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 HNPCC review
Diagnosis, genetic testing, cancer risks, risk reduction strategies
Other Hereditary GI syndromes:
FAP, AFAP/MAP, HDGC
Criteria 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 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
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.
“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 reported
Dr. 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 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
Synchronous, metachronous primaries
Pathology: mucinous, poorly differentiated, peri-tumoural lymphocytic infiltration
Prognosis: ?
Response to chemo?

13. General Population Risk
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
2-7%
Not reported
Urinary tract
4-5%
~ 55 years
Small bowel
1-4%
49 years
Brain/central nervous system
1-3%
~ 50 years

14. Cancer risk (%) by age 70 CRC 71 39 96 Endometrium 42 61 Ovary 3.4
Type of Cancer
MLH1
MSH2
MSH6
CRC
Female 71 39
Lower than MLH1/MSH2
Male 96
Endometrium 42 61
Higher than MLH1/MSH2
Ovary
3.4
10.4
specific risk unknown
Stomach
2.1
4.3
Small bowel
7.2
4.5
Urinary Tract
1.3 12
Other
Extracolonic- 11
Extracolonic -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 2
2 successive generations
1 before age 50
Histological verification
Revised Bethesda (Umar et al, 2004)
CRC in pt under 50
Synch/metachronous, or other associated ca
CRC with MSI under 60
CRC with one or more 1st degree relative (under 50)
CRC with 2 or more 1st/ 2nd degree relative (any age)
50% by mutation analysis
15% 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”

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

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
Defects in mismatch repair genes (MLH1, MSH2, MLH6) lead to the mutator phenotype: high frequency microsatellite instability or “MSI-H”

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 1st diagnosis d/t risk of 2nd primaries
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 

32. HNPCC Colorectal Ca Prognosis
many studies: stage-for-stage survival advantage in HNPCC-CRC
landmark paper: Gryfe (NEJM 2000):
607 consecutive cases CRC <age 50
17% had MSI-H
Multivariate 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 MSH2
Are 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 & 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)
Genotype: APC mutation b/w codons
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)

44. FAP-other tumours Upper GI tumours
80-90% FAP mutation carriers have duodenal or periampullary polyps, of which
36% will develop advanced polyposis
3-5% will develop invasive carcinoma
Surveillance: side-viewing endoscopy + bx suspicious yrs
Polypectomy 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 effects
Calcium
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
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:

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):

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