Mismatch repair (MMR) genes mutation carriers are a subgroup of colorectal cancer prone persons whose identification leads to a highly-effective risk management. The clinical condition, Lynch syndrome, has a fair pathological hallmark, the microsatellite DNA instability (MSI) caused by germ-line mutations in either the MLH1, MSH2, MSH6 or PMS2 gene. This condition accounts for about 3% of colorectal cancer. Amsterdam criteria have been first established to identify such condition based on patients’ personal and family history of colorectal cancer. These initial criteria were too stringent to detect Lynch patients in medical practice and were progressively enlarged to consider the complete tumor spectrum and the tumor status regarding MSI.
Genetic testing results now guide screening programs for patients and families and consensus clinical guidelines have been proposed allowing the efficient detection of curable lesions.
Supported by the French national cancer institute, the French network of sixteen laboratories involved in Lynch syndrome genetic testing collected their clinic, histological and molecular data regarding all MMR variations identified since 1995. This joint venture enabled to detail the mechanisms of large genomic rearrangements, to develop methods searching for splicing anomalies, to study cancer risks associated with validated pathogenic mutations, to set up the external quality assessment of MMR genetic testing for EMQN.
Publications of the French network involved in Lynch syndrome genetic testing
1. Charbonnier F, Raux G, Wang Q, Drouot N, Cordier F, Limacher JM, Saurin JC, Puisieux A, Olschwang S, Frebourg T: Detection of exon deletions and duplications of the mismatch repair genes in hereditary nonpolyposis colorectal cancer families using multiplex polymerase chain reaction of short fluorescent fragments. Cancer Res. 2000;60:2760-2763.
2. Charbonnier F, Olschwang S, Wang Q, Boisson C, Martin C, Buisine MP, Puisieux A, Frebourg T. MSH2 in contrast to MLH1 and MSH6 is frequently inactivated by exonic and promoter rearrangements in hereditary nonpolyposis colorectal cancer. Cancer Res. 2002;62:848-853.
3. Parc Y, Boisson C, Thomas G, Olschwang S. Cancer risk in 348 french MSH2 or MLH1 gene carriers. J Med Genet 2003;40:208-213.
4. Di Fiore F, Charbonnier F, Martin C, Frérot S, Olschwang S, Wang Q, Boisson C, Buisine MP, Nilbert M, Lindblom A, Frébourg T. Screening for genomic rearrangements of the MMR genes must be included in the routine diagnosis of HNPCC. J Med Genet. 2004;41:18-20.
5. Tournier I, Raux G, Di Fiore F, Maréchal I, Leclerc C, Martin C, Wang Q, Buisine MP, Stoppa-Lyonnet D, Olschwang S, Frébourg T, Tosi M. Analysis of the allele-specific expression of the mismatch repair gene MLH1 using a simple DHPLC-based method. Hum Mutat. 2004;23:379-384.
6. Olschwang S, Bonaiti C, Feingold J, Frebourg T, Grandjouan S, Lasset C, Laurent-Puig P, Lecuru F, Millat B, Sobol H, Thomas G, Eisinger F. Identification and management of HNPCC syndrome (hereditary non polyposis colon cancer), hereditary predisposition to colorectal and endometrial adenocarcinomas. Bull Cancer.2004;91:303-15.
7. Charbonnier F, Baert-Desurmont S, Liang P, Di Fiore F, Martin C, Frerot S, Olschwang S, Wang Q, Buisine MP, Gilbert B, Nilbert M, Lindblom A, Frebourg T. The 5' region of the MSH2 gene involved in hereditary non-polyposis colorectal cancer contains a high density of recombinogenic sequences. Hum Mutat. 2005;26:255-261
8. Baert-Desurmont S, Buisine MP, Bessenay E, Frerot S, Lovecchio T, Martin C, Olschwang S, Wang Q, Frebourg T. Partial duplications of the MSH2 and MLH1 genes in hereditary nonpolyposis colorectal cancer. Eur J Hum Genet 2007;15:383-6
9. Tournier I, Vezain M, Martins A, Charbonnier F, Baert-Desurmont S, Olschwang S, Wang Q, Buisine MP, Soret J, Tazi J, Frébourg T, Tosi M. A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects. Hum Mutat 2008;29:1412-24
10. Olschwang S, Lasset C, Baert-Desurmont S, Buisine MP, Wang Q, Hutter P, Rouleau E, Caron O, Bourdon V, Thomas G. Age dependent cancer risk is not different in between MSH2 and MLH1 mutation carriers. J Cancer Epidemiol. 2009; 2009: 791754
11. Rouleau E, Lefol C, Bourdon V, Coulet F, Noguchi T, Soubrier F, Bièche I, Olschwang S, Sobol H, Lidereau R. Quantitative PCR high-resolution melting (qPCR-HRM) curve analysis, a new approach to simultaneously screen point mutations and large rearrangements: application to MLH1 germline mutations in Lynch syndrome. Hum Mutation 2009; 30:867-75
12. Qiu J, Hutter P, Rahner N, Patton S, Olschwang S. The educational role of External Quality Assessment in genetic testing: a 7-year experience of The European Molecular Genetics Quality Network (EMQN) in Lynch syndrome. Hum Mutat 2011;32:696.
13. Bonadona V, Bonaïti B, Olschwang S, Grandjouan S, Huiart L, Longy M, Guimbaud R, Buecher B, Bignon YJ, Caron O, Colas C, Noguès C, Lejeune-Dumoulin S, Olivier-Faivre L, Polycarpe-Osaer F, Nguyen TD, Desseigne F, Saurin JC, Berthet P, Leroux D, Duffour J, Manouvrier S, Frébourg T, Sobol H, Lasset C, Bonaïti-Pellié C; for the French Cancer Genetics Network. Cancer Risks Associated With Germline Mutations in MLH1, MSH2, and MSH6 Genes in Lynch Syndrome. JAMA 2011;305:2304-2310
14. Grandval P, Baert-Desurmont S, Bonnet F, Bronner M, Buisine MP, Colas C, Noguchi T, North MO, Rey JM, Tinat J, Toulas C, OlschwangS. Colon-specific phenotype in Lynch syndrome associated with EPCAM deletion. Clin Genet 2012;82:97-99.
15. Grandval P, Barouk E, Bronner E, Buisine MP, Moretta J, Tinat J, Olschwang S. Is the controversy on breast cancer as part of the Lynch-related tumor spectrum still open? Fam Cancer 2012, DOI: 10.1007/s10689-012-9562-2.
16. Grandval P, Fabre AJ, Gaildrat P, Baert-Desurmont S, Buisine MP, Ferrari A, Wang Q, Béroud C, Olschwang S. UMD-MLH1/MSH2/MSH6 databases: description and analysis of genetic variations in French Lynch syndrome families. Database 2013; 31.
17. Grandval P, Fabre AJ, Olschwang S. Design of a core classification process for DNA mismatch repair variations of a priori unknown functional significance.. Hum Mutat 2013; 34(6): 920-2.