARE CALLED
SERRATED ADENOMAS.
IN CERTAIN DISEASE SETTINGS SUCH
AS ULCERATIVE COLITIS ONE CAN
FIND THE EMERGENCE OF LESIONS
THAT HAVE THIS PLASTIC HISTOLOGY
THAT APPEAR TO BE IN A DIRECTLY
DEVELOPED DYSPLASIAS IN THE
COLONIC MUCOSA WITHOUT THE
CLASSIC EITHER TUBULAR OR
SERRATED ADENOMA.
INDEED THESE ARE HARD TO DETECT
SCOPICALLY AND ONE MUCH THE
REASONS INDIVIDUALS WITH
ULCERATIVE COLITIS ARE SURVEYED
WITH BIOPSIES TO SEE WHERE THE
LESIONS ARE ARRIVING.
CLOSELY RELATED TO THIS ARE
POTENTIALLY A RARER FORM OF
COLON CANCER RESPONSIBLE FOR
SINGLE DIGIT PERCENTAGES OF
COLORECTAL CANCER AND SIGNET
RATE COLON CANCER IS ENRICHED IN
THE EARLY ONSET COLON CANCERS.
IT'S ENRICHED IN INDIVIDUALS.
I WOULD SAY THE GENESIS OF
SIGNET COLON CANCER IS LESS
SIGNIFICANT AND THE PRESENCE OF
THE GENE THOUGH PRESENT IS LESS
COMMON IN SIGNET COLON CANCERS
THAN CLASSIC SPORADIC COLON
CANCER.
TO FIRST APPROVXIMATION TO DO
THEY ALL ORIGINATE IN POLYPS,
THEY ARE DO.
TO A MORE GRAND RESPONSE THERE
ARE SOME SPECIFIC EXCEPTIONS TO
THAT GENERALIZATION INCLUDING
COLORECTAL CANCERS THAT ARISE IN
THE SETTING OF ULCERATIVE
COLITIS AND THEY DO TEND TO
ARISE IN A YOUNGER POPULATION
AND INDEED THIS IS A DISEASE
THAT'S BEEN OF INTEREST FOR
LABORATORY AND WE'VE BEEN
SUPPORTED BY A CROWD SOURCE
CONSORTIUM OF FAMILIES WHO HAVE
HAD PATIENTS WITH THESE DISEASE
WITH SIGNIFICANT COLON CANCER
AND THE PATIENTS AS YOUNG AS 14
YEARS OLD SO YOU SEE SHOCKINGLY
YOUNG INDIVIDUALS WITH THIS
DISEASE.
>> THANK YOU.
SO REBECCA, SEVERAL PEOPLE HAVE
BEEN CURIOUS ABOUT WHAT DO YOU
THINK HAPPENED IN 1990 AND HOW
DOES AN EPIDEMIOLOGIST GO ABOUT
TRYING TO SORT OUT POSSIBLE
MECHANISMS TO BE TESTED?
>> IT'S NOT SOMETHING THAT
CHANGED IN THE 1990s BUT THE
MIDDLE OF THE 20th CENTURY.
THAT'S WHEN WE START THE TO SEE
THE ELEVATED RISK.
AND EVEN EARLIER FOR RECTAL
CANCER.
I MEAN, IF WE THINK ABOUT --
THINK ABOUT WHEN I WAS A KID AND
WHAT I WAS EATING FOR DINNER
VERSUS WHAT MOST PEOPLE ARE
EATING FOR DINNER NOW, OUR FOOD
SUPPLY HAS CHANGED TREMENDOUSLY.
MY GUESS IS IT WILL HAVE
SOMETHING TO DO WITH SOMETHING
TH
THAT'S BEING CONSUMED BECAUSE
THAT'S WHAT YOU WOULD THINK OF
WHEN YOU THINK OF THE GUT AND
INFLUENCES THERE.
I THINK IT'S GOING TO REQUIRE A
PROSPECTIVE COHORT SO PEOPLE CAN
BE STUDIED AND FOLLOWED OVER
TIME.
UNFORTUNATELY, MOST COHORTS ARE
OLDER ADULTS.
SO I KNOW THAT THERE IS THERE
ARE NEWER COHORTS JUST BEING
STARTED BUT UNFORTUNATELY THAT
IS GOING TO TAKE A VERY LONG
TIME.
>> WE'VE IDENTIFIED SOMETHING
BUT SO FAR THERE ISN'T
ANYTHING -- I THINK THERE'S SO
MANY MIXED EXPOSURES.
THERE'S SO MUCH GOING ON IN THE
ENVIRONMENT.
WHETHER IT'S PESTICIDES OR
CHANGES IN FOOD AND THE
MICROPLASTIC EXPOSURES.
AUTOPSY STUDIES ARE SHOWING
MICROPLASTICS IN THE BRAIN
BREAKING THROUGH THE BLOOD BRAIN
BARRIER.
IT'S OVERWHELMING TO THINK.
>> I EXPECT PART OF THE
CHALLENGE IS GOING TO BE VERY
OFTEN WHAT ONE IS LOOKING AT IS
THE INTERACTION OF AN
ENVIRONMENTAL EXPOSURE AT A
GENETIC SUSCEPTIBILITY.
IF YOU LOOK AT THE HISTORY OF
SYNDROME, IT WAS ACTUALLY FIRST
DESCRIBED AT THE UNIVERSITY OF
MICHIGAN AT THE TURN OF THE
CENTURY OVER A CENTURY AGO AND
THERE WAS A SEAMSTRESS HE
CHASTISED AND SHE DIED YOUNG AND
WHAT HE DESCRIBED WAS GASTRIC
CANCER.
AND HE DESCRIBED A KINDRED THE
SEAMSTRESS'S KINDRED OF
HEREDITARY CANCER.
THE SAMPLED WERE PRESERVED AT
THE UNIVERSITY OF MICHIGAN AND
THE SEAMSTRESS HAD LYNCH
SYNDROME AND THEY DEVELOPED
GASTRIC NOT COLON CANCER.
CLEARLY A GENETIC SUSCEPTIBILITY
IN THE EXPRESSION AND AT THE
TURN OF THE 20th CENTURY GASTRIC
CANCER WAS COMMON NOT COLON AND
THINGS ARE ASSOCIATED WITH
GASTRIC CANCER.
THERE MAY BE A UBIQUITOUS
ENVIRONMENTAL EXPOSURE FOR THE
ONSET OF EARLY AGE COLORECTAL
CANCER NOW BUT IT'S NOT 100% OF
YOUNG PEOPLE GETTING COLON
CANCER.
IT'S A SMALL SUBSET.
MY GUESS IS THE SMALL SUBSET HAS
A PARTICULAR GENETIC
SUSCEPTIBILITY AND WHATEVER THAT
ENVIRONMENTAL EXPOSURE IS.
THE SAME THING IS TRUE OF
SMOKERS.
IT WAS UBIQUITOUS AND ALL THE
G.I.'S WERE GIVING CIGARETTES
A
AND ABOUT WHAT UNDER LIES THOSE
WHO SMOKED AND DEVELOPED LUNG
CANCER THOSE THAT LIVED TO A
RIPE OLD AGE.
THE EPIDEMIOLOGY WILL NEED TO BE
INFORMED BY SOME SHREWD GUESSES
TO WHAT THE SUSCEPTIBLE
POPULATION LOOKS LIKE.
>> ARE THERE OTHER STUDIES ALONG
BACTERIAL FREE MICE THAT ALSO
HAVE MUTATIONS IN THE TGF BETA
SYSTEM THAT MAY LEND SOME CLUES
AS TO THE ROLE OF THE MICROBIOME
AND THE DEVELOPMENT OF CANCER.
>> THE MICROBIOME PLAYS A
CRUCIAL ROLE IN VIRTUALLY EVERY
MOUSE MODEL.
THE DSS MODEL I PRESENTED IS A
MICROBIOME DEPENDENT MODEL
RAISED IN A GERM-FREE
ENVIRONMENT.
DON'T DEVELOP AND SO THERE HAVE
BEEN A COUPLE OF SPECIES BUGS
AND REASONABLY CONVINCINGLY
ASSOCIATED WITH COLON
CARCINOGENESIS.
THERE ARE STRAINS OF E. COLI
THAT PRODUCE COLOBACTINS AND CAN
DAMAGE DNA AND THE MUTATIONAL
SIGNATURE OF BACTINS ARE
DISTINCT ENOUGH TO BE DETECTED
IN COLON CANCERS BUT WE'RE
TALKING A SMALL SLICE OF PIE.
THERE'S BEEN STUDIES WITH
FUSERBACTERIUM ASSOCIATED AS
BEING INCREASED IN THE
MICROBIOME OF HUMANS WITH COLON
CANCER AND TRANSPLANTED INTO
MICE AND CAN INCREASE THE
INCIDENTS OF TUMORS IN MOUSE
MODELS.
THAT'S MORE OF A CORRELATIVE
DEVELOPMENT WHEN THERE'S NOT A
MUTATIONAL FINGERPRINT SAYING
IT'S NOT JUST THEIR FELLOW
TRAVELLERS THAT LIKE TO GROW ON
TUMORS.
WHAT WE'RE SAYING IS WE KNOW THE
MICROBIOME MATTERS AND HOW IT
WORKS.
>> SO REBECCA, IN YOUR TALK YOU
MENTIONED AS POSSIBLE FACTORS IN
THE DEVELOPMENT OF COLORECTAL
CANCER AND THE EFFECT OF WATER
CONTAMINATION AND ALL SORTS OF
THINGS AND YOU MADE A COMMENT
SHOWING DIFFERENT ARTICLES
PUBLISHED BUT YOU SAID THAT NONE
OF THESE ARE DEFINITIVE.
SO WE HAVE AN INTERESTING
QUESTION, THAT IS WHAT
CONSTITUTES A DEFINITIVE
EPIDEMIOLOGIC STUDY DEALING WITH
ANY OF THESE OR MAYBE IT'S A
GENERAL CONSIDERATION OF
EPIDEMIOLOGY ITSELF.
DO YOU WANT TO INFORM US ABOUT
THAT?
>> I WOULD SAY THAT I MEANT BY
THAT THAT NONE OF THEM ARE FULLY
CONSISTENT WITH THE INCIDENCE
PATTERNS SO SURVEILLANCE OFFERS
CLUES AND WE LOOK AT DIFFERENCES
BY RACE AND ETHNICITY AND ATOMIC
SUBSITE AND BIOLOGICAL CHARA
CHARACTERISTICS AND ALL THESE
THINGS.
THERE HASN'T BEEN ANY STUDY THAT
I'VE SEEN WHERE YOU SAY AHA,
THIS MAKES SENSE AND MAY BE A
COMBINATION OF MANY CONTRIBUTING
FACTORS.
GENETIC SUSCEPTIBILITY IS ALWAYS
ASTOUNDING TO ME THAT ONLY 23%
OF HEAVY SMOKERS DEVELOP LUNG
CANCER DESPITE THE RISK BEING 25
TIMES THAT OF NON-SMOKERS.
IT'S HARD TO WRAP YOUR HEAD
AROUND.
IT'S COMPLICATED.
THAT'S ALL I MEANT FOR THAT IS
IT DOESN'T NECESSARILY FIT ABOUT
WHAT WE KNOW ABOUT THE PATTERNS
WE'RE SEEING.
>> WHY DO YOU THINK CANCERS OF
THE SMALL INTESTINE ARE RARE,
RARE, RARE?
WHEREAS CANCERS OF THE LARGE
INTESTINE AS YOU'VE DESCRIBED
ARE MAJOR HEALTH CHALLENGES.
>> A CLASSIC QUESTION TO WHICH
THERE IS NOT AN ANSWER.
THOUGH THE BACTERIA POPULATION
OF THE SMALL BOWEL IS MUCH
SCANTER THAN IN THE LARGE BOWEL.
WE USED TO THINK THE SMALL BOWEL
IS STERILE, THAT'S NOT THE CASE
BUT HAS A MUCH LOWER MICROBIOME
BOTH NUMERICALLY IN TERMS OF
SPECIES.
IF THERE IS A MICROBIOME
CO-FACTOR IT'S LIKELY MISSING IN
THE SMALL BOWEL.
I DON'T THINK WE UNDERSTAND WHY
ONE ORGAN IS PROTECTED AND THE
OTHER IS NOT.
>> COULD IT BE RELATED TO
CELLULAR TURNOVER RATES?
>> NO, THEY'RE SIMILAR.
>> THERE'S CELLS IN THE LARGE
INTESTINE AND NOT IN THE COLON.
>> REBECCA HOW EFFECTIVE ARE
TESTING THE STOOL FOR BLOOD?
HOW EFFECTIVE IS THAT AS A
SIMPLER PROCEDURE THAN
COLONOSCOPY IN EARLY DETECTION
OF COLON CANCER?
>> IT'S A GREAT QUESTION BECAUSE
THE ABSOLUTE RISK OF DISEASE IN
PEOPLE UNDER 50 IS STILL VERY
LOW.
AND THERE'S AN IMPORTANT OPTION
AND BECAUSE IT'S MORE
CONVENIENCE AND YOU CAN DO IT IN
PRIVATE.
THESE PEOPLE ARE BUSY.
80% OF PEOPLE DIAGNOSED WITH
EARLY ONSET COLORECTAL CANCER
HAVE SMALL CHILDREN SO IT'S A
DIFFERENT POPULATION THAN IT
USED TO BE.
AND IN TERMS OF AND IN TEMS OF
REDUCES DEATHS COMPARABLY IT
DOESN'T REDUCE INCIDENTS IN THE
SAME WAY AS COLONOSCOPY.
ALTHOUGH IT SHOWS A REDUCTION IN
INCIDENTS UP TO 20% FOR STOOL
TESTING.
THE PROBLEM WITH STOOL TESTING
IS IT HAS TO BE DONE ON A
REGULAR BASIS SO IF IT'S A FECAL
BLOOD TEST IT HAS TO BE DONE
ANNUALLY.
IT'S DIFFICULT TO ENSURE PEOPLE
ARE DOING THAT AND THEN IF
THERE'S A POSITIVE TEST IT HAS
TO BE FOLLOWED UP WITH A
COLONOSCOPY.
THERE ARE CHALLENGES BUT THIS IS
HOW THEY SCREEN IN MOST OTHER
COUNTRIES.
THEY USE STOOL TESTING.
SO IT'S EFFECTIVE AND I THINK IT
SHOULD BE GIVEN AS AN OPTION TO
THESE YOUNGER ADULTS ESPECIALLY
WHO DON'T HAVE OTHER RISK
FACTORS.
>> WE HAVE ANOTHER HERE.
DOES YOUR DATA SUGGEST WHAT IS
YOUR DATA SUGGEST AS TO WHETHER
SCREENING COLONOSCOPY IS A GOOD
THING FOR PEOPLE SAY OVER THE
AGE OF I THINK IT WOULD BE 70 OR
75 IN YOUR DATA?
WHEN DO YOU STOP DOING ROUTINE
COLONOSCOPY BASED ON
EPIDEMIOLOGIC DATA?
>> THAT'S A GREAT QUESTION.
THE ACS GUIDELINES DIFFER FROM
THE U.S. GUIDELINE US BECAUSE WE
RECOMMEND PEOPLE SHOULD SCREEN
AS LONG AS THEY HAVE A 10-YEAR
LIFE EXPECTANCY, ARE IN GOOD
HEALTH.
PEOPLE ARE LIVING LONGER AND
IT'S REALLY HARD TO IDENTIFY
THAT CUT POINT.
WHEREAS THE TASK FORCE
RECOMMENDS PEOPLE STOP SCREENING
AT 75.
I THINK IT SHOULD BE AN
INDIVIDUAL CHOICE BETWEEN THE
PATIENT AND THEIR PHYSICIAN.
IT'S A LOT OF SCREENING.
WE HAD SCREENING OVER 75 IN THAT
PREVALENCE FIGURE AND PEOPLE DO
SCREEN AND SO I AM NOT A
SCREENING EFFORT WOULD SAY IT'S
AN INDIVIDUAL CHOICE OVER 75.
>> I CONCUR.
>> SANDY, AS YOU LOOK TO THE
FUTURE, DO YOU SEE PROJECTS LIKE
ALL OF US AND THESE MASSIVE
ACCUMULATION OF SEQUENCE DATA
AND LARGE NUMBERS OF THE
POPULATION?
DO YOU SEE THAT AS A POTENTIAL
WAY FOR IDENTIFYING RISK FACTORS
OVER THE LONG RUN FOR COLON
CANCER?
WHAT IS YOUR -- WHAT COMES NEXT?
>> THERE'S BEEN LARGE NUMBERS OF
GENOME WIDE ASSOCIATION STUDIES
FOR COLON CANCER.
THERE'S TENS OF THOUSANDS OF
INDIVIDUALS WITH RISK ALLELES.
I'M NOT SURE ANY OF IT HAS BEEN
CLINICALLY ACTIONABLE AND MY
GUESS WOULD BE THE POWER OF IT
HAS BEEN RESTRICTED BECAUSE IT
HASN'T BEEN WELL INTEGRATED WITH
THE TYPE OF EPIDEMIOLOGY THAT
REBECCA REPRESENTS.
AND IF YOU WANT TO FIND RISK
FACTORS FOR COLORECTAL CANCER
YOU'LL PROBABLY HAVE TO ANNOTATE
THE DATABASES NOT JUST WITH
GENETIC ALLELES BUT WITH MASSIVE
AMOUNTS OF DEMOGRAPHIC DATA AND
EXPOSURE DATA SO YOU CAN
RECOGNIZE THE PATTERNS.
>> OKAY.
WE'RE ALMOST OUT OF TIME.
>> I THINK WE ARE.
>> WOULD YOU PLEASE HAVE THE
LAST WORD AS TO WHAT YOU SEE ARE
THE CHALLENGES AND WHAT DOES THE
FUTURE HOLD WITH RESPECT
PARTICULARLY WITH EPIDEMIOLOGY
IN THE STUDY OF THIS DISEASE?
>> I THINK THAT THERE SHOULD BE
A LITTLE BIT -- THERE'S A LOT
OF -- IT'S VERY IMPORTANT TO
FOCUS ON RESEARCH AND TRY TO
IDENTIFY THE CAUSE BUT GIVEN ALL
THE CHALLENGES THAT WE'VE
DISCUSSED HERE, I THINK THERE
SHOULD BE A LITTLE MORE EMPHASIS
ON WHAT WE CAN DO NOW.
WE HAVE THIS GROWING BURDEN.
IT'S A VERY UNIQUE PATIENT
POPULATION.
THE WAY THESE PEOPLE ARE BEING
TREATED IS NOT MEETING THEIR
NEEDS.
A LOT OF COLORECTAL PATIENTS
COME OUT OF TREATMENT BEING
INFERTILE AND THERE WAS NO
CONVERSATION ABOUT OPTIONS FOR
PRESERVING FERTILITY.
I THINK IT TYPICALLY IS THIS
WOULD NOT BE A DISEASE OF
SOMEONE CONCERNED ABOUT THEIR
FERTILITY.
I THINK THERE'S A LOT OF GAPS
THAT NEED TO BE CONSIDERED TO
HELP THESE PEOPLE WHO ARE
DEALING WITH THIS NOW.
WHENEVER WE LOOK FOR THE CAUSE
AND PERHAPS SCREENING MORE TOOL
TESTING AND ALSO I THINK STIGMA
IS A HUGE ISSUE.
THAT FAMOUS ACTOR THE BLACK
PANTHER ACTOR I'M FORGETTING HIS
NAME, NO ONE EVEN KNEW HE HAD
COLORECTAL CANCER UNTIL HE
PASSED.
I THINK IF WE COULD TALK ABOUT
THIS MORE LIKE WE'RE DOING TODAY
AND REDUCE THE STIGMA AND TALK
ABOUT SYMPTOMS, YOU KNOW, TALK
ABOUT RECTUM.
IT'S VERY INTERESTING.
WE CAN'T EVEN LOOK AT RECTAL
CANCER DEATHS SEPARATE FROM
COLON CANCER DEATHS BECAUSE
THERE'S SO MUCH
MISCLASSIFICATION BECAUSE FOR
YEARS PEOPLE REFERRED TO
COLORECTAL CANCER AS COLON
CANCER.
AND WE'D GET INQUIRIES FROM
CONSTITUENTS WELL, THE
INFORMATION SAYS COLON CANCER
AND THIS SAYS RECTAL CANCER AND
I DON'T KNOW IF THIS APPLIES TO
ME.
SO A LITTLE IN OUR MESSAGING
COULD GO A LONG WAY AND
CLARIFIES THE ETIOLOGY.
>> LISTEN, WE HAVE REACHED OUR
LIMIT BUT ON BEHALF OF ALL THE
PEOPLE LISTENING AND WE'LL SEND
YOU SOME INFORMATION AS TO HOW
MANY THERE WERE AND WHERE
THEY'RE DOING IT BUT WE WANT TO
REALLY THANK YOU VERY MUCH FOR
BRINGING TO LIGHT SOMETHING THAT
IS INCREASINGLY BECOMING A MORE
SERIOUS PROBLEM PARTICULARLY FOR
YOUNG PEOPLE AND PUTTING THIS IN
THE PERSPECTIVE OF BOTH THE
EPIDEMIOLOGY AND STUDIES OF
BASIC MECHANISMS DERIVED FROM
INHERITABLE DISORDERS PUTS US AT
THE FOREFRONT OF WHERE WE ARE
AND APPRECIATE YOU TAKING THE
TIME TO DO THIS.
THANK YOU AGAIN AND I THINK WE
HAVE TO DISCONNECT AT THIS POINT
AS OUR TIME HAS RUN OUT.