Screening of the DNA mismatch repair genes MLH1, MSH2 and MSH6in a Greek cohort of Lynch syndrome suspected families

Abstract

BackgroundGermline mutations in the DNA mismatch repair genes predispose to Lynch syndrome, thus conferring a high relative risk of colorectal and endometrial cancer. The MLH1, MSH2 and MSH6 mutational spectrum reported so far involves minor alterations scattered throughout their coding regions as well as large genomic rearrangements. Therefore, a combination of complete sequencing and a specialized technique for the detection of genomic rearrangements should be conducted during a proper DNA-testing procedure. Our main goal was to successfully identify Lynch syndrome families and determine the spectrum of MLH1, MSH2 and MSH6 mutations in Greek Lynch families in order to develop an efficient screening protocol for the Greek colorectal cancer patients' cohort.MethodsForty-two samples from twenty-four families, out of which twenty two of Greek, one of Cypriot and one of Serbian origin, were screened for the presence of germline mutations in the major mismatch repair genes through direct sequencing and MLPA. Families were selected upon Amsterdam criteria or revised Bethesda guidelines.ResultsTen deleterious alterations were detected in twelve out of the twenty-four families subjected to genetic testing, thus our detection rate is 50%. Four of the pathogenic point mutations, namely two nonsense, one missense and one splice site change, are novel, whereas the detected genomic deletion encompassing exon 6 of the MLH1 gene has been described repeatedly in the LOVD database. The average age of onset for the development of both colorectal and endometrial cancer among mutation positive families is 43.2 years.ConclusionThe mutational spectrum of the MMR genes investigated as it has been shaped by our analysis is quite heterogeneous without any strong indication for the presence of a founder effect.

Systematic Study on Genetic and Epimutational Profile of a Cohort of Amsterdam Criteria-Defined Lynch Syndrome in Singapore

“…This is the first description of a large deletion in Singapore and it accounts for 5.9% (1 out of 17) of local LS families. This prevalence is slightly lower than other reports in various ethnic groups ranging from 6- 20% [23] , especially in North America where this has been described as a founder mutation [24] . Although promoter methylation was examined in seven DNA repair genes, no families in this cohort were identified positively.…”

Implication of Microsatellite Instability Pathway in Outcome of Colon Cancer in Moroccan Population

“…These proteins form heterodimers that repair DNA damage (mismatches as well as short insertion or deletion loops) [4]. In hereditary nonpolyposis CCRs (e.g., Lynch syndrome), 90% of the MMR alterations are mainly due to constitutional mutations of the MLH1 and MSH2 gene (more rarely MSH6 or PMS2 gene) or alteration in EPCAM (TACSTD1) gene that causes epigenetic silencing of MSH2 [5, 6], while 10 to 15% of all sporadic CCRs are due to hypermethylation of CpG islands in the MLH1 promoter [6].…”

Charge transport properties of ideal and natural DNA segments, as mutation detectors

“…Another category of mutations is germline mutations 60 , i.e. a gene change in a reproductive cell that becomes incorporated into the DNA of every cell in the body of the offspring.…”