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Hereditary GI Cancer-a Primer Hereditary GI Cancer-a Primer for Medical Oncologistsfor Medical Oncologists
Ophira GinsburgOphira Ginsburg, MD, MSc, FRCPC, MD, MSc, FRCPC
Clinical Lead, Cancer Prevention & ScreeningClinical Lead, Cancer Prevention & Screening
Director Familial OncologyDirector Familial Oncology
Central East Regional Cancer ProgramCentral East Regional Cancer Program
March, 2009March, 2009
ObjectivesObjectives
1.1. HNPCC reviewHNPCC review
Diagnosis, genetic testing, cancer risks, risk Diagnosis, genetic testing, cancer risks, risk reduction strategiesreduction strategies
2.2. Other Hereditary GI syndromes: Other Hereditary GI syndromes:
FAP, AFAP/MAP, HDGCFAP, AFAP/MAP, HDGC
3.3. Criteria for referral to Familial Oncology ProgramsCriteria for referral to Familial Oncology Programs
Hereditary GI CancerHereditary GI Cancer
Examples [gene]Examples [gene]
• HNPCCHNPCC [[MLH1, MSH2, MSH6, PMS2]]
• FAPFAP [[APC]]
• AFAP AFAP [APC, MUTYH1][APC, MUTYH1]
• FHDG FHDG [CDH1][CDH1]
Why do genetic testing?Why do genetic testing?
To To confirmconfirm there is a genetic there is a genetic predisposition to cancer predisposition to cancer
To To predictpredict which family which family members are at increased members are at increased risk of cancerrisk of cancer
To To preventprevent cancer or detect cancer or detect it earlyit early
GENETICS SERVICE
Genetic Counselling Genetic Counselling ProcessProcess
REFERRAL•Triage
•Family hx forms
Chart Prep•Forms received•Pedigree drawn
•Pathology verification
Case conference/Counselling +
Testing (if indicated/accepted)
Result session
•Follow-up apptsarranged
Standard Timeframe6-8 months
Seen <2wksif urgent
Courtesy of Lori Van Manen, 2008
What Happens During a Genetic What Happens During a Genetic Counselling Session?Counselling Session?
Risk AssessmentRisk Assessment Review of hereditary cancerReview of hereditary cancer
Discussions regarding testing:Discussions regarding testing:ProsObtain information about personal riskProvide incentives for surveillanceClarifies uncertaintyPatient empowermentAssists ongoing research
Cons
Inconclusive results (often)
Feelings of guilt or anxiety
Family tensions
Ethical issues
Insurance issues
Decreased compliance with screening
History of Familial Oncology History of Familial Oncology ProgramsPrograms
1995: counselling and genetic testing became 1995: counselling and genetic testing became available through research in 1995available through research in 1995 . .
2001: Ministry of Health established recommended 2001: Ministry of Health established recommended referral and testing criteria, and began funding referral and testing criteria, and began funding BRCA1/2 testing.BRCA1/2 testing.
Since 2001: HNPCC counselling/testing fundedSince 2001: HNPCC counselling/testing funded BUT. Local estimates of uptake/referrals given 5-10% CRC BUT. Local estimates of uptake/referrals given 5-10% CRC caused by HNPCC, ~ 20-25% CRC incident cases *should* caused by HNPCC, ~ 20-25% CRC incident cases *should* be referred. Est: 10% capture so farbe referred. Est: 10% capture so far
CRCCRC
Lynch Syndrome in Lynch Syndrome in Family “G”Family “G”
Dr. Aldred Scott Warthin, MD, PhD described Dr. Aldred Scott Warthin, MD, PhD described “Family G” in a 1913 publication based on “Family G” in a 1913 publication based on records ascertained from the University of records ascertained from the University of Michigan hospitals between 1895 and 1913.Michigan hospitals between 1895 and 1913.
““Of the 48 descendants of the cancerous Of the 48 descendants of the cancerous grandfather, 17 have died or been operated grandfather, 17 have died or been operated on for cancer. The preponderance of on for cancer. The preponderance of carcinoma of the uterus (ten cases) and of the carcinoma of the uterus (ten cases) and of the stomach (seven cases) is very striking in the stomach (seven cases) is very striking in the family history” Dr. Warthin, 1913.family history” Dr. Warthin, 1913.
Douglas et al. (2005) History of Molecular Genetics of Lynch Syndrome in Family G; JAMA; Vol. 294 (17), 2195-2202
Progenitorsite unknown
d. 60y
B
d. 64yStomach
H
d. 60yStomach
F
d. 55yColon, NOS
G
d. 42yRectum
A
d. 47ySite Unknown
C
d. 84y
E
d. 63y
I
d. 55yUterus, NOS
D
d. 26y
Why HNPCC is importantWhy HNPCC is important
HNPCC/Lynch syndrome- 3 to 5 times HNPCC/Lynch syndrome- 3 to 5 times more common than FAPmore common than FAP
Harder to diagnose: many non CRC Harder to diagnose: many non CRC tumours, families with more “other tumours, families with more “other tumours” than colorectaltumours” than colorectal
potential for 1potential for 1 or 2 or 2 prevention of prevention of other HNCC cancers: endometrial, other HNCC cancers: endometrial, urothelial, ovarian?urothelial, ovarian?
HNPCC -CRC Unique HNPCC -CRC Unique FeaturesFeatures
Colorectal cancer: Colorectal cancer: • 70% right sided distribution70% right sided distribution• Synchronous, metachronous Synchronous, metachronous
primariesprimaries• Pathology: mucinous, poorly Pathology: mucinous, poorly
differentiated, peri-tumoural differentiated, peri-tumoural lymphocytic infiltrationlymphocytic infiltration
• Prognosis: ?Prognosis: ?• Response to chemo?Response to chemo?
Cancer General Population Risk
HNPCC
Risks Mean Age of Onset
Colon 5.5% 80% 44 years
Endometrium 2.7% 20-60% 46 years
Stomach < 1% 11-19% 56 years
Ovary 1.6% 9-12% 42.5 years
Hepatobiliary tract < 1% 2-7% Not reported
Urinary tract < 1% 4-5% ~ 55 years
Small bowel < 1% 1-4% 49 years
Brain/central nervous system < 1% 1-3% ~ 50 years
Cancer risk (%) by age 70
Type of Cancer MLH1 MSH2 MSH6
CRC
Female
71
39Lower than
MLH1/MSH2Male 96
Endometrium 42 61 Higher than MLH1/MSH2
Ovary 3.4 10.4 specific risk unknown
Stomach 2.1 4.3 specific risk unknown
Small bowel 7.2 4.5 specific risk unknown
Urinary Tract 1.3 12 specific risk unknown
OtherExtracolonic- 11 Extracolonic -48
specific risk unknown
Family History in HNPCC-Family History in HNPCC-more than meets the eyemore than meets the eye
Lynch and de la Chapelle
HNPCC-criteria for testing-HNPCC-criteria for testing-beyondbeyond Amsterdam* Amsterdam*
Revised AmsterdamRevised Amsterdam (ICG-HNPCC, (ICG-HNPCC, 1999)1999)
o 3 relatives with CRC or assoc 3 relatives with CRC or assoc ca (uterine, small bowel, ca (uterine, small bowel, ureter, renal pelvis)ureter, renal pelvis)
o 11stst degree of the other 2 degree of the other 2o 2 successive generations2 successive generationso 1 before age 501 before age 50o Histological verificationHistological verification
Revised BethesdaRevised Bethesda (Umar et al, (Umar et al, 2004)2004)
o CRC in pt under 50CRC in pt under 50o Synch/metachronous, or Synch/metachronous, or
other associated caother associated cao CRC with MSI under 60CRC with MSI under 60o CRC with one or more 1CRC with one or more 1stst
degree relative (under 50)degree relative (under 50)o CRC with 2 or more 1CRC with 2 or more 1stst/ 2nd / 2nd
degree relative (any age)degree relative (any age)
50% by mutation analysis 15% by mutation analysis*R/O *R/O FAPFAP
2 main classes of CRC: 2 main classes of CRC: different models of different models of
tumourigenesistumourigenesis Chromosomal instability: 85% distal; Chromosomal instability: 85% distal;
aneuploid; APC, p53 K-Ras mutations; aneuploid; APC, p53 K-Ras mutations; more aggressive; prototype FAPmore aggressive; prototype FAP““APC= the gatekeeper of CRC”APC= the gatekeeper of CRC”
Microsatellite instability: 15%Microsatellite instability: 15% proximal: diploid; MSI, MMR proximal: diploid; MSI, MMR
mutations; mutations; less aggressive?, prototype HNPCCless aggressive?, prototype HNPCC
““MMR genes = caretakers of CRC” MMR genes = caretakers of CRC”
Genetic Testing in Genetic Testing in HNPCCHNPCC
MSI- microsatellite instability MSI- microsatellite instability (tumour)(tumour)
IHC- immunohistochemistry (tumour)IHC- immunohistochemistry (tumour)
Germ-line DNA for mutations in one of Germ-line DNA for mutations in one of 3 genes (MLH1, MSH2, MSH6) PMS2 3 genes (MLH1, MSH2, MSH6) PMS2 Amsterdam or research labAmsterdam or research lab
Microsatellite instabilityMicrosatellite instability
hallmark of tumours in HNPCChallmark of tumours in HNPCC Microsatellites: genomic regions Microsatellites: genomic regions
with repetitive short DNA sequences with repetitive short DNA sequences (often single nucleotides) (often single nucleotides)
prone to mutation during DNA prone to mutation during DNA replicationreplication
Results in elongation or contraction Results in elongation or contraction = instability= instability
Microsatellite InstabilityMicrosatellite Instability
• When DNA polymerase inserts the When DNA polymerase inserts the wrong bases in newly synthesized wrong bases in newly synthesized DNA, the “mismatch repair” DNA, the “mismatch repair” enzymes repair the mistakeenzymes repair the mistake
• Defects in mismatch repair genes Defects in mismatch repair genes (MLH1, MSH2, MLH6) lead to the (MLH1, MSH2, MLH6) lead to the mutator phenotype: high frequency mutator phenotype: high frequency microsatellite instability or “MSI-H”microsatellite instability or “MSI-H”
Gryfe et al, NEJM 2000
NEJM May 5,2005 Hampel et al
HNPCC: Risk Reduction HNPCC: Risk Reduction OptionsOptions
ColorectalColorectal Unaffected: colonoscopy to cecum q Unaffected: colonoscopy to cecum q
1-2 years1-2 years Affected w CRC: consider subtotal Affected w CRC: consider subtotal
colectomy at 1colectomy at 1stst diagnosis d/t risk of diagnosis d/t risk of 22ndnd primaries primaries
http://www.nccn.org/professionals/physician_gls/PDF/colorectal_screening.pdfhttp://www.nccn.org/professionals/physician_gls/PDF/colorectal_screening.pdf
Seminars in Oncology, Oct 2007
HNPCC: Risk Reduction HNPCC: Risk Reduction Gynecological CancersGynecological Cancers
Screening for ovarian caScreening for ovarian ca: CA125 + TVUS: CA125 + TVUS
jury still out- jury still out- Lancet Oncology online Mar 09Lancet Oncology online Mar 09
Screening for endometrial ca:Screening for endometrial ca:
annual TVUS + random endometrial bx (age annual TVUS + random endometrial bx (age 30+)30+)
few studies: review few studies: review Lindor et al, JAMA 2006Lindor et al, JAMA 2006
See also current NCCN guidelinesSee also current NCCN guidelines
Surgical Options for Gyne CaSurgical Options for Gyne Ca
Prophylactic BSOProphylactic BSO
Ovarian/FT risk reduction > 80-90% Ovarian/FT risk reduction > 80-90%
nb/ primary peritoneal carcinomatosis ~5-7%)nb/ primary peritoneal carcinomatosis ~5-7%)
Prophylactic TAH/BSOProphylactic TAH/BSO
-less studied but likely >90% RR for endometrial -less studied but likely >90% RR for endometrial ca in HNPCC mutation carriersca in HNPCC mutation carriers
Recent meta-analysis for HBOC (BRCA carriers) : J Natl Cancer Inst. 2009;101(2):80-87
HNPCC Colorectal Ca HNPCC Colorectal Ca PrognosisPrognosis
many studies: stage-for-stage many studies: stage-for-stage survival advantage in HNPCC-CRCsurvival advantage in HNPCC-CRC
landmark paper: landmark paper: Gryfe (NEJM 2000):Gryfe (NEJM 2000):• 607 consecutive cases CRC <age 50607 consecutive cases CRC <age 50• 17% had MSI-H17% had MSI-H• Multivariate analysis showed a sigificant Multivariate analysis showed a sigificant
survival advantage for MSI-H patients survival advantage for MSI-H patients versus MSS, independent of ALL other versus MSS, independent of ALL other prognostic factors.prognostic factors.
The “atypical family The “atypical family history”history”
Families w multiple cases of non-CRC Families w multiple cases of non-CRC HNPCC- associated cancersHNPCC- associated cancers
*GU-TCC renal pelvis, bladder, ovarian, *GU-TCC renal pelvis, bladder, ovarian, squamous cell endometrial, no colorectal squamous cell endometrial, no colorectal cancer in “line of fire” + mutation MSH2cancer in “line of fire” + mutation MSH2
Are the carriers at Are the carriers at risk of colorectal ca?risk of colorectal ca?
YES, and should be screened appropriatelyYES, and should be screened appropriately
+1927
80TAH @ 41
transitional cell ca of Rt. ureter, dx. 60Stage 1C ovarian ca, dx. 67 - tx with BSO + adjuvant chemo
peritoneal recurrence - transitional cell ca dx 74
1925d. 59
colon cadx. 56
12/17/195254
+1945
60endometrial ca; dx. 52
MSI + IHC testing 2002 - unstable at BAT26DNA Sequencing 2004 - MSH2 mut. +ve
+1961
44squamous cell carcinoma
dx. 38Rt. shoulder
(Growing like keratoacanthoma)
1/16/1899d. 49
ovarian ca; dx. 46
12/1/193166
pancreatic cadx. 68
d. 33appendix ruptured
d. 84
27 31 34 10 8
34 36
5
no info bladder ca COD unknown
ca, type unknown
28
12/20/1899d. 49
PA
PA
PA
d. 82 d. 62colon ca dx. 55
uterine ca? or kidney ca?
d. 60colon ca dx. 59
d. 77colon ca dx. 77
d. stroke
+
d. 77uterine ca dx. ?
MSH2 +ve
n
4/5/1925 - ?d. 71
colorectal ca (3 sep primaries)dx. 55, 62, 69
?
195048
19
195642
MLH1 +ve
11/27/196038
1924 - ?d. 68
stroke
PApresumed MLH1 carrier
2
1921 - ?77
endometrial cadx. 53
colon cadx. 77
d. 45stroke
bowel problems
d. 64
colon cadx. 70-Toronto
80's 70-80
d. 48colon cadx. 45
MSI unstable at Bat26 locusIHC deficiency on MLH1
d. 33rectal cadx. 26
46France
44colonoscopy
4548 44
3
2
16-25 16-25
2
15-21
3
15-21
195642
MLH1 +ve
11/27/196038
11/10/199214
198719
3/12/199710
1924 - ?d. 68stroke
PA
PA
PA PA
presumed MLH1 carrier
FAP- prototype for FAP- prototype for hereditary cancerhereditary cancer
100s to 1000s of adenomatous 100s to 1000s of adenomatous polyps throughout colon & rectumpolyps throughout colon & rectum
100% penetrance without surgery100% penetrance without surgery Very early age of onset (polyposis by Very early age of onset (polyposis by
20’s most ca by 40s)20’s most ca by 40s) APC gene chromosome 5APC gene chromosome 5
Risk-reducing surgery in FAPRisk-reducing surgery in FAP
Sigmoidoscopy: q1-2 ~ age 10-12, genetic testing
Colonoscopy: once polyps + annually if colectomy is delayed more than one year
Prophylactic Colectomy: recommended- TPC, IRA, IPAA (ileal pouch)
Follow-up screening is necessary
JCO Oct 1, 2006 ASCO reviewJCO Oct 1, 2006 ASCO review::
FAP- DesmoidsFAP- Desmoids12-17% of FAP patients12-17% of FAP patients• Intra-abdominal 80%, small bowel mesentery Intra-abdominal 80%, small bowel mesentery
>50% (present w SBO)>50% (present w SBO)• Genotype: APC mutation b/w codons 1310-2011Genotype: APC mutation b/w codons 1310-2011• Tend to occur AFTER surgery, high RR, high Tend to occur AFTER surgery, high RR, high
morbiditymorbidity
• RxRx: : sxsx for small, well defined desmoids; for small, well defined desmoids; TamoxifenTamoxifen, , chemochemo: vinblastine, MTX (RR 40-: vinblastine, MTX (RR 40-50%) or for rapidly progressive desmoids per 50%) or for rapidly progressive desmoids per sarcoma protocol (adriamycin, dacarbazine)sarcoma protocol (adriamycin, dacarbazine)
Upper GI tumours Upper GI tumours • 80-90% FAP mutation carriers have 80-90% FAP mutation carriers have
duodenal or periampullary polyps, of duodenal or periampullary polyps, of whichwhich
• 36% will develop advanced polyposis36% will develop advanced polyposis• 3-5% will develop invasive carcinoma3-5% will develop invasive carcinoma• Surveillance: side-viewing endoscopy Surveillance: side-viewing endoscopy
+ bx suspicious polyps @ 25-30 yrs+ bx suspicious polyps @ 25-30 yrs• Polypectomy for high-grade dysplasia, Polypectomy for high-grade dysplasia,
villous changes, ulceration, > 1 cm villous changes, ulceration, > 1 cm sizesize
FAP-other tumoursFAP-other tumours
chemoprevention?chemoprevention?
• NSAIDS: level 1 evidenceNSAIDS: level 1 evidence
sulindac, celecoxib, rofecoxib shown to sulindac, celecoxib, rofecoxib shown to reduce # polyps in FAP, but not proven reduce # polyps in FAP, but not proven to reduce cancer incidence or mortalityto reduce cancer incidence or mortality
** long term use as an ** long term use as an alternative alternative to sx to sx is NOT recommended + adverse is NOT recommended + adverse effectseffects
• CalciumCalcium• HRTHRT
FAP: natural history—FAP: natural history—revisedrevised
Due to improved diagnosis, and Due to improved diagnosis, and prevention/screening for CRC, prevention/screening for CRC, periampullary cancer and desmoids periampullary cancer and desmoids have become the leading causes of have become the leading causes of death for FAP(APC) mutation death for FAP(APC) mutation carrierscarriers
Other Polyposis Other Polyposis SyndromesSyndromes
AFAP-attenuated familial polyposisAFAP-attenuated familial polyposis
10-100 polyps, proximal location, later age of onset 10-100 polyps, proximal location, later age of onset
((1307K allele ~ 6% Ashkenazi Jews, 2x CRC1307K allele ~ 6% Ashkenazi Jews, 2x CRC risk) risk)
MUTYH1 mutations: “MAP” recessive MUTYH1 mutations: “MAP” recessive inheritanceinheritance
-7.5 % of pts w classical phenotype -7.5 % of pts w classical phenotype but APC but APC --
J. Jass. Pathology Res & Practice (2008) 204: 431-447J. Jass. Pathology Res & Practice (2008) 204: 431-447
Attenuated FAPAttenuated FAP
““MAP” MYH-associated MAP” MYH-associated polyposis colipolyposis coli
Nielsen et al, Journal of Medical Genetics 2005
Hereditary Diffuse Gastric Hereditary Diffuse Gastric CancerCancer
E-cadherin CDH1 geneE-cadherin CDH1 gene 70% risk of diffuse gastric ca70% risk of diffuse gastric ca 40% risk of lobular breast ca40% risk of lobular breast ca Prophylactic total gastrectomyProphylactic total gastrectomy ?screening chromoendoscopy?screening chromoendoscopy
Lynch et al, Cancer 2008 Jun 15;112(12):2655-63Lynch et al, Cancer 2008 Jun 15;112(12):2655-63
ObjectivesObjectives
HNPCC reviewHNPCC review
Diagnosis, genetic testing, cancer risks, risk Diagnosis, genetic testing, cancer risks, risk reduction strategiesreduction strategies
Other Hereditary GI syndromes: Other Hereditary GI syndromes:
FAP, AFAP/MAP, HDGCFAP, AFAP/MAP, HDGC
Criteria for referral to Familial Oncology ProgramsCriteria for referral to Familial Oncology Programs