Screening the APC, MLH1, MSH2 and TP53 Mutations in Patients with Early Onset of Colorectal Cancer

Abstract

Objective: A molecular-genetic study of early onset colorectal cancer (CRC) patients in Kazakhstan. Methods: The direct sequencing of crucial regions of key CRC genes (APC codons between nucleotides 967-1386 and 1286–1513; exons 8 and 16 of MLH1 and exon 7 of MSH2; exons 5-9 of TP53) was performed for early cancer-onset and suspected familial cases.Results: Blood was collected from 249 patients diagnosed with rectal or colon cancer. There were 32 patients with early onset CRC (28-50 yrs), including 10 patients with a family history of cancer. Two types of nucleotide replacements were detected in intron 4 (c.376-19C>T) and intron 9 (c.993+12T>C) of TP53, both in the heterozygous state. Another nucleotide substitution was present in 15 patients in intron 15 of MLH1 (c.1732-90C>A) while known coding polymorphisms were observed in exon 8 of MLH1 (rs1799977-A655G/Ile219Val), in exon 7 of MSH2 (rs5028341-C1168T/Leu390Phe), in exon 15 of APC (rs1801166-G3949C/p.Glu1317Gln and rs41115– 4479G>A). The single deletion, c.3613delA (p.Ser1205fs), located in exon 15 of APC gene, was found in the heterozygous state in two patients with a family history of adenomatous polyposis.Conclusion: We suggest a possible role of MLH1 655A>G, MSH2 1168C>T, APC 4479G>A, and APC 3949G>C polymorphisms in the susceptibility to early onset of CRC. A single base pair deletion at codon 1205 (c.3613delA) of APC gene seems to be differentially associated with early-onset cases depending on having a family history of CRC.