HEREDITARY COLON CANCER: LYNCH SYNDROME – PAST, PRESENT AND THE FUTURE HENRY T. LYNCH, MD JANE F. LYNCH, BSN Creighton University School of Medicine Omaha, Nebraska
Problem Areas • • Dx of Lynch syndrome (LS) frequently missed. • • Classification of LS may be ambiguous. • • More than CRC (numerous extracolonic • cancers). • • Multiple molecular/phenotypic heterogeneous • concerns.
Family History • Must be comprehensive; • Cancer of all anatomic sites, verification whenever possible.
Why Pursue Cancer of All Anatomic Sites? • Pertinent for any hereditary cancer syndrome • Most identified by pattern of cancer expression, e.g.: • breast and ovary (HBOC syndrome); • CRC, endometrium, ovary, others (Lynch syndrome); • sarcomas, breast, brain, multiple others in SBLA (Li- Fraumeni syndrome); • medullary thyroid carcinoma and pheochromocytoma (MEN-2a and MEN-2b); • melanoma and pancreatic cancer with CDKN2A (p16) mutation (FAMMM syndrome); • diffuse gastric cancer and lobular breast cancer with CDH1 mutation (HDGC syndrome); ...and the list goes on.
Genetic Counseling • Mandatory • Centers of Cancer Genetic Expertise • Physician Role, unfortunately, often insufficient
Colorectal Cancer • Worldwide estimates for colorectal cancer during 2008*: • Incidence – 1,233,711 • Mortality – 608,644 • Worldwide estimates for familial/hereditary CRC during 2008*: • Lynch syndrome 3-5% of all CRC 37,011-61,686 • FAP <1% of all CRC <12,337 • Familial 20% of all CRC 246,742 • *GLOBOCAN. The International Agency for Research • on Cancer web site. URL: http://www.iarc.fr/
Familial/Hereditary CRC in US Annual CRC incidence in US: 142,570 Lynch syndrome 3-5% of all CRC 4,277 - 7,129 FAP <1% of all CRC <1,426 Familial 20% of all CRC 28,514 Jemal et al. CA Cancer J Clin 60:277-300,2010. 10
Magnitude of the Problem • Question: Why are these figures of such significant public health impact? • Answer: Each hereditary cancer comes from a family that could benefit immensely from genetic counseling. • DNA testing, surveillance, and highly-targeted management are the key! • Problem: Significance of family frequently missed!
Archives of Internal Medicine Vol. 12, July-Dec., 1913
How Aggressive? • Of 225 CRC patients with LS, 10.2 % had CRC within 5 yr of colonoscopy. • Other studies showed CRC within 3 yrs of colonoscopy. • Conclusion: • 1) Accelerated carcinogenesis; • 2) Need shorter colonoscopy intervals. • Am J Gastrology 89:1978-1980, 1994.
Survival continued • Results: • Compared with the unselected series, the HNPCC cases had lower stage disease (P < 0.001), and fewer had distant metastases at diagnosis (P < 0.001 in an analysis stratified by T classification); • In stage-stratified survival analysis, the HNPCC cases had a significant overall survival advantage regardless of adjustment for their younger age; • Cancer 83:259-266, 1998.
Survival continued • Results: • A conservative estimate of the hazard ratio (of HNPCC cases to the unselected series) was 0.67 (P < 0.0012). • The estimated death rate for the HNPCC cases, adjusted for stage and age differences, was at most two-thirds of the rate for the hospital series. • Cancer 83:259-266, 1998.
Genetic Heterogeneity in HNPCC MSH6 MLH1 MSH2 PMS2 PMS1 Chr 7 Chr 3 Chr 2 HNPCC is associated with germline mutations in any one of at least five genes
Should we test all colorectal cancer for Lynch Syndrome? YES! Test everybody.
Search for LS Among CRC Affecteds* Evidence: Among 500 CRC patients, 18 (3.6%) had LS. Of these 18: 18 (100%) had MSI-H CRCs; 17 (94%) were correctly predicted by IHC; only 8 (44%) were dx < 50 years; only 13 (72%) met the revised Bethesda guidelines; 1/35 cases of CRC show LS. *Hampel et al. J Clin Oncol 26:5783-5788, 2008.
Molecular Genetic Screening for LS • Recommendation*: • All incident CRC and EC cases should be molecularly screened for LS. • MSI highly sensitive (89.3%). • IHC equally sensitive (91.2%), is inexpensive, is more readily available, and predicts the nonworking gene. • IHC is preferred method to screen for LS*. • *Hampel et al. J Clin Oncol 26:5783-5788, 2008.
Increased risk for certain extracolonic malignancies • Endometrial • Ovary • Stomach • Small bowel • Pancreas • Liver and biliary tree • Muir-Torre cutaneous features • Brain, (glioblastoma) – Turcot’s syndrome • Possible Prostate cancer and others • Breast cancer - controversial.
Cardinal Features of Lynch Syndrome • • Differentiating pathology features of LS CRCs: • - more often poorly differentiated; • - excess of mucoid and signet-cell features; • - Crohn’s-like reaction; • - medullary features; • - significant excess of infiltrating lymphocytes • within the tumor. • • Increased survival from CRC. • • Sine qua non for diagnosis is identification of germline mutation in MMR gene (most commonly MLH1, MSH2, MSH6) segregating in the family.
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Breast Cancer in the Danish HNPCC Register* 20 ♀ mutation carriers dx with BC at mean age of 50 years (33-66). Predominantly ductal carcinoma with extensive lymphocytic reactions in 8/14 evaluated tumors. MMR protein immunostaining showed loss of expression of MLH1, MSH2, or MSH6 corresponding to the mutations found in 7/16 investigated cases. *Jensen et al. Breast Cancer Res Treat 120:777- 782, 2010.
Times to subsequent CRC and subsequent abdominal surgery were significantly shorter in the control group (P < .006 and P < .04, respectively). • No significant difference was identified with respect to survival time between the cases and controls. • Conclusion: Even though no survival benefit was identified between the cases and controls the increased incidence of metachronous colorectal cancer and increased abdominal surgeries among controls warrant the recommendation of subtotal colectomy in patients with LS.
BRAFV600E Mutations in MSI* • The BRAFV600E mutation occurs exclusively in sporadic forms of MSI CRC. • Combined analysis of MSI and BRAFV600E mutation is included in current protocols of LS since it is a reliable, fast, and low-cost strategy. • Helps identify sporadic cases and avoids time-consuming and expensive screening of MMR germline mutation analysis. • *Seruca et al. Expert Rev Gastroenterol Hepatol 3:5-9, 2009.
Algorithm • IHC on all colorectal patients on tumor block; • If positive, BRAF (if positive, then sporadic); • Only do full MMR genetic tests on patient IHC +. BRAF neg.
MORPHOLOGY SUSPICIOUS FOR MSI-H Run PCR test for MSI status Is there MSI-H? FAMILIAL CRC TYPE “X” NO EVIDENCE OF LYNCH SYNDROME NO NO YES Is there loss of staining with any of the Abs? PUTATIVE LYNCH SYNDROME Run mutation analysis for BRAF V600E YES Is there BRAF V600E mutation? NO MMR GENES MUTATION ANALYSIS IHC for MLH1, MSH2, MSH6, PMS2 YES Is there a mutation in MMR gene? SPORADIC CRC WITH MSI-H NO YES LYNCH SYNDROME Gatalica Z, Torlakovic E. Fam Cancer 2008;7:15-26
MSI Analysis A functional assay for the MMR proteins