Zsofia K Stadler MD Clinical Genetics amp GI Oncology Services Memorial SloanKettering Cancer Center March 27 2015 The heritable fraction of many human cancers is high Sweden Denmark Finland registry of 44788 twin pairs ID: 774975
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Slide1
Genetic Findings in Familial Gastrointestinal Cancers
Zsofia K. Stadler, MD Clinical Genetics & GI Oncology ServicesMemorial Sloan-Kettering Cancer Center
March 27, 2015
Slide2The heritable fraction of many human cancers is high:Sweden, Denmark, Finland registry of 44,788 twin pairs
NEJM
343:78-85, 2000
Slide3Hereditary 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
Slide4Risk of Colorectal Cancer
15-40%
40%
Slide5Lynch Syndrome Autosomal dominantEarly onset colorectal cancer Multiple primariesRight colon predominance
Associated extracolonic cancers
Endometrium
Ovary
Stomach
Urinary tract
Small bowel
Bile ducts
Sebaceous skin tumors
Brain
Slide6Germline mutations in mismatch repair (MMR) genes: MLH1 MSH2 MSH6 PMS2 EPCAM
Lynch Syndrome
Slide7DNA mismatch repair
Microsatellite Instability
Microsatellites: short, tandemly repeated DNA sequencesFailure of DNA mismatch repair system leads to changes in length of a microsatellite allele due to deletions or insertions
SJ Sherer, Biochem. Soc. Trans. 2005
X
Slide8Identifying
defective MMR
IHC staining for MMR proteins
-MLH1, PMS2, MSH2, MSH6-Loss of expression of one or more proteins is indicative of dMMR
Microsatellite instability analysis
Concordance between MSI-H and IHC is ~92-97%
MLH1 present
MLH1 absent
-
Use of marker mono- and
dinucleotide
DNA repeats to identify presence of MSI
-High-MSI: ≥2/5 markers with instability
Slide92004 Bethesda Criteria*
Colon or Endometrial Cancer at age < 50****NCCN: All CRC regardless of age or CRC at age < 70Two LS cancers in a single individual at any ageColon or Endometrial Cancer in an individual with one or more 1st degree relatives with a LS- cancer, with at least 1 diagnosed < 50Colon 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 2004 96:261
Slide10Cancer Risks in Lynch syndrome
Adapted from
Aarnio
M et al. 1995, 1999
% with cancer
100
80
60
40
20
0
20
40
60
80
0
Age (years)
Colorectal 60-80%
Endometrial 40-60%
Stomach 4-13%
Ovarian 4-12%
Biliary tract 2%
Urinary tract
2-12%
Slide11Pancreatic Cancer in Lynch Syndrome
AgeCumulative Risk PopulationFamilies with MMR Gene Mutations 20003000.03%400.01%0.23%500.04%1.31%600.18%1.98%700.52%3.68%
Patients with Lynch syndrome have an 8.6-fold increased risk of pancreatic cancer
Kastrinos
et al., JAMA 2009
Slide12“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
Slide13Colonoscopy Improves Survival in Lynch Syndrome
Jarvinen HJ et al. Gastroenterology. 2000; 118:829-34
Survival
80
60
0
5
10
Follow-up time (years)
40
100
15
92.2%
Surveillance
73.9%
No surveillance
Slide14Risk-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
Slide15Emerging Data in Lynch Syndrome: Genotype-Phenotype Correlations
Hendriks Y. et al., Gastroenterology, 2004; 127:17-25.
Colorectal Cancer Risk
Endometrial Cancer Risk
Slide16Emerging 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
Slide17Causes of Hereditary Susceptibility to CRC
Sporadic
(65
%
–
85)
Familial
(SNPs?)
Lynch syndrome (HNPCC)
(3%
)
Familial adenomatous
polyposis (FAP) (1%)
MYH, POLE, POLD1
syndromes
(<0.1%)
Slide18Familial Adenomatous Polyposis
Essentially 100% penetrance with inevitable development of CRC if colon not removed
Site Type of Cancer Lifetime RiskSmall bowel (duodenum, periampulla) Duodenum, periampulla4-12%Small bowel Distal to duodenumRarePancreasAdenocarcinoma~2%ThyroidPapillary thyroid cancer1-2%CNSMedulloblastoma<1%Liver Hepatoblastoma1.6%Bile ductsAdenocarcinomaRare
Slide19Management 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
?
Slide20Genotype-phenotype correlations
M
Nieuwenhuis
, Crit Rev Onc Hem, 2007
Slide21Attenuated FAP
< 100 adenomas (ave. 30)Adenomas often R sidedOlder at presentation (ave. >50)UGI, thyroid risk similar to classicCHRPE, desmoids, Gardner’s rareMost often 5’, 3’ APC mutations
MYH-associated colon cancer
MYH
:
base-excision repair gene
First
common recessive cancer
syndrome
Biallelic
presents like FAP or
AFAP
Test
if 10-15 or more adenomas,
and
APC
negative
2
common
mutations (Y165C,
G382D),
full
sequencing
~2
% population carrier
rate
C
arrier
state not yet fully understood
Slide22Mutations in polymerase proofreading linked to CRC/polyposis
(
Palles
et al., Nat Genet. 2013)
POLE
POLD1
Autosomal dominant
Early-onset CRC, multiple or large adenomas with conventional pathology
Tumors: MSS
?
extracolonic
tumors
Slide23Cancer Syndromes Associated with Gastric Cancer Susceptibility
Syndrome Implicated Gene(s)Other Associated CancersHereditary Diffuse Gastric CancerCDH1 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 syndromep53Sarcoma, leukemia, BC, brain cancer, ACCPeutz-Jeghers syndromeSTK11Pancreas, 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, ENGCRC, UGI tract, Pancreas
Slide241964: Familial Gastric Cancer in a kindred of Maori ethnicity
Guilford et al., Nature 1998; 392:402-405.
CDH1 encodes E-cadherin
Slide25Updated IGCLC criteria for HDGC (2010)
2 cases of GC in 1st or 2nd degree relatives, one confirmed DGC diagnosed <503 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;
47:436-444.
Slide26Risk of Diffuse Gastric Cancer
Lifetime risk >80% Men 40%-67% by age 80Women 63-83% by age 80 (Pharaoh et al., Gastroenterology 2001)Age at onset is highly variable Mean: age 40 (Range 14-85 years)New Zealand: Mean age 33Lobular BC: Cumulative risk for CDH1 female mutation carriers is ~40% by age 80Management: Prophylactic gastrectomyRole of endoscopy?
Slide27Rogers WM et al.,
Am J
Surg
Pathol
2008; Vol32 No.6.
Slide28Genetic Basis of Pancreatic Cancer (PC)
~10% of PCs are hereditary/familialFamilial Pancreatic Cancer PC in the setting of a known hereditary cancer predisposition syndromeInherited factors may account for as much as 36% of PC cases (Lichenstein P et al., NEJM 2000)
Sporadic
Hereditary
Familial
Slide29Familial Pancreatic Cancer
≥ 2 first-degree relatives with pancreatic cancer without a known genetic defect
??
Slide30Hereditary 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
Slide31Phenotypic Effect Size
Population Frequency
BRCA1
BRCA2
PTEN
P53
MLH1 MSH2
APC
ATM
CYP1A1
APC (I1307K)
CHEK2
PALB2
FGFR2
8q24 locus
MSMB
GSTM1
CDH1
PMS2
MSH6
BRIP1
CDKN2A
CHRNA3 CHRNA5 CHRNB4
KITLG**
JAK2**
STK11
BLM (BLMAsh )
NUDT10 NUDT11
Very Rare Common
Low-penetrance High-penetrance
TP63
TERT
Candidate gene analysis
GWAS (Common, small effect size)
Mendelian Families(Linkage analysis)
Hard to Identify(Rare variants with small effects)
Unlikely to exist (Common, large effect size)
Potential of next-generation sequencing
technologies
Slide32Multiplex testing for CRC susceptibility?
Colon Cancer Genes Included in Commercially Available NGS PanelsAmbry 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, TP53Mayo Medical Laboratories APC, AXIN2, BMPR1A, CDH1, CHEK2, EPCAM, GREM1, MLH1, MLH3, MSH2, MSH6, MUTYH, PMS2, PTEN, SMAD4, STK11, TP53
Slide33Limitations and Future Directions
Barriers to genetic testingLack 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 cancersBenefit for patientBenefit for familyIncreasing number of cancer susceptibility genes Emergence of multigene panels for specific cancer typeVariants and incidental findings a real limitation at presentNext-generation sequencing identifying novel syndromes, genes