1. Genetic Findings in Familial Gastrointestinal Cancers
Zsofia K. Stadler, MD
Clinical Genetics & GI Oncology Services
Memorial Sloan-Kettering Cancer Center
March 27, 2015

2. The heritable fraction of many human cancers is high:Sweden, Denmark, Finland registry of 44,788 twin pairs
NEJM 343:
78-85, 2000

3. Hereditary GI Cancer Syndromes
Colorectal cancer
Lynch syndrome
Polyposis syndromes
FAP, AFAP, MAP, Newly implicated genes
Gastric Cancer
Hereditary Diffuse Gastric Cancer
Syndromes associated with intestinal-type gastric cancer
Pancreatic Cancer

4. Risk of Colorectal Cancer
15-40%
40%

5. Lynch Syndrome Associated extracolonic cancers Autosomal dominant
Early onset colorectal cancer
Multiple primaries
Right colon predominance
Associated extracolonic cancers
Endometrium
Ovary
Stomach
Urinary tract
Small bowel
Bile ducts
Sebaceous skin tumors
Brain

6. Lynch Syndrome Germline mutations in mismatch repair (MMR) genes: MLH1
MSH2
MSH6
PMS2
EPCAM

7. X DNA mismatch repair Microsatellite Instability
Microsatellites: short, tandemly repeated DNA sequences
Failure of DNA mismatch repair system leads to changes in length of a microsatellite allele due to deletions or insertions X
SJ Sherer, Biochem. Soc. Trans. 2005

8. Identifying defective MMR
IHC staining for MMR proteins
Microsatellite instability analysis
MLH1 present
MLH1 absent
-Use of marker mono- and dinucleotide DNA repeats to identify presence of MSI
-High-MSI: ≥2/5 markers with instability
-MLH1, PMS2, MSH2, MSH6
-Loss of expression of one or more proteins is indicative of dMMR
Concordance between MSI-H and IHC is ~92-97%

9. Colon or Endometrial Cancer at age < 50**
2004 Bethesda Criteria*
Colon or Endometrial Cancer at age < 50**
**NCCN: All CRC regardless of age or CRC at age < 70
Two LS cancers in a single individual at any age
Colon or Endometrial Cancer in an individual with one or more 1st degree relatives with a LS- cancer, with at least 1 diagnosed < 50
Colon or Endometrial cancer at any age, in an individual with 2 or more 1st or 2nd degree relatives with LS cancers
*Modified to include Endometrial Cancer as defining diagnosis
Umar et al. JNCI :261

10. Cancer Risks in Lynch syndrome
100 80
Colorectal 60-80%
% with cancer 60
Endometrial 40-60% 40
Stomach 4-13% 20
Ovarian 4-12%
Urinary tract 2-12%
Biliary tract 2% 20 40 60 80
Age (years)
Adapted from Aarnio M et al. 1995, 1999

11. Pancreatic Cancer in Lynch Syndrome
Age
Cumulative Risk
Population
Families with MMR Gene Mutations 20 30
0.03% 40
0.01%
0.23% 50
0.04%
1.31% 60
0.18%
1.98% 70
0.52%
3.68%
Patients with Lynch syndrome have an 8.6-fold increased risk of pancreatic cancer
Kastrinos et al., JAMA 2009

12. “Sentinel Cancer” in Women with Lynch syndrome
117 women from 223 Lynch/HNPCC families with dual primary cancers
In 13.6% endometrial and colorectal cancers diagnosed simultaneously
In remaining 101 women:
Lu KH, et al. Obstet Gynecol. 2005; 105:569-74

13. Colonoscopy Improves Survival in Lynch Syndrome
Surveillance
Survival
No surveillance
100
92.2% 80
73.9% 60 40 5 10 15
Follow-up time (years)
Jarvinen HJ et al. Gastroenterology. 2000; 118:829-34

14. Risk-Reduction Strategies in Lynch Syndrome
Colorectal
Colonoscopy every 1-2 years starting at 20-25
Chemoprevention options –ASA?
Risk-reducing colectomy
Gastric cancer
Screening EGD, age 30-35
Endometrium / Ovary
(Annual Endometrial Biopsy, starting at 30-35)
(Transvaginal Ultrasound +/- CA125, 1-2 times per year, starting at 30-35)
Risk-Reducing Hysterectomy with BSO
Urinary Tract (only for patients at highest-risk (ie.: MSH2, male)?)
Urinalysis every 1-2 years, starting at 25-35
Renal Ultrasound every 1-2 years, starting at 25-35

15. Emerging Data in Lynch Syndrome: Genotype-Phenotype Correlations
Endometrial Cancer Risk
Colorectal Cancer Risk
Hendriks Y. et al., Gastroenterology, 2004; 127:17-25.

16. Emerging Data in Lynch Syndrome
Genotype-phenotype correlations
MLH1 mutation - higher risk of CRC
MSH2 mutation - higher risk of extracolonic cancers (urothelial, sebaceous adenocarcinoma, ovary, etc)
MSH6 mutation - higher risk of endometrial cancer
PMS2- not enough data to date
EPCAM – new gene, risks unknown
Other possibly associated cancers
Pancreas cancer
Recent studies demonstrate possible increased risk of prostate and breast cancer
Has NOT resulted in change in screening recommendations

17. Causes of Hereditary Susceptibility to CRC
Sporadic
(65 % –
85)
Familial
MYH, POLE, POLD1
(SNPs?)
syndromes
Lynch syndrome (HNPCC)
(<0.1%)
(3%)
Familial adenomatous
polyposis (FAP) (1%)

18. Familial Adenomatous Polyposis
Essentially 100% penetrance with inevitable development of CRC if colon not removed
Site
Type of Cancer
Lifetime Risk
Small bowel (duodenum, periampulla)
Duodenum, periampulla
4-12%
Small bowel
Distal to duodenum
Rare
Pancreas
Adenocarcinoma
~2%
Thyroid
Papillary thyroid cancer
1-2%
CNS
Medulloblastoma
<1%
Liver
Hepatoblastoma
1.6%
Bile ducts

19. Management of FAP
Start sigmoidoscopy/colonoscopy every 1-2 years by age 10-12
Prophylactic colectomy (Annual colonoscopy once polyps detected until colectomy)
Surveillance for adenomas (rectum, rectal pouch)
Endoscopic surveillance and prophylactic colectomy improves survival in at-risk patients
UGI screening q1-3 years
Thyroid? Hepatoblastoma?

20. Genotype-phenotype correlations
M Nieuwenhuis , Crit Rev Onc Hem, 2007

21. MYH-associated colon cancer
Attenuated FAP
< 100 adenomas (ave. 30)
Adenomas often R sided
Older at presentation (ave. >50)
UGI, thyroid risk similar to classic
CHRPE, desmoids, Gardner’s rare
Most often 5’, 3’ APC mutations
MYH: base-excision repair gene
First common recessive cancer
syndrome
Biallelic presents like FAP or
AFAP
Test if or more adenomas,
and APC negative
2 common mutations (Y165C,
G382D), full sequencing
~2% population carrier rate
Carrier state not yet fully understood

22. Mutations in polymerase proofreading linked to CRC/polyposis (Palles et al., Nat Genet. 2013)
POLE
Autosomal dominant
Early-onset CRC, multiple or large adenomas with conventional pathology
Tumors: MSS
?extracolonic tumors
POLD1

23. Cancer Syndromes Associated with Gastric Cancer Susceptibility
Implicated Gene(s)
Other Associated Cancers
Hereditary Diffuse Gastric Cancer
CDH1
Lobular BC, CRC?
Lynch syndrome
MMR genes (MLH1, MSH2, MSH6, PMS2)
CRC, endometrial, small intestine, ureter/renal pelvis, ovary, pancreas, biliary tract, skin, brain, etc.
Li-Fraumeni syndrome
p53
Sarcoma, leukemia, BC, brain cancer, ACC
Peutz-Jeghers syndrome
STK11
Pancreas, small bowel, gastroesophageal, CRC, BC, ovary etc.
Familial adenomatous polyposis ? (ethnic/geographic variation?)
APC
CRC, Papillary thyroid, Medulloblastoma, Pancreatic (ampullary), Hepatoblastoma (child)
Juvenile polyposis
SMAD4, BMPR1A, ENG
CRC, UGI tract, Pancreas

24. 1964: Familial Gastric Cancer in a kindred of Maori ethnicity
CDH1 encodes E-cadherin
Guilford et al., Nature 1998; 392:

25. Updated IGCLC criteria for HDGC (2010)
2 cases of GC in 1st or 2nd degree relatives, one confirmed DGC diagnosed <50
3 confirmed DGC cases in 1st or 2nd degree relatives independent of age
Age <40 at DGC diagnosis*
Personal or family history of DGC and lobular breast cancer, one diagnosed <50*
Fitzgerald et al., J Med Genet 2010; 47:

26. Risk of Diffuse Gastric Cancer
Lifetime risk >80%
Men 40%-67% by age 80
Women 63-83% by age 80 (Pharaoh et al., Gastroenterology 2001)
Age at onset is highly variable
Mean: age 40 (Range years)
New Zealand: Mean age 33
Lobular BC: Cumulative risk for CDH1 female mutation carriers is ~40% by age 80
Management:
Prophylactic gastrectomy
Role of endoscopy?

27. Rogers WM et al., Am J Surg Pathol 2008; Vol32 No.6.

28. Genetic Basis of Pancreatic Cancer (PC)
Sporadic
Hereditary
Familial
~10% of PCs are hereditary/familial
Familial Pancreatic Cancer
PC in the setting of a known hereditary cancer predisposition syndrome
Inherited factors may account for as much as 36% of PC cases (Lichenstein P et al., NEJM 2000)

29. Familial Pancreatic Cancer
≥ 2 first-degree relatives with pancreatic cancer without a known genetic defect ??

30. Hereditary Pancreatic Cancer
Syndrome
Genes
Other Associated Cancers
Hereditary Breast/Ovarian Cancer
BRCA2, BRCA1
Breast, ovary,
male breast
Lynch syndrome
MLH1, MSH2, MSH6, PMS2
Colon, endometrial, gastric, ovary, others
Familial Atypical Multiple Mole Melanoma (FAMMM)
CDKN2A , CDK4
Melanoma
Peutz-Jeghers syndrome
STK11
Colon, breast, stomach, ovary
Hereditary Pancreatitis
PRSS1
Others?
PALB2, APC, ATM

31. Potential of next-generation sequencing technologies
Mendelian Families
(Linkage analysis)
P53
APC
Unlikely to exist
(Common, large effect size)
CDH1
BRCA1 BRCA2
MLH1 MSH2
PTEN
STK11
Potential of next-generation sequencing
technologies
CDKN2A
Phenotypic Effect Size
MSH6
Candidate gene analysis
PMS2
Low-penetrance High-penetrance
ATM
CYP1A1
CHEK2
APC (I1307K)
BRIP1
PALB2
Hard to Identify
(Rare variants with small effects)
GWAS
(Common, small effect size)
BLM (BLMAsh )
JAK2**
GSTM1
KITLG**
8q24 locus
MSMB
CHRNA3 CHRNA5 CHRNB4
TP63
TERT
FGFR2
NUDT10 NUDT11
Very Rare Common
Population Frequency

32. Multiplex testing for CRC susceptibility?
Colon Cancer
Genes Included in Commercially Available NGS Panels
Ambry Genetics
APC, BMPR1A, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, TP53
University of Washington
APC, BMPR1A, CDH1, CHEK2, EPCAM, GALNT12, GREM1, MLH1, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, TP53
Mayo Medical Laboratories
APC, AXIN2, BMPR1A, CDH1, CHEK2, EPCAM, GREM1, MLH1, MLH3, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, TP53

33. Limitations and Future Directions
Barriers to genetic testing
Lack of insurance reimbursement for the cost of genetic testing
Advanced stage of disease at diagnosis
Especially relevant in GI Oncology…
Must improve awareness about inherited GI cancers
Benefit for patient
Benefit for family
Increasing number of cancer susceptibility genes
Emergence of multigene panels for specific cancer type
Variants and incidental findings a real limitation at present
Next-generation sequencing identifying novel syndromes, genes