Screening for the Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer)
Heather Hampel, M.S., Wendy L. Frankel, M.D., Edward Martin, M.D., Mark Arnold, M.D., Karamjit Khanduja, M.D., Philip Kuebler, M.D., Ph.D., Hidewaki Nakagawa, M.D., Ph.D., Kaisa Sotamaa, M.D., Thomas W. Prior, Ph.D., Judith Westman, M.D., Jenny Panescu, B.S., Dan Fix, B.S., Janet Lockman, B.S., Ilene Comeras, R.N., and Albert de la Chapelle, M.D., Ph.D.
Background Germ-line mutations in the mismatch-repair genesMLH1, MSH2, MSH6, and PMS2 lead to the development of the Lynchsyndrome (hereditary nonpolyposis colorectal cancer), conferringa strong susceptibility to cancer. We assessed the frequencyof such mutations in patients with colorectal cancer and examinedstrategies for molecular screening to identify patients withthe syndrome.
Methods Patients with a new diagnosis of colorectal adenocarcinomaat the major hospitals in metropolitan Columbus, Ohio, wereeligible for the study. Genotyping of the tumor for microsatelliteinstability was the primary screening method. Among patientswhose screening results were positive for microsatellite instability,we searched for germ-line mutations in the MLH1, MSH2, MSH6,and PMS2 genes with the use of immunohistochemical stainingfor mismatch-repair proteins, genomic sequencing, and deletionstudies. Family members of carriers of the mutations were counseled,and those found to be at risk were offered mutation testing.
Results Of 1066 patients enrolled in the study, 208 (19.5 percent)had microsatellite instability, and 23 of these patients hada mutation causing the Lynch syndrome (2.2 percent). Among the23 probands with the Lynch syndrome, 10 were more than 50 yearsof age and 5 did not meet the Amsterdam criteria or the Bethesdaguidelines for the diagnosis of hereditary nonpolyposis colorectalcancer (including the use of age and family history to identifypatients at high risk for the Lynch syndrome). Genotyping formicrosatellite instability alone and immunohistochemical analysisalone each failed to identify two probands. In the familiesof 21 of the probands, 117 persons at risk were tested, andof these, 52 had Lynch syndrome mutations and 65 did not.
Conclusions Routine molecular screening of patients with colorectaladenocarcinoma for the Lynch syndrome identified mutations inpatients and their family members that otherwise would not havebeen detected. These data suggest that the effectiveness ofscreening with immunohistochemical analysis of the mismatch-repairproteins would be similar to that of the more complex strategyof genotyping for microsatellite instability.
Source Information
From the Human Cancer Genetics Program, Comprehensive Cancer Center (H.H., H.N., K.S., J.W., J.P., D.F., J.L., I.C., A.C.), the Department of Pathology (W.L.F., T.W.P.), the Department of Surgery (E.M., M.A.), and the Department of Medicine (H.H., J.W., I.C., A.C.), Ohio State University; Mount Carmel Health System (K.K.); and Riverside Methodist Hospital (OhioHealth) (P.K.) — all in Columbus.
Address reprint requests to Dr. de la Chapelle at the Human Cancer Genetics Program, 646 Medical Research Facility, 420 W. 12th Ave., Columbus, OH 43210, or at delachapelle-1{at}medctr.osu.edu.
Ramsoekh, D, van Leerdam, M E, Wagner, A, Kuipers, E J, Steyerberg, E W
(2009). Mutation prediction models in Lynch syndrome: evaluation in a clinical genetic setting. J. Med. Genet.
46: 745-751
[Abstract][Full Text]
Mueller, J., Gazzoli, I., Bandipalliam, P., Garber, J. E., Syngal, S., Kolodner, R. D.
(2009). Comprehensive Molecular Analysis of Mismatch Repair Gene Defects in Suspected Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) Cases. Cancer Res.
69: 7053-7061
[Abstract][Full Text]
Garg, K, Soslow, R A
(2009). Lynch syndrome (hereditary non-polyposis colorectal cancer) and endometrial carcinoma. J. Clin. Pathol.
62: 679-684
[Abstract][Full Text]
Paya, A., Alenda, C., Perez-Carbonell, L., Rojas, E., Soto, J.-L., Guillen, C., Castillejo, A., Barbera, V. M., Carrato, A., Castells, A., Llor, X., Andreu, M., Koh, J., Enders, G. H., Benlloch, S., Jover, R.
(2009). Utility of p16 Immunohistochemistry for the Identification of Lynch Syndrome. Clin. Cancer Res.
15: 3156-3162
[Abstract][Full Text]
Vilar, E., Mukherjee, B., Kuick, R., Raskin, L., Misek, D. E., Taylor, J. M.G., Giordano, T. J., Hanash, S. M., Fearon, E. R., Rennert, G., Gruber, S. B.
(2009). Gene Expression Patterns in Mismatch Repair-Deficient Colorectal Cancers Highlight the Potential Therapeutic Role of Inhibitors of the Phosphatidylinositol 3-Kinase-AKT-Mammalian Target of Rapamycin Pathway. Clin. Cancer Res.
15: 2829-2839
[Abstract][Full Text]
Green, R. C., Parfrey, P. S., Woods, M. O., Younghusband, H. B.
(2009). Prediction of Lynch Syndrome in Consecutive Patients With Colorectal Cancer. JNCI J Natl Cancer Inst
101: 331-340
[Abstract][Full Text]
Bapat, B., Lindor, N. M., Baron, J., Siegmund, K., Li, L., Zheng, Y., Haile, R., Gallinger, S., Jass, J. R., Young, J. P., Cotterchio, M., Jenkins, M., Grove, J., Casey, G., Thibodeau, S. N., Bishop, D. T., Hopper, J. L., Ahnen, D., Newcomb, P. A., Le Marchand, L., Potter, J. D., Seminara, D., and the Colon Cancer Family Registry,
(2009). The Association of Tumor Microsatellite Instability Phenotype with Family History of Colorectal Cancer. Cancer Epidemiol. Biomarkers Prev.
18: 967-975
[Abstract][Full Text]
Asaka, S.-i., Arai, Y., Nishimura, Y., Yamaguchi, K., Ishikubo, T., Yatsuoka, T., Tanaka, Y., Akagi, K.
(2009). Microsatellite instability-low colorectal cancer acquires a KRAS mutation during the progression from Dukes' A to Dukes' B. Carcinogenesis
30: 494-499
[Abstract][Full Text]
Oman, S. A., Ballinger, L., Cerilli, L. A.
(2009). Small Cell Carcinoma: Arising in Lynch Syndrome: A Previously Undocumented Occurrence. INT J SURG PATHOL
17: 46-50
[Abstract]
Hampel, H., Frankel, W. L., Martin, E., Arnold, M., Khanduja, K., Kuebler, P., Clendenning, M., Sotamaa, K., Prior, T., Westman, J. A., Panescu, J., Fix, D., Lockman, J., LaJeunesse, J., Comeras, I., de la Chapelle, A.
(2008). Feasibility of Screening for Lynch Syndrome Among Patients With Colorectal Cancer. JCO
26: 5783-5788
[Abstract][Full Text]
Ramsoekh, D, Wagner, A, van Leerdam, M E, Dinjens, W N M, Steyerberg, E W, Halley, D J J, Kuipers, E J, Dooijes, D
(2008). A high incidence of MSH6 mutations in Amsterdam criteria II-negative families tested in a diagnostic setting. Gut
57: 1539-1544
[Abstract][Full Text]
Bujalkova, M., Zavodna, K., Krivulcik, T., Ilencikova, D., Wolf, B., Kovac, M., Karner-Hanusch, J., Heinimann, K., Marra, G., Jiricny, J., Bartosova, Z.
(2008). Multiplex SNaPshot Genotyping for Detecting Loss of Heterozygosity in the Mismatch-Repair Genes MLH1 and MSH2 in Microsatellite-Unstable Tumors. Clin. Chem.
54: 1844-1854
[Abstract][Full Text]
Balmana, J, Balaguer, F, Castellvi-Bel, S, Steyerberg, E W, Andreu, M, Llor, X, Jover, R, Castells, A, Syngal, S, for the Gastrointestinal Oncology Group of the Spa,
(2008). Comparison of predictive models, clinical criteria and molecular tumour screening for the identification of patients with Lynch syndrome in a population-based cohort of colorectal cancer patients. J. Med. Genet.
45: 557-563
[Abstract][Full Text]
Shia, J.
(2008). Immunohistochemistry versus Microsatellite Instability Testing For Screening Colorectal Cancer Patients at Risk For Hereditary Nonpolyposis Colorectal Cancer Syndrome: Part I. The Utility of Immunohistochemistry. J. Mol. Diagn.
10: 293-300
[Abstract][Full Text]
Zhang, L.
(2008). Immunohistochemistry versus Microsatellite Instability Testing for Screening Colorectal Cancer Patients at Risk for Hereditary Nonpolyposis Colorectal Cancer Syndrome: Part II. The Utility of Microsatellite Instability Testing. J. Mol. Diagn.
10: 301-307
[Abstract][Full Text]
Clendenning, M, Senter, L, Hampel, H, Robinson, K L., Sun, S, Buchanan, D, Walsh, M D, Nilbert, M, Green, J, Potter, J, Lindblom, A, de la Chapelle, A
(2008). A frame-shift mutation of PMS2 is a widespread cause of Lynch syndrome. J. Med. Genet.
45: 340-345
[Abstract][Full Text]
Clendenning, M., Baze, M. E., Sun, S., Walsh, K., Liyanarachchi, S., Fix, D., Schunemann, V., Comeras, I., Deacon, M., Lynch, J. F., Gong, G., Thomas, B. C., Thibodeau, S. N., Lynch, H. T., Hampel, H., de la Chapelle, A.
(2008). Origins and Prevalence of the American Founder Mutation of MSH2. Cancer Res.
68: 2145-2153
[Abstract][Full Text]
Kurnat-Thoma, E. L.
(2008). Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome): Molecular Pathogenesis and Clinical Approaches to Diagnosis and Management for Nurses. Biol Res Nurs
9: 185-199
[Abstract]
Mrkonjic, M., Raptis, S., Green, R. C., Monga, N., Daftary, D., Dicks, E., Younghusband, H.B., Parfrey, P. S., Gallinger, S. S., McLaughlin, J. R., Knight, J. A., Bapat, B.
(2007). MSH2 118T>C and MSH6 159C>T promoter polymorphisms and the risk of colorectal cancer. Carcinogenesis
28: 2575-2580
[Abstract][Full Text]
Kauff, N. D.
(2007). How Should Women With Early-Onset Endometrial Cancer Be Evaluated for Lynch Syndrome?. JCO
25: 5143-5146
[Full Text]
Lynch, P. M.
(2007). New Issues in Genetic Counseling of Hereditary Colon Cancer. Clin. Cancer Res.
13: 6857s-6861s
[Abstract][Full Text]
Young, L. C., Keuling, A. M., Lai, R., Nation, P. N., Tron, V. A., Andrew, S. E.
(2007). The associated contributions of p53 and the DNA mismatch repair protein Msh6 to spontaneous tumorigenesis. Carcinogenesis
28: 2131-2138
[Abstract][Full Text]
Svrcek, M., El-Bchiri, J., Chalastanis, A., Capel, E., Dumont, S., Buhard, O., Oliveira, C., Seruca, R., Bossard, C., Mosnier, J.-F., Berger, F., Leteurtre, E., Lavergne-Slove, A., Chenard, M.-P., Hamelin, R., Cosnes, J., Beaugerie, L., Tiret, E., Duval, A., Flejou, J.-F.
(2007). Specific Clinical and Biological Features Characterize Inflammatory Bowel Disease Associated Colorectal Cancers Showing Microsatellite Instability. JCO
25: 4231-4238
[Abstract][Full Text]
Watson, N., Grieu, F., Morris, M., Harvey, J., Stewart, C., Schofield, L., Goldblatt, J., Iacopetta, B.
(2007). Heterogeneous Staining for Mismatch Repair Proteins during Population-Based Prescreening for Hereditary Nonpolyposis Colorectal Cancer. J. Mol. Diagn.
9: 472-478
[Abstract][Full Text]
Lynch, H. T., Boland, C. R., Rodriguez-Bigas, M. A., Amos, C., Lynch, J. F., Lynch, P. M.
(2007). Who Should Be Sent for Genetic Testing in Hereditary Colorectal Cancer Syndromes?. JCO
25: 3534-3542
[Abstract][Full Text]
Vasen, H F A, Moslein, G, Alonso, A, Bernstein, I, Bertario, L, Blanco, I, Burn, J, Capella, G, Engel, C, Frayling, I, Friedl, W, Hes, F J, Hodgson, S, Mecklin, J-P, Moller, P, Nagengast, F, Parc, Y, Renkonen-Sinisalo, L, Sampson, J R, Stormorken, A, Wijnen, J
(2007). Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J. Med. Genet.
44: 353-362
[Abstract][Full Text]
Takahashi, M., Shimodaira, H., Andreutti-Zaugg, C., Iggo, R., Kolodner, R. D., Ishioka, C.
(2007). Functional Analysis of Human MLH1 Variants Using Yeast and In vitro Mismatch Repair Assays. Cancer Res.
67: 4595-4604
[Abstract][Full Text]
Wolpin, B. M., Meyerhardt, J. A., Mamon, H. J., Mayer, R. J.
(2007). Adjuvant Treatment of Colorectal Cancer. CA Cancer J Clin
57: 168-185
[Abstract][Full Text]
Xu, Y., Pasche, B.
(2007). TGF-{beta} signaling alterations and susceptibility to colorectal cancer. Hum Mol Genet
16: R14-R20
[Abstract][Full Text]
Cahill, D. P., Levine, K. K., Betensky, R. A., Codd, P. J., Romany, C. A., Reavie, L. B., Batchelor, T. T., Futreal, P. A., Stratton, M. R., Curry, W. T., Iafrate, A. J., Louis, D. N.
(2007). Loss of the Mismatch Repair Protein MSH6 in Human Glioblastomas Is Associated with Tumor Progression during Temozolomide Treatment. Clin. Cancer Res.
13: 2038-2045
[Abstract][Full Text]
Raptis, S., Mrkonjic, M., Green, R. C., Pethe, V. V., Monga, N., Chan, Y. M., Daftary, D., Dicks, E., Younghusband, B. H., Parfrey, P. S., Gallinger, S. S., McLaughlin, J. R., Knight, J. A., Bapat, B.
(2007). MLH1 -93G>A Promoter Polymorphism and the Risk of Microsatellite-Unstable Colorectal Cancer. JNCI J Natl Cancer Inst
99: 463-474
[Abstract][Full Text]
Georgitsi, M., Raitila, A., Karhu, A., Tuppurainen, K., Makinen, M. J., Vierimaa, O., Paschke, R., Saeger, W., van der Luijt, R. B., Sane, T., Robledo, M., De Menis, E., Weil, R. J., Wasik, A., Zielinski, G., Lucewicz, O., Lubinski, J., Launonen, V., Vahteristo, P., Aaltonen, L. A.
(2007). Molecular diagnosis of pituitary adenoma predisposition caused by aryl hydrocarbon receptor-interacting protein gene mutations. Proc. Natl. Acad. Sci. USA
104: 4101-4105
[Abstract][Full Text]
Lynch, H. T., Lynch, J. F., Lynch, P. M.
(2007). Toward a Consensus in Molecular Diagnosis of Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome). JNCI J Natl Cancer Inst
99: 261-263
[Full Text]
Lagerstedt Robinson, K., Liu, T., Vandrovcova, J., Halvarsson, B., Clendenning, M., Frebourg, T., Papadopoulos, N., Kinzler, K. W., Vogelstein, B., Peltomaki, P., Kolodner, R. D., Nilbert, M., Lindblom, A.
(2007). Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) Diagnostics. JNCI J Natl Cancer Inst
99: 291-299
[Abstract][Full Text]
Niessen, R C, Berends, M J W, Wu, Y, Sijmons, R H, Hollema, H, Ligtenberg, M J L, de Walle, H E K, de Vries, E G E, Karrenbeld, A, Buys, C H C M, van der Zee, A G J, Hofstra, R M W, Kleibeuker, J H
(2006). Identification of mismatch repair gene mutations in young patients with colorectal cancer and in patients with multiple tumours associated with hereditary non-polyposis colorectal cancer. Gut
55: 1781-1788
[Abstract][Full Text]
Guillem, J. G., Wood, W. C., Moley, J. F., Berchuck, A., Karlan, B. Y., Mutch, D. G., Gagel, R. F., Weitzel, J., Morrow, M., Weber, B. L., Giardiello, F., Rodriguez-Bigas, M. A., Church, J., Gruber, S., Offit, K.
(2006). ASCO/SSO Review of Current Role of Risk-Reducing Surgery in Common Hereditary Cancer Syndromes. JCO
24: 4642-4660
[Abstract][Full Text]
Balmana, J., Stockwell, D. H., Steyerberg, E. W., Stoffel, E. M., Deffenbaugh, A. M., Reid, J. E., Ward, B., Scholl, T., Hendrickson, B., Tazelaar, J., Burbidge, L. A., Syngal, S.
(2006). Prediction of MLH1 and MSH2 mutations in Lynch syndrome.. JAMA
296: 1469-1478
[Abstract][Full Text]
Ford, J. M., Whittemore, A. S.
(2006). Predicting and preventing hereditary colorectal cancer.. JAMA
296: 1521-1523
[Full Text]
Hampel, H., Frankel, W., Panescu, J., Lockman, J., Sotamaa, K., Fix, D., Comeras, I., La Jeunesse, J., Nakagawa, H., Westman, J. A., Prior, T. W., Clendenning, M., Penzone, P., Lombardi, J., Dunn, P., Cohn, D. E., Copeland, L., Eaton, L., Fowler, J., Lewandowski, G., Vaccarello, L., Bell, J., Reid, G., de la Chapelle, A.
(2006). Screening for Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) among Endometrial Cancer Patients.. Cancer Res.
66: 7810-7817
[Abstract][Full Text]
Barnetson, R. A., Tenesa, A., Farrington, S. M., Nicholl, I. D., Cetnarskyj, R., Porteous, M. E., Campbell, H., Dunlop, M. G.
(2006). Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer.. NEJM
354: 2751-2763
[Abstract][Full Text]
Carethers, J M
(2006). Prospective evaluation of fluorouracil chemotherapy based on the genetic makeup of colorectal cancer.. Gut
55: 759-761
[Full Text]
Chao, E. C., Lipkin, S. M.
(2006). Molecular models for the tissue specificity of DNA mismatch repair-deficient carcinogenesis. Nucleic Acids Res
34: 840-852
[Abstract][Full Text]
Llor, X., Pons, E., Xicola, R. M., Castells, A., Alenda, C., Pinol, V., Andreu, M., Castellvi-Bel, S., Paya, A., Jover, R., Bessa, X., Giros, A., Roca, A., Gassull, M. A., for the Gastrointestinal Oncology Group of the Spa,
(2005). Differential Features of Colorectal Cancers Fulfilling Amsterdam Criteria without Involvement of the Mutator Pathway. Clin. Cancer Res.
11: 7304-7310
[Abstract][Full Text]
Sotamaa, K., Liyanarachchi, S., Mecklin, J.-P., Jarvinen, H., Aaltonen, L. A., Peltomaki, P., de la Chapelle, A.
(2005). p53 Codon 72 and MDM2 SNP309 Polymorphisms and Age of Colorectal Cancer Onset in Lynch Syndrome. Clin. Cancer Res.
11: 6840-6844
[Abstract][Full Text]
Ramsey, S. D., Hampel, H., de la Chapelle, A., Benton, W.C.
(2005). Screening for the Lynch Syndrome. NEJM
353: 524-525
[Full Text]
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