NDLI: Selection of patients with germline MLH1 mutated Lynch syndrome by determination of MLH1 methylation and BRAF mutation

Content Provider	Springer Nature Link
Author	Bouzourene, Hanifa Hutter, Pierre Losi, Lorena Martin, Patricia Benhattar, Jean
Copyright Year	2009
Abstract	Lynch syndrome is one of the most common hereditary colorectal cancer (CRC) syndrome and is caused by germline mutations of MLH1, MSH2 and more rarely MSH6, PMS2, MLH3 genes. Whereas the absence of MSH2 protein is predictive of Lynch syndrome, it is not the case for the absence of MLH1 protein. The purpose of this study was to develop a sensitive and cost effective algorithm to select Lynch syndrome cases among patients with MLH1 immunohistochemical silencing. Eleven sporadic CRC and 16 Lynch syndrome cases with MLH1 protein abnormalities were selected. The BRAF c.1799T> A mutation (p.Val600Glu) was analyzed by direct sequencing after PCR amplification of exon 15. Methylation of MLH1 promoter was determined by Methylation-Sensitive Single-Strand Conformation Analysis. In patients with Lynch syndrome, there was no BRAF mutation and only one case showed MLH1 methylation (6%). In sporadic CRC, all cases were MLH1 methylated (100%) and 8 out of 11 cases carried the above BRAF mutation (73%) whereas only 3 cases were BRAF wild type (27%). We propose the following algorithm: (1) no further molecular analysis should be performed for CRC exhibiting MLH1 methylation and BRAF mutation, and these cases should be considered as sporadic CRC; (2) CRC with unmethylated MLH1 and negative for BRAF mutation should be considered as Lynch syndrome; and (3) only a small fraction of CRC with MLH1 promoter methylation but negative for BRAF mutation should be true Lynch syndrome patients. These potentially Lynch syndrome patients should be offered genetic counselling before searching for MLH1 gene mutations.
Starting Page	167
Ending Page	172
Page Count	6
File Format	PDF
ISSN	13899600
Journal	Familial Cancer
Volume Number	9
Issue Number	2
e-ISSN	15737292
Language	English
Publisher	Springer Netherlands
Publisher Date	2009-12-01
Publisher Place	Dordrecht
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	BRAF gene BRAF mutation Germline mutations Hereditary colorectal cancer Lynch syndrome MLH1 gene MLH1 methylation Biomedicine general Epidemiology Human Genetics Cancer Research
Content Type	Text
Resource Type	Article
Subject	Genetics Cancer Research Genetics (clinical) Oncology

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