A Single Nucleotide Substitution (−107C → G) in the hMLH1 Promoter Found in Colorectal Cancer Population Reduces Transcriptional Activity

Abstract

Inactivation of the DNA mismatch repair gene hMLH1 predisposes one to colorectal cancer. We have identified a C to G nucleotide substitution at position -107 relative to the hMLH1 gene translation initiation site in three of 163 colorectal cancer patients with an allele frequency of 0.0092 (3/326). One of the three -107G alleles occurred in one patient out of five with reduced hMLH1 expression in the tumor tissue. The -107G was not found in 63 healthy individuals. This substitution reduced transcriptional activity by 51% compared with -107C (P<0.01) and impeded the promoter-binding capacity of nuclear proteins. Although the small number of identified -107G alleles is insufficient to evaluate the contribution to the carcinogenesis and clinicopathological properties of the tumors, the effects of -107G on hMLH1 gene transcription and nuclear protein binding to the promoter sequence implicate the site, including -107C, as a crucial element interacting with the activator that maintains hMLH1 gene expression.

MLH1-rheMac hereditary nonpolyposis colorectal cancer syndrome in rhesus macaques

“…This MLH1 promoter region includes the DNA binding sequence of the CDP-CR transcription factor, which interacts with CCAAT boxes to facilitate transcription ( 41 ). Similarly, a single-nucleotide substitution (−107C → G) in the MLH1 promoter found in colorectal cancer populations has been shown to reduce transcriptional activity ( 42 ). The mutation −42C > T in the promoter region of the MLH1 gene, localized within a putative Myb protooncogene binding site, has been described in a Newfoundland kindred, meeting the Amsterdam Criteria for Lynch syndrome (or HNPCC) ( 43 ).…”

Diagnosis of Lynch syndrome in cancer patients: the position of the Interregional organization of molecular geneticists in Oncology and Oncohematology

“…В отдельных случаях даже выполнение высокопроизводительного секвенирования панели генов или целого экзома не позволяет установить патогенный структурный вариант. В таких ситуациях, при условии доступности исследовательских проектов, можно рассматривать вопрос о выполнении полногеномного секвенирования, которое позволит диагностировать варианты, расположенные в промоторных или интронных областях генов MMR [28,29].…”