Lynch syndrome in Tunisia: first description of clinical features and germline mutations
- 226 Downloads
High rates of early colorectal cancers (CRC) are observed in Tunisia suggesting genetic susceptibility. Nevertheless, up to now, no molecular study has been performed in the Tunisian population. In our research, we evaluated the clinical characteristics of Tunisian families suspected of Lynch syndrome and the contribution of DNA mismatch repair (MMR) genes.
Thirty-one unrelated families suspected of Lynch syndrome were studied. Probands were tested for the presence of germline mutations in the MMR genes MLH1, MSH2, MSH6 and in MUTYH. Available tumours were analysed for microsatellite instability and expression of MMR proteins. Detailed family and medical histories were collected.
A total of 134 cancers were noted in the 31 families, the most frequent type of cancer corresponding to CRC (69%), followed by uterine cancer (7.5%). Germline mutations were identified in 11 (35.5%) families (six MSH2, five MLH1, including seven novel mutations), seven of which fulfilled the Amsterdam criteria (sensitivity, 63.6%; positive predictive value, 58.3%). Noteworthy, germline mutations were detected in 52.6% of male patients tested, but in only 8.3% of females (p = 0.02). Moreover, CRC were essentially left sided in families without detected mutation (p = 0.017). Ages of onset of cancers and tumour spectrum were very similar in families with or without MMR germline mutation, contrasting with previous studies performed in other populations.
MMR genes contribute significantly to CRC susceptibility in the Tunisian population. However, the cause of early CRC susceptibility remains unknown in most cases, especially in women and in patients with early left colon or rectal cancer.
KeywordsLynch syndrome Hereditary nonpolyposis colorectal cancer DNA mismatch repair Microsatellite instability MUTYH
Hereditary nonpolyposis colorectal cancer
Multiplex ligation dependent probe amplification
This study was the result of collaboration between the Universities of Tunis-El Manar and Lille Nord de France. S.A.B. was supported in part by a grant from the Tunisian government. We are indebted to all family members who agreed to attend our study. We also thank Dr O. Trabelsi, gastroenterologist in Tunis, Tunisia for providing us with families, Dr A. Wacrenier, Department of Pathology of the CHRU of Lille, France, for her help in immunohistochemistry of MMR proteins, Dr M. Crépin, Platform of Molecular Biology of the CHRU of Lille, France, and S. Aissi for revision of the text.
Conflict of interest
- 1.Ben Abdalla M (1998) Registre des cancers Nord-Tunisie 1995–1998Google Scholar
- 4.Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, Clendenning M, Sotamaa K, Prior T, Westman JA, 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. J Clin Oncol 26:5783–5788PubMedCrossRefGoogle Scholar
- 5.Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, Nakagawa H, Sotamaa K, Prior TW, Westman J, Panescu J, Fix D, Lockman J, Comeras I, de la Chapelle A (2005) Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 352:1851–1860PubMedCrossRefGoogle Scholar
- 6.Vasen HF, Möslein G, Alonso A, Bernstein I, Bertario L, Blanco I, Burn J, Capella G, Engel C, Frayling I, Friedl W, Hes FJ, Hodgson S, Mecklin JP, Møller P, Nagengast F, Parc Y, Renkonen-Sinisalo L, Sampson JR, Stormorken A, Wijnen J (2007) Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet 44:353–362PubMedCrossRefGoogle Scholar
- 7.Aaltonen LA, Peltomäki P, Mecklin JP, Järvinen H, Jass JR, Green JS, Lynch HT, Watson P, Tallqvist G, Juhola M, Sistonen P, Hamilton SR, Kinzler KW, Vogelstein B, de la Chapelle A (1994) Replication errors in benign and malignant tumours from hereditary nonpolyposis colorectal cancer patients. Cancer Res 54:1645–1648PubMedGoogle Scholar
- 8.Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MR, Fodde R, Ranzani GN, Srivastava S (1998) A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 8:5248–5257Google Scholar
- 10.Veigl ML, Kasturi L, Olechnowicz J, Ma AH, Lutterbaugh JD, Periyasamy S, Li GM, Drummond J, Modrich PL, Sedwick WD, Markowitz SD (1998) Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc Natl Acad Sci USA 95:8698–8702PubMedCrossRefGoogle Scholar
- 13.Rodriguez-Bigas MA, Boland CR, Hamilton SR, Henson DE, Jass JR, Khan PM, Lynch HT, Perucho M, Smyrk T, Sobin L, Srivasta SA (1997) A national cancer institute workshop on hereditary nonpolyposis colorectal cancer syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst 89:1758–1762PubMedCrossRefGoogle Scholar
- 14.Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Rüschoff J, Fishel R, Lindor NM, Burgart LJ, Hamelin R, Hamilton SR, Hiatt RA, Jass J, Lindblom A, Lynch HT, Peltomaki P, Ramsey SD, Rodriguez-Bigas MA, Vasen HF, Hawk ET, Barrett JC, Freedman AN, Srivastava S (2004) Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261–268PubMedCrossRefGoogle Scholar
- 17.Nyström-Lahti M, Wu Y, Moisio AL, Hostra RMW, Osinga J, Mecklin JP, Järvinen HJ, Leisti J, Buys CHCM, de La Chapelle A, Peltomäki P (1996) DNA mismatch repair gene mutations in 55 kindreds with verified or putative hereditary non-polyposis colorectal cancer. Hum Mol Genet 5:763–769PubMedCrossRefGoogle Scholar
- 19.Aissi-Ben Moussa S, Moussa A, Lovecchio T, Kourda N, Najjar T, Ben Jilani S, El Gaaied A, Porchet N, Manai M, Buisine MP (2008) Identification and characterization of a novel MLH1 genomic rearrangement as the cause of HNPCC in a Tunisian family: evidence for a homologous Alu-mediated recombination. Fam Cancer 8:119–126PubMedCrossRefGoogle Scholar
- 22.Wang L, Baudhuin LM, Boardman LA, Steenblock KJ, Petersen GM, Halling KC, French AJ, Johnson RA, Burgart LJ, Rabe K, Lindor NM, Thibodeau SN (2004) MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps. Gastroenterology 127:9–16PubMedCrossRefGoogle Scholar
- 25.Park JG, Kim DW, Hong CW, Nam BH, Shin YK, Hong SH, Kim IJ, Lim SB, Aronson M, Bisgaard ML, Brown GJ, Burn J, Chow E, Conrad P, Douglas F, Dunlop M, Ford J, Greenblatt MS, Heikki J, Heinimann K, Lynch EL, Macrae F, McKinnon WC, Möeslein G, Rossi BM, Rozen P, Schofield L, Vaccaro C, Vasen H, Velthuizen M, Viel A, Wijnen J (2006) Germ line mutations of mismatch repair genes in hereditary nonpolyposis colorectal cancer patients with small bowel cancer: International Society for Gastrointestinal Hereditary Tumours Collaborative Study. Clin Cancer Res 12:3389–3393PubMedCrossRefGoogle Scholar
- 26.Wijnen J, Khan PM, Vasen H, Menko F, Van der Klift H, Van dan Broek M, Van Leeuwen-Cornelisse I, Nagengast F, Meijers-Heijboer EJ, Lindhout D, Griffioen G, Cats A, Kleibeuker J, Varesco L, Bertario L, Bisgaard ML, Mohr J, Kolodner R, Fodde R (1996) Majority of hMLH1 mutations responsible for hereditary nonpolyposis colorectal cancer cluster at the exonic region 15–16. Am J Hum Genet 58:300–307PubMedGoogle Scholar
- 31.Menigatti M, Di Gregorio C, Borghi F, Sala E, Scarselli A, Pedroni M, Foroni M, Benatti P, Roncucci L, Ponz de Leon M, Percesepe A (2001) Methylation pattern of different regions of the MLH1 promoter and silencing of gene expression in hereditary and sporadic colorectal cancer. Genes Chromosomes Cancer 31:357–361PubMedCrossRefGoogle Scholar
- 32.Bettstetter M, Dechant S, Ruemmele P, Grabowski M, Keller G, Holinski-Feder E, Hartmann A, Hofstaedter F, Dietmaier W (2007) Distinction of hereditary nonpolyposis colorectal cancer and sporadic microsatellite-unstable colorectal cancer through quantification of MLH1 methylation by real-time PCR. Clin Cancer Res 13:3221–3228PubMedCrossRefGoogle Scholar
- 37.Southey MC, Jenkins MA, Mead L, Whitty J, Trivett M, Tesoriero AA, Smith LD, Jennings K, Grubb G, Royce SG, Walsh MD, Barker MA, Young JP, Jass JR, St John DJ, Macrae FA, Giles GG, Hopper JL (2005) Use of molecular tumour characteristics to prioritize mismatch repair gene testing in early-onset colorectal cancer. J Clin Oncol 23:6524–6532PubMedCrossRefGoogle Scholar
- 39.Lipton LR, Johnson V, Cummings C, Fisher S, Risby P, Eftekhar Sadat AT, Cranston T, Izatt L, Sasieni P, Hodgson SV, Thomas HJ, Tomlinson IP (2004) Refining the Amsterdam criteria and Bethesda guidelines: testing algorithms for the prediction of mismatch repair mutation status in the familial cancer clinic. J Clin Oncol 22:4934–4943PubMedCrossRefGoogle Scholar
- 40.Balmaña J, Balaguer F, Castellví-Bel S, Steyerberg EW, Andreu M, Llor X, Jover R, Castells A, Syngal S (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 45:557–563PubMedCrossRefGoogle Scholar
- 42.Koch-Muller Y, Vogelsang H, Kopp R, Lohse P, Keller G, Aust D, Muders M, Gross M, Daum J, Schiemann U, Grabowski M, Scholz M, Kerker B, Becker I, Henke G, Holinski-Feder E (2005) Hereditary non-polyposis colorectal cancer: clinical and molecular evidence for a new entity of hereditary colorectal cancer. Gut 54:1733–1740CrossRefGoogle Scholar
- 43.Lindor NM, Rabe K, Petersen GM, Haile R, Casey G, Baron J, Callinger S, Bapat B, Aronson M, Hopper J, Jass J, Le Marchand L, Grove J, Potter J, Newcomb P, Terdiman JP, Conrad P, Moslein G, Goldberg R, Ziogas A, Anton-Culver H, de Andrade M, Siegmund M, Thibodeau SN, Boardman LA, Seminara D (2005) Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency:familial colorectal cancer type X. JAMA 293:1979–1985PubMedCrossRefGoogle Scholar
- 44.Llor X, Pons E, Xicola RM, Castells A, Alenda C, Piñol V, Andreu M, Castellví-Bel S, Payá A, Jover R, Bessa X, Girós A, Roca A, Gassull MA (2005) Differential features of colorectal cancers fulfilling Amsterdam criteria without involvement of the mutator pathway. Clin Cancer Res 11:7304–7310PubMedCrossRefGoogle Scholar
- 45.Vasen HFA, Stormorken A, Menko FH, Nagengast FM, Kleibeuker JH, Griffioen G, Taal BG, Moller P, Wijnen JT (2001) MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. J Clin Oncol 19:4074–4080PubMedGoogle Scholar