These authors contributed equally to the work.
Evidence of constitutional MLH1 epimutation associated to transgenerational inheritance of cancer susceptibility†
Article first published online: 31 OCT 2011
© 2011 Wiley Periodicals, Inc.
Volume 33, Issue 1, pages 180–188, January 2012
How to Cite
Crépin, M., Dieu, M.-C., Lejeune, S., Escande, F., Boidin, D., Porchet, N., Morin, G., Manouvrier, S., Mathieu, M. and Buisine, M.-P. (2012), Evidence of constitutional MLH1 epimutation associated to transgenerational inheritance of cancer susceptibility. Hum. Mutat., 33: 180–188. doi: 10.1002/humu.21617
Communicated by Rolf H. Sijmons
- Issue published online: 14 DEC 2011
- Article first published online: 31 OCT 2011
- Accepted manuscript online: 22 SEP 2011 09:53AM EST
- Manuscript Accepted: 7 SEP 2011
- Manuscript Received: 6 JUN 2011
- Lynch syndrome;
Constitutional epimutations of DNA mismatch repair (MMR) genes have been recently reported as a possible cause of Lynch syndrome. However, little is known about their prevalence, the risk of transmission through the germline and the risk for carriers to develop cancers. In this study, we evaluated the contribution of constitutional epimutations of MMR genes in Lynch syndrome. A cohort of 134 unrelated Lynch syndrome-suspected patients without MMR germline mutation was screened for constitutional epimutations of MLH1 and MSH2 by quantitative bisulfite pyrosequencing. Patients were also screened for the presence of EPCAM deletions, a possible cause of MSH2 methylation. Tumors from patients with constitutional epimutations were extensively analyzed. We identified a constitutional MLH1 epimutation in two proband patients. For one of them, we report for the first time evidence of transmission to two children who also developed early colonic tumors, indicating that constitutional MLH1 epimutations are associated to a real risk of transgenerational inheritance of cancer susceptibility. Moreover, a somatic BRAF mutation was detected in one affected child, indicating that tumors from patients carrying constitutional MLH1 epimutation can mimic MSI-high sporadic tumors. These findings may have important implications for future diagnostic strategies and genetic counseling. Hum Mutat 33:180–188, 2012. © 2011 Wiley Periodicals, Inc.