Lynch Syndrome (HNPCC) Who to test? How to test?

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1 Lynch Syndrome (HNPCC) Who to test? How to test? Disclosures: None Jonathan P. Terdiman, M.D. Professor of Clinical Medicine and Surgery University of California, San Francisco Causes of Hereditary Susceptibility to CRC Clinical Features of Lynch Syndrome Sporadic (65% 85%) Rare CRC syndromes (<0.1%) Familial adenomatous polyposis (FAP and MAP) (1%) Familial (10% 20%) Hereditary nonpolyposis colorectal cancer (HNPCC) (5%) Adapted from Burt RW et al. Prevention and Early Detection of CRC, 1996 Early CRC diagnosis (~45 years, lifetime risk 50-80%) Multiple primary cancers Tumor site in proximal colon Extracolonic cancers: endometrium (20-60%), ovary, stomach, urinary tract, pancreas, others 1

2 Lynch Screening Recommendations Cumulative Proportion Free of CRC Kidney / Ureteral cancer MRI Urogram +/- urine cytology (?) Stomach cancer EGD (Optional) Ovarian cancer Endometrial cancer Annual TVUS, CA-125 Annual TVUS / endometrial aspiration Colorectal cancer Colonoscopy every 1-2 years Annual H&P, ROS, education, counseling Birth 10 years 20 years 30 years 50 years Jama 2007;296: Jarvinen HJ et al., Gastro 2000; 118:829 Aspirin Chemoprevention Burn J, et al. Lancet 2011;378: Cumulative Incidence: Endometrial CA Schmeler KM et al., NEJM 2006; 354:261 2

3 Cumulative Incidence: Ovarian CA Lynch syndrome results from failure of mismatch repair (MMR) gene function Base pair mismatch Normal DNA repair T C G A C A G C T G T C T A C A G C T G Schmeler KM et al., NEJM 2006; 354:261 Defective DNA repair (MMR+) = MSI-H T C T A C A G C T G T C T A C A G A T G MSI Testing Immunohistochemistry Identify MMR proteins Normally present If protein is absent, gene is not being expressed (mutation or methylation) Helps direct gene testing by predicting likely involved gene If abnormal IHC (absent), MSI+ MLH1 MSH2 PMS2 MSH6 3

4 Contribution of Gene Mutations to Lynch Families Unknown ~20% MSH2 ~35% So, Who to Test and How? First select by clinical criteria, or test all CRC patients? Tumor MSI or IHC or combination? When to do germline genetic test? MSH6 ~ 10% PMS2 (< 5%) MLH1 ~35% What if clinical suspicion high but lab tests normal? Amsterdam II criteria 3 or more relatives with verified HNPCCassociated cancer in family Two or more generations One case a first-degree relative of the other two One CRC dx <50 FAP excluded Bethesda Guidelines Individual with CRC dx <50 Individual with synchronous or metachronous CRC, or other HNPCC-associated tumors regardless of age Individual with CRC with MSI-H histology dx <60 Individual with CRC with >1 FDR with an HNPCCassociated tumor, with one cancer dx <50 Individual with CRC with >2 FDRs or SDRs with an HNPCC-associated tumor, regardless of age Vasen HFA et al. Gastroenterology. 116:1453, 1999 Umar A, et al. JNCI. 2004;96(4):

5 Diagnostic Models for Lynch Warning: Family Histories can be Deceiving Family size is getting smaller Wider use of colonoscopy likely to prevent many colon cancers MSH6/PMS2 may have lower cancer risks Population-based case ascertainment may be associated with lower cancer risks JAMA Sept 2006 The Columbus Area Lynch Study Flow Columbus-Area Lynch Study MSI unselected newly diagnosed patients Columbus OH MSI-H and L MSI stable No further action IHC 4 proteins Methylation MLH1 promoter/braf Mutation analysis by sequencing MLH1, MSH2, MSH6 and deletion analysis by MLPA Germline mutations Mutation analysis of selected patients for PMS2 based on IHC Mutation positive Colorectal cancer Total accrued N = 1600 Testing completed N = 1566 MSI positive (high & low) N = 307 (19.6%) N = 44* 2.7% (1/35) Sequence MLH1, MSH2, MSH6 Immunohistochemistry Methylation of MLH1 promoter Mutation result not yet interpretable N =55 3.5% MSI negative N =1259 (80.4%) Mutation negative or polymorphism found N = % Hampel et al. NEJM 2005;352: ; Unpublished 5

6 Summary of Findings 1 out of 35 colon cancer patients has Lynch syndrome 50% of CRC patients with LS are diagnosed over age 50 24% of CRC patient with LS do not meet any family history criteria IHC easier logistically, cheaper, predicts the mutated MMR gene when screening cancer patients CRC dx >45 & No personal or family history Stop Recommended Approach in 2013 All Present 80% CRC dx <45; OR FDR with CRC; OR Multiple primaries MLH1 & PMS2 Absent 15% CRC dx <60; OR Family or personal history of Lynch cancer BRAF (-) Refer to Clinical Cancer Genetics CRC dx >60 & No suggestive history, BRAF + Stop MSH2& MSH6, or MSH6 or PMS2 Absent - 5% Refer to Clinical Cancer Genetics Conclusions Ladabaum et al, Ann Intern Med 2011;155:69 Important to identify Lynch Syndrome Different outcomes for probands and relatives with more intensive surveillance Lynch = hereditary defective mismatch repair Best method for detection? UNIVERSAL TUMOR TESTING OF CRC CASES AND ENDOMETRIAL CANCER TOO GERMLINE TESTING FOR THOSE WITH POSITIVE TUMORS GERMLINE TESTING OF NON AFFECTED RELATIVES ONCE MUTATION FOUND IN PROBAND COMPREHENSIVE CANCER FAMILY HISTORY STILL IMPORTANT TO DETECT LYNCH IN NON CRC CANCER PATIENTS AND NON LYNCH CANCER FAMILIES 6

7 UCSF Universal Testing Testing Protocol MSI and 4 protein IHC If MLH1 is absent, we do BRAF testing Reflex genetics referral for positives based on this screening procedure 278 colon cancers tested 45/278 (16%) with abnormal results 13/45 with BRAF mutations found- so no Lynch 13/45 refused further genetic work-up 19/45 underwent genetic counseling and testing for Lynch Mutations: MSH2 in 7, MLH1 in 5, MSH6 in 1, no mutation found in 3 and pending in 3 So 12 (4%) of entire population with confirmed Lynch 7