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Hereditary GI Cancer-a Primer for Medical Oncologists Ophira Ginsburg, MD, MSc, FRCPC Clinical Lead, Cancer Prevention & Screening Director Familial Oncology.

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Presentation on theme: "Hereditary GI Cancer-a Primer for Medical Oncologists Ophira Ginsburg, MD, MSc, FRCPC Clinical Lead, Cancer Prevention & Screening Director Familial Oncology."— Presentation transcript:

1 Hereditary GI Cancer-a Primer for Medical Oncologists Ophira Ginsburg, MD, MSc, FRCPC Clinical Lead, Cancer Prevention & Screening Director Familial Oncology Central East Regional Cancer Program March, 2009

2 Objectives 1. HNPCC review Diagnosis, genetic testing, cancer risks, risk reduction strategies 2. Other Hereditary GI syndromes: FAP, AFAP/MAP, HDGC 3. Criteria for referral to Familial Oncology Programs

3 Hereditary GI Cancer Examples [gene] HNPCC [] HNPCC [MLH1, MSH2, MSH6, PMS2] FAP [] FAP [APC] AFAP [APC, MUTYH1] AFAP [APC, MUTYH1] FHDG [CDH1] FHDG [CDH1]

4 Why do genetic testing?  To confirm there is a genetic predisposition to cancer  To predict which family members are at increased risk of cancer  To prevent cancer or detect it early

5 GENETICS SERVICE

6 Genetic Counselling Process REFERRAL Triage Family hx forms Chart Prep Forms received Pedigree drawn Pathology verification Case conference/ Counselling + Testing (if indicated /accepted) Result session Follow-up appts arranged Standard Timeframe 6-8 months Seen <2wks if urgent Courtesy of Lori Van Manen, 2008

7 What Happens During a Genetic Counselling Session?  Risk Assessment  Review of hereditary cancer  Discussions regarding testing: Pros Obtain information about personal risk Provide incentives for surveillance Clarifies uncertainty Patient empowerment Assists ongoing research Cons Inconclusive results (often) Feelings of guilt or anxiety Family tensions Ethical issues Insurance issues Decreased 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 funded BUT. 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

9 CRC

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. 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. Douglas et al. (2005) History of Molecular Genetics of Lynch Syndrome in Family G; JAMA; Vol. 294 (17), 2195-2202

11 Why HNPCC is important  HNPCC/Lynch syndrome- 3 to 5 times more common than FAP  Harder to diagnose: many non CRC tumours, families with more “other tumours” than colorectal  potential for 1  or 2  prevention of other HNCC cancers: endometrial, urothelial, ovarian?

12 HNPCC -CRC Unique Features Colorectal cancer: 70% right sided distribution 70% right sided distribution Synchronous, metachronous primaries Synchronous, metachronous primaries Pathology: mucinous, poorly differentiated, peri- tumoural lymphocytic infiltration Pathology: mucinous, poorly differentiated, peri- tumoural lymphocytic infiltration Prognosis: ? Prognosis: ? Response to chemo? Response to chemo?

13 Cancer General Population Risk HNPCC RisksMean 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

14 Cancer risk (%) by age 70 Type of CancerMLH1MSH2MSH6 CRC Female 71 39 Lower than MLH1/MSH2 Male 96 Endometrium 4261 Higher than MLH1/MSH2 Ovary3.4 10.4 specific risk unknown Stomach 2.1 4.3 specific risk unknown Small bowel7.24.5 specific risk unknown Urinary Tract 1.3 12 specific risk unknown Other Extracolonic- 11Extracolonic -48 specific risk unknown

15 Family History in HNPCC- more than meets the eye Lynch and de la Chapelle

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18 HNPCC-criteria for testing- beyond Amsterdam* Revised Amsterdam (ICG-HNPCC, 1999) o 3 relatives with CRC or assoc ca (uterine, small bowel, ureter, renal pelvis) o 1 st degree of the other 2 o 2 successive generations o 1 before age 50 o Histological verification Revised Bethesda (Umar et al, 2004) o CRC in pt under 50 o Synch/metachronous, or other associated ca o CRC with MSI under 60 o CRC with one or more 1 st degree relative (under 50) o CRC with 2 or more 1 st / 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; proximal: diploid; MSI, MMR mutations; less aggressive?, prototype HNPCC less aggressive?, prototype HNPCC “MMR genes = caretakers of CRC”

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21 Genetic Testing in HNPCC  MSI- microsatellite instability (tumour)  IHC- immunohistochemistry (tumour)  Germ-line DNA for mutations in one of 3 genes (MLH1, MSH2, MSH6) PMS2 Amsterdam or research lab

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23 Microsatellite instability  hallmark of tumours in HNPCC  Microsatellites: genomic regions with repetitive short DNA sequences (often single nucleotides)  prone to mutation during DNA replication  Results 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 mistake When DNA polymerase inserts the wrong bases in newly synthesized DNA, the “mismatch repair” enzymes repair the mistake Defects in mismatch repair genes (MLH1, MSH2, MLH6) lead to the mutator phenotype: high frequency microsatellite instability or “MSI-H” Defects in mismatch repair genes (MLH1, MSH2, MLH6) lead to the mutator phenotype: high frequency microsatellite instability or “MSI-H”

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26 Gryfe et al, NEJM 2000

27 NEJM May 5,2005 Hampel et al

28 HNPCC: Risk Reduction Options Colorectal  Unaffected: colonoscopy to cecum q 1-2 years  Affected w CRC: consider subtotal colectomy at 1 st diagnosis d/t risk of 2 nd primaries http://www.nccn.org/professionals/physician_gls/PDF/colorectal_screening.pdf Seminars in Oncology, Oct 2007

29 HNPCC: Risk Reduction Gynecological Cancers Screening for ovarian ca: CA125 + TVUS jury still out- Lancet Oncology online Mar 09 Screening for endometrial ca: annual TVUS + random endometrial bx (age 30+) few studies: review Lindor et al, JAMA 2006 See also current NCCN guidelines

30 Surgical Options for Gyne Ca Prophylactic BSO Ovarian/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 carriers Recent meta-analysis for HBOC (BRCA carriers) : J Natl Cancer Inst. 2009;101(2):80-87

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32 HNPCC Colorectal Ca Prognosis  many studies: stage-for-stage survival advantage in HNPCC-CRC landmark paper: Gryfe (NEJM 2000): 607 consecutive cases CRC { "@context": "http://schema.org", "@type": "ImageObject", "contentUrl": "http://images.slideplayer.com/8/2409318/slides/slide_32.jpg", "name": "HNPCC Colorectal Ca Prognosis  many studies: stage-for-stage survival advantage in HNPCC-CRC landmark paper: Gryfe (NEJM 2000): 607 consecutive cases CRC

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 MSH2  Are the carriers at  risk of colorectal ca? YES, and should be screened appropriately

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41 FAP- prototype for hereditary cancer  100s to 1000s of adenomatous polyps throughout colon & rectum  100% penetrance without surgery  Very 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 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 review:

43 FAP- Desmoids 12-17% of FAP patients Intra-abdominal 80%, small bowel mesentery >50% (present w SBO) Intra-abdominal 80%, small bowel mesentery >50% (present w SBO) Genotype: APC mutation b/w codons 1310-2011 Genotype: APC mutation b/w codons 1310-2011 Tend to occur AFTER surgery, high RR, high morbidity Tend to occur AFTER surgery, high RR, high morbidity Rx: sx for small, well defined desmoids; Tamoxifen, chemo: vinblastine, MTX (RR 40- 50%) or for rapidly progressive desmoids per sarcoma protocol (adriamycin, dacarbazine) Rx: sx for small, well defined desmoids; Tamoxifen, chemo: vinblastine, MTX (RR 40- 50%) or for rapidly progressive desmoids per sarcoma protocol (adriamycin, dacarbazine)

44 Upper GI tumours 80-90% FAP mutation carriers have duodenal or periampullary polyps, of which 80-90% FAP mutation carriers have duodenal or periampullary polyps, of which 36% will develop advanced polyposis 36% will develop advanced polyposis 3-5% will develop invasive carcinoma 3-5% will develop invasive carcinoma Surveillance: side-viewing endoscopy + bx suspicious polyps @ 25-30 yrs Surveillance: side-viewing endoscopy + bx suspicious polyps @ 25-30 yrs Polypectomy for high-grade dysplasia, villous changes, ulceration, > 1 cm size Polypectomy for high-grade dysplasia, villous changes, ulceration, > 1 cm size FAP-other tumours

45 chemoprevention? NSAIDS: level 1 evidence 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 effects Calcium Calcium HRT HRT

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 polyposis 10-100 polyps, 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: 431-447

48 Attenuated FAP

49 “ MAP” MYH-associated polyposis coli Nielsen et al, Journal of Medical Genetics 2005

50 Hereditary Diffuse Gastric Cancer  E-cadherin CDH1 gene  70% risk of diffuse gastric ca  40% risk of lobular breast ca  Prophylactic total gastrectomy  ?screening chromoendoscopy Lynch et al, Cancer 2008 Jun 15;112(12):2655-63

51 Objectives HNPCC review HNPCC review Diagnosis, genetic testing, cancer risks, risk reduction strategies Other Hereditary GI syndromes: Other Hereditary GI syndromes: FAP, AFAP/MAP, HDGC Criteria for referral to Familial Oncology Programs Criteria for referral to Familial Oncology Programs


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