Presentation on theme: "Hereditary GI Cancer-a Primer for Medical Oncologists"— Presentation transcript:
1 Hereditary GI Cancer-a Primer for Medical Oncologists Ophira Ginsburg, MD, MSc, FRCPCClinical Lead, Cancer Prevention & ScreeningDirector Familial OncologyCentral East Regional Cancer ProgramMarch, 2009
2 Objectives HNPCC review Diagnosis, genetic testing, cancer risks, risk reduction strategiesOther Hereditary GI syndromes:FAP, AFAP/MAP, HDGCCriteria for referral to Familial Oncology Programs
3 Hereditary GI Cancer Examples [gene] HNPCC [MLH1, MSH2, MSH6, PMS2] FAP [APC]AFAP [APC, MUTYH1]FHDG [CDH1]
4 Why do genetic testing?To confirm there is a genetic predisposition to cancerTo predict which family members are at increased risk of cancerTo prevent cancer or detect it early
6 Genetic Counselling Process StandardTimeframe6-8 monthsSeen <2wksif urgentCourtesy of Lori Van Manen, 2008
7 What Happens During a Genetic Counselling Session? Risk AssessmentReview of hereditary cancerDiscussions regarding testing:ProsObtain information about personal riskProvide incentives for surveillanceClarifies uncertaintyPatient empowermentAssists ongoing researchConsInconclusive results (often)Feelings of guilt or anxietyFamily tensionsEthical issuesInsurance issuesDecreased compliance with screening
8 History of Familial Oncology Programs 1995: counselling and genetic testing became available through research in 1995.2001: Ministry of Health established recommended referral and testing criteria, and began funding BRCA1/2 testing.Since 2001: HNPCC counselling/testing fundedBUT. Local estimates of uptake/referrals given 5-10% CRC caused by HNPCC, ~ 20-25% CRC incident cases *should* be referred. Est: 10% capture so far
10 Lynch Syndrome in Family “G” Dr. Aldred Scott Warthin, MD, PhD described “Family G” in a 1913 publication based on records ascertained from the University of Michigan hospitals between 1895 and 1913.“Of the 48 descendants of the cancerous grandfather, 17 have died or been operated on for cancer. The preponderance of carcinoma of the uterus (ten cases) and of the stomach (seven cases) is very striking in the family history” Dr. Warthin, 1913.One of the longest family cancer histories ever recorded of a Lynch-syndrome family was reported nearly 100 years ago by Dr. Aldred Scott Warthin. He reviewed the medical histories of cancer patients treated at the University of Michigan hospitals between 1895 and He published his findings on “Family G” - a family characterized at the time by a distinct susceptibility to cancer of the uterus and stomach.Family ‘G’ started with a man born in Plattenhardt, Germany in 1796 and who subsequently immigrated to the US in He had 9 children. As of 2005, 929 known descendants of the original progenitor have been reportedDr. Warthin first published his findings in 1913 – this excerpt was taken from the publication:“Of the 48 descendants of the cancerous grandfather, 17 have died or been operated on for cancer. The preponderance of carcinoma of the uterus (ten cases) and of the stomach (seven cases) is very striking in the family history”Douglas et al. (2005) History of Molecular Genetics of Lynch Syndrome in Family G; JAMA; Vol. 294 (17),
11 Why HNPCC is importantHNPCC/Lynch syndrome- 3 to 5 times more common than FAPHarder to diagnose: many non CRC tumours, families with more “other tumours” than colorectalpotential for 1 or 2 prevention of other HNCC cancers: endometrial, urothelial, ovarian?
12 HNPCC -CRC Unique Features Colorectal cancer:70% right sided distributionSynchronous, metachronous primariesPathology: mucinous, poorly differentiated, peri-tumoural lymphocytic infiltrationPrognosis: ?Response to chemo?
13 General Population Risk CancerGeneral Population RiskHNPCCRisksMean Age of OnsetColon5.5%80%44 yearsEndometrium2.7%20-60%46 yearsStomach< 1%11-19%56 yearsOvary1.6%9-12%42.5 yearsHepatobiliary tract2-7%Not reportedUrinary tract4-5%~ 55 yearsSmall bowel1-4%49 yearsBrain/central nervous system1-3%~ 50 years
14 Cancer risk (%) by age 70 CRC 71 39 96 Endometrium 42 61 Ovary 3.4 Type of CancerMLH1MSH2MSH6CRCFemale7139Lower than MLH1/MSH2Male96Endometrium4261Higher than MLH1/MSH2Ovary3.410.4specific risk unknownStomach2.14.3Small bowel7.24.5Urinary Tract1.312OtherExtracolonic- 11Extracolonic -48
15 Family History in HNPCC-more than meets the eye Lynch and de la Chapelle
18 HNPCC-criteria for testing- beyond Amsterdam* Revised Amsterdam (ICG-HNPCC, 1999)3 relatives with CRC or assoc ca (uterine, small bowel, ureter, renal pelvis)1st degree of the other 22 successive generations1 before age 50Histological verificationRevised Bethesda (Umar et al, 2004)CRC in pt under 50Synch/metachronous, or other associated caCRC with MSI under 60CRC with one or more 1st degree relative (under 50)CRC with 2 or more 1st/ 2nd degree relative (any age)50% by mutation analysis15% by mutation analysis*R/O FAP
19 2 main classes of CRC: different models of tumourigenesis Chromosomal instability: 85% distal; aneuploid; APC, p53 K-Ras mutations; more aggressive; prototype FAP“APC= the gatekeeper of CRC”Microsatellite instability: 15%proximal: diploid; MSI, MMR mutations;less aggressive?, prototype HNPCC“MMR genes = caretakers of CRC”
23 Microsatellite instability hallmark of tumours in HNPCCMicrosatellites: genomic regions with repetitive short DNA sequences (often single nucleotides)prone to mutation during DNA replicationResults in elongation or contraction = instability
24 Microsatellite Instability When DNA polymerase inserts the wrong bases in newly synthesized DNA, the “mismatch repair” enzymes repair the mistakeDefects in mismatch repair genes (MLH1, MSH2, MLH6) lead to the mutator phenotype: high frequency microsatellite instability or “MSI-H”
28 HNPCC: Risk Reduction Options Colorectal Unaffected: colonoscopy to cecum q 1-2 yearsAffected w CRC: consider subtotal colectomy at 1st diagnosis d/t risk of 2nd primariesSeminars in Oncology, Oct 2007
29 HNPCC: Risk Reduction Gynecological Cancers Screening for ovarian ca: CA125 + TVUSjury still out- Lancet Oncology online Mar 09Screening for endometrial ca:annual TVUS + random endometrial bx (age 30+)few studies: review Lindor et al, JAMA 2006See also current NCCN guidelines
30 Surgical Options for Gyne Ca Prophylactic BSOOvarian/FT risk reduction > 80-90%nb/ primary peritoneal carcinomatosis ~5-7%)Prophylactic TAH/BSO-less studied but likely >90% RR for endometrial ca in HNPCC mutation carriersRecent meta-analysis for HBOC (BRCA carriers) : J Natl Cancer Inst. 2009;101(2):80-87
32 HNPCC Colorectal Ca Prognosis many studies: stage-for-stage survival advantage in HNPCC-CRClandmark paper: Gryfe (NEJM 2000):607 consecutive cases CRC <age 5017% had MSI-HMultivariate analysis showed a sigificant survival advantage for MSI-H patients versus MSS, independent of ALL other prognostic factors.
33 The “atypical family history” Families w multiple cases of non-CRC HNPCC- associated cancers*GU-TCC renal pelvis, bladder, ovarian, squamous cell endometrial, no colorectal cancer in “line of fire” + mutation MSH2Are the carriers at risk of colorectal ca?YES, and should be screened appropriately
35 This is one of our Muir-torre families: The mother was referred in 1998 but it was the son who was interested in knowing whether or not the cancers were genetic. Although the family was worked up, no testing was done, although blood had been banked in 1999 and tumour tissue testing was requested in The son was referred directly in 2001 with a newly diagnosed squamous cell carcinoma of the right chest wall. Mother had a transitional cell carcinoma of the renal pelvis at age 60, a Stage 1 ovarian cancer at age 67, and a recurrence of her transitional cell ca in the ureter last year. Proband’s sister had an endometrioid endometrial carcinoma at age 52, treated by TAH and BSO, and this person is currently well. Maternal uncle had pancreatic ca at age 66 and maternal grandmother had ovarian cancer at age 46 and died at age 49. This individual’s sister had bladder cancer, the details of which are unknown. Incidentally, the only case of colon cancer in a relative of the proband is in his father, who had the disease at age 56. He does not have a strong family history to suggest any cancer syndrome, however. Our proband’s sister had MSI/IHC testing and on subsequent germline analysis was found to carry an MSH2 mutation. Mother is a confirmed to be a carrier, as is the other sister.This family took 8 years to work up from the time of referral
38 Some families with Lynch Syndrome present with later onset CRC and may be missed by our current guidelines for genetic testing – guidelines are subject to interpretation and offer we will consider doing MSI/IHC on borderline-eligible families.This proband was referred to us in 1999 and received counseling. At the time testing was offered to the family through paternal aunt (I believe MSI/IHC testing was done on her father’s tumour first). Subsequently, an MSH2 mutation was found. In the meantime, some maternal relatives were part of the OFCCR in Toronto and appeared that the maternal family history was also concerning for HNPCC. Therefore, in 2005 at the request of our proband, germline testing was initiated for the known paternal MSH2 mutation in herself, and MSI/IHC testing was initiated on her maternal cousin(s) with CRC (next slide).
39 The first tumour accessed was on the 26 year old dx with rectal cancer at the age of 26. Unfortunately no tumour tissue was available. So, we accessed the tumour tissue of the brother and it showed a deficiency on MLH1. Therefore, we did germline sequencing of the MLH1 gene on our proband in addition to MSH2 carrier testing and voila – and MLH1 mutation was confirmed. Therefore, both of her parents had Lynch Syndrome – different genes involved. This means that our proband’s brother would have a 75% chance of inheriting one, or both of the mutations.Management is a big issue – particularly where the onset of cancers are early. We do not usually test children or adolescents for hereditary adult-onset cancer syndromes, however, the youngest age reported for colon cancer in such a family is 13. In this family, it is 26, so we would start screening with colonoscopy at age 16 and suggest that this be repeated every 1-2 years.This family took about 10 years to work up, and a few genetic counselling centres were involved.
41 FAP- prototype for hereditary cancer 100s to 1000s of adenomatous polyps throughout colon & rectum100% penetrance without surgeryVery early age of onset (polyposis by 20’s most ca by 40s)APC gene chromosome 5
42 Risk-reducing surgery in FAP Sigmoidoscopy: q1-2 ~ age 10-12, genetic testingColonoscopy: once polyps + annually if colectomy is delayed more than one yearProphylactic Colectomy: recommended- TPC, IRA, IPAA (ileal pouch)Follow-up screening is necessaryJCO Oct 1, 2006 ASCO review:
43 FAP- Desmoids 12-17% of FAP patients Intra-abdominal 80%, small bowel mesentery >50% (present w SBO)Genotype: APC mutation b/w codonsTend to occur AFTER surgery, high RR, high morbidityRx: sx for small, well defined desmoids; Tamoxifen, chemo: vinblastine, MTX (RR 40-50%) or for rapidly progressive desmoids per sarcoma protocol (adriamycin, dacarbazine)
44 FAP-other tumours Upper GI tumours 80-90% FAP mutation carriers have duodenal or periampullary polyps, of which36% will develop advanced polyposis3-5% will develop invasive carcinomaSurveillance: side-viewing endoscopy + bx suspicious yrsPolypectomy for high-grade dysplasia, villous changes, ulceration, > 1 cm size
45 chemoprevention? NSAIDS: level 1 evidence sulindac, celecoxib, rofecoxib shown to reduce # polyps in FAP, but not proven to reduce cancer incidence or mortality** long term use as an alternative to sx is NOT recommended + adverse effectsCalciumHRT
46 FAP: natural history—revised Due to improved diagnosis, and prevention/screening for CRC, periampullary cancer and desmoids have become the leading causes of death for FAP(APC) mutation carriers
47 Other Polyposis Syndromes AFAP-attenuated familial polyposispolyps, proximal location, later age of onset(1307K allele ~ 6% Ashkenazi Jews, 2x CRC risk)MUTYH1 mutations: “MAP” recessive inheritance-7.5 % of pts w classical phenotype but APC -J. Jass. Pathology Res & Practice (2008) 204:
49 “MAP” MYH-associated polyposis coli Nielsen et al, Journal of Medical Genetics 2005
50 Hereditary Diffuse Gastric Cancer E-cadherin CDH1 gene70% risk of diffuse gastric ca40% risk of lobular breast caProphylactic total gastrectomy?screening chromoendoscopyLynch et al, Cancer 2008 Jun 15;112(12):
51 Objectives HNPCC review Diagnosis, genetic testing, cancer risks, risk reduction strategiesOther Hereditary GI syndromes:FAP, AFAP/MAP, HDGCCriteria for referral to Familial Oncology Programs
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