Methylation analysis of MLH1 improves the selection of patients for genetic testing in Lynch syndrome

Lucía Pérez-Carbonell, Cristina Alenda, Artemio Payá, Adela Castillejo, Víctor M. Barberá, Carmen Guillén, Estefanía Rojas, Nuria Acame, Francisco J. Gutiérrez-Aviñõ, Antoni Castells, Xavier Llor, Montserrat Andreu, Josẽ Luis Soto, Rodrigo Jover

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


Inactivation of MLH1 due to promoter hypermethylation strongly suggests a sporadic origin, providing exclusion criteria for Lynch syndrome. The aim of this study is to compare the utility of methylation analysis of MLH1 and BRAF V600E mutations for the selection of patients with MLH1 negative colorectal cancer for genetic testing. MLH1 methylation status was evaluated by MethyLight and methylation-specific MLPA (MS-MLPA) in tumor DNA from 73 colorectal cancer patients with loss of MLH1 protein expression. These tumors were analyzed for BRAF V600E mutations, and genetic testing for germline MLH1 mutations was performed in all corresponding patients. Ten patients had germline mutations in MLH1 and none of their tumors showed significant MLH1 methylation or BRAF V600E mutation. MLH1 genetic testing excluded patients by MethyLight in 47 patients (64%), by MS-MLPA in 49 (67%), and BRAF V600E mutation in only 25 patients (34%) (χ2 P = 0.00001). Specificity was 75% for MethyLight, 78% for MS-MLPA and 40% for BRAF V600E mutation. The use of MethyLight or MS-MLPA instead of BRAF mutation resulted in a cost reduction of 41% and 45%, respectively, per every MLH1 mutation detected. Taken together, methylation analysis of MLH1 shows better performance characteristics than BRAF V600E mutation in the selection of patients for genetic testing of MLH1, especially when using MS-MLPA.

Original languageEnglish
Pages (from-to)498-504
Number of pages7
JournalJournal of Molecular Diagnostics
Issue number4
StatePublished - 1 Jul 2010

Bibliographical note

Funding Information:
Supported in part by a grant from the Fundación de la CV para la investigación en el Hospital General Universitario de Alicante ( Grupos consolidados 2008 ). L.P.-C. is the recipient of a grant from the Instituto de Salud Carlos III ( FI07/00303 ). N.A. is supported by Schering-Plough.


Dive into the research topics of 'Methylation analysis of MLH1 improves the selection of patients for genetic testing in Lynch syndrome'. Together they form a unique fingerprint.

Cite this