Abstract
Mutations in the mutL homolog 1 (MLH1) gene are frequent in patients with hereditary non-polyposis colorectal cancer (CRC). The MLH1 gene was screened for mutations in patients with sporadic CRC. The nucleotide sequences for all 19 exons of MLH1 were analyzed by high resolution melting and sequenced in a group of 104 sporadic CRC patients, and the results were verified in a replication group of 1,095 patients and 1,469 controls. Different melting profiles for exon 2 of the MLH1 gene were observed in the germline DNA of one patient. Sequencing of the patient’s DNA resulted in the identification of a heterozygous C>G variant at c.204, which resulted in an Ile68Met change in the amino acid. A detailed search of the National Center for Biotechnology Information and the 1000 Genomes databases indicated that the detected variant was unique. According to the SIFT and PolyPhen-2 algorithms, the substitution of Ile to Met was predicted to decrease the activity of the MLH1 protein. The newly identified, functional germline variant was not present in any other CRC patient or control. Thus, a novel germline variant in the MLH1 gene was identified, representing a rare event in sporadic CRC. The occurrence and relevance of this mutation in other types of cancer requires additional investigation.
Highlights
MutL homolog 1 (MLH1), a constituent gene in the mismatch repair pathway, carries germline mutations in individuals with Lynch syndrome, termed hereditary non‐polyposis colorectal cancer (HNPCC)
The identification of a novel germline variant in MLH1 with putative impact on the protein function is of significant importance in colorectal cancer (CRC)
The novel variant in MLH1 gene presents a rare event in sporadic CRC, which was identified in 1/1,199 patients
Summary
MutL homolog 1 (MLH1), a constituent gene in the mismatch repair pathway, carries germline mutations in individuals with Lynch syndrome, termed hereditary non‐polyposis colorectal cancer (HNPCC). The gene is reported to acquire 300 different germline mutations, which in addition to mutations in other genes involved in mismatch repair pathway, mainly mutS homolog 2 (MSH2), predispose individuals to the disease [1]. MLH1, a key protein of the mismatch repair process, contains interaction domains for MutS homologs, including MSH2, MSH3 and MSH6, postmeiotic segregation increased 2 (PMS2), MLH3 and PMS1(2). The germline mutations in MLH1 in HNPCC include nucleotide substitutions, which result in missense, nonsense or splicing errors and comprise insertions/deletions. A number of founder mutations, which account for a high proportion of mutations in families with HNPCC, which have been reported in patients with Lynch syndrome [3]. The MLH1 gene is highly polymorphic, with >1,600 variants reported to date (http://genecards. org/cgi-bin/carddisp.pl?gene=MLH1&search=mlh1%23snp)
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