Diversity of the clinical presentation of the MMR gene biallelic mutations
- 652 Downloads
Constitutional mismatch repair-deficiency, due to biallelic mutations of MMR genes, results in a tumour spectrum characterized by leukaemias, lymphomas, brain tumours and adenocarcinomas of the gastro-intestinal tract, occurring mostly in childhood. We report here two families illustrating the phenotypic diversity associated with biallelic MMR mutations. In the first family, two siblings developed six malignancies including glioblastoma, lymphoblastic T cell lymphoma, rectal and small bowel adenocarcinoma with onset as early as 6 years of age. We showed that this dramatic clinical presentation was due to the presence of two complex genomic PMS2 deletions in each patient predicted to result into complete PMS2 inactivation. In the second family, the index case presented with an early form of Lynch syndrome with colorectal adenocarcinomas at ages 17 and 20 years, and urinary tract tumours at the age of 25 years. We identified in this patient two MSH6 mutations corresponding to a frameshift deletion and an in frame deletion. The latter was not predicted to result into complete inactivation of MSH6. These reports show that the clinical expression of biallelic MMR mutations depends on the biological impact of the second MMR mutation and that, in clinical practice, the presence of a second MMR mutation located in trans should also be considered in patients suspected to present a Lynch syndrome with an unusual early-onset of tumours.
KeywordsMMR Mutation Tumour
This work was supported by the INCa, the French National Cancer Institute.
Conflict of interest
The authors declared that they have no conflict of interest.
- 5.Barwell J, Pangon L, Hodgson S, Georgiou A, Kesterton I, Slade T, Taylor M, Payne SJ, Brinkman H, Smythe J, Sebire NJ, Solomon E, Docherty Z, Camplejohn R, Homfray T, Morris JR (2007) Biallelic mutation of MSH2 in primary human cells is associated with sensitivity to irradiation and altered RAD51 foci kinetics. J Med Genet 44:516–520PubMedCrossRefGoogle Scholar
- 6.Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, 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 58:5248–5257PubMedGoogle Scholar
- 9.Auclair J, Leroux D, Desseigne F, Lasset C, Saurin JC, Joly MO, Pinson S, Xu XL, Montmain G, Ruano E, Navarro C, Puisieux A, Wang Q (2007) Novel biallelic mutations in MSH6 and PMS2 genes: gene conversion as a likely cause of PMS2 gene inactivation. Hum Mutat 28:1084–1090PubMedCrossRefGoogle Scholar
- 10.Senter L, Clendenning M, Sotamaa K, Hampel H, Green J, Potter JD, Lindblom A, Lagerstedt K, Thibodeau SN, Lindor NM, Young J, Winship I, Dowty JG, White DM, Hopper JL, Baglietto L, Jenkins MA, de la Chapelle A (2008) The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology 135:419–428PubMedCentralPubMedCrossRefGoogle Scholar
- 12.Leenen CH, Geurts-Giele WR, Dubbink HJ, Reddingius R, van den Ouweland AM, Tops CM, van de Klift HM, Kuipers EJ, van Leerdam ME, Dinjens WN, Wagner A (2011) Pitfalls in molecular analysis for mismatch repair deficiency in a family with biallelic pms2 germline mutations. Clin Genet 80:558–565PubMedCrossRefGoogle Scholar
- 13.Vasovcak P, Krepelova A, Menigatti M, Puchmajerova A, Skapa P, Augustinakova A, Amann G, Wernstedt A, Jiricny J, Marra G, Wimmer K (2012) Unique mutational profile associated with a loss of TDG expression in the rectal cancer of a patient with a constitutional PMS2 deficiency. DNA Repair (Amst) 11:616–623CrossRefGoogle Scholar
- 15.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, French Cancer Genetics Network (2001) Cancer risk associated with germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. JAMA 305:2304–2310CrossRefGoogle Scholar