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Abstract
Background. CHEK2-associated neoplasms account for a significant proportion of hereditary breast cancer (BC) in Russia. The phenomenon of somatic deletion of the normal allele of a gene affected by a hereditary mutation, or loss of heterozygosity (LOH), is a frequent mechanism of complete inactivation of the corresponding protein, which is realized during the development of hereditary breast carcinomas. The contribution of the LOH phenomenon to the pathogenesis of CHEK2-dependent tumors is poorly understood, and almost all available data concern only one type of mutations - CHEK2 1100delC.
The aim of the study was to characterize the frequency of LOH in breast tumor tissues from carriers of the three types of CHEK2 alterations: CHEK2 1000delC, CHEK2 IVS2+1G>A, and CHEK2 del5395.
Materials and methods. LOH analysis was performed in a group of 50 breast cancer cases from women carrying CHEK2 1000delC (n = 19), CHEK2 IVS2+1G>A (n = 12), and CHEK2 del5395 (n = 19) mutations. Detection of LOH was carried out using a combination of methods that directly analyze the mutation locus (allele-specific PCR, Sanger sequencing, digital droplet PCR), and assess the status of single nucleotide polymorphisms surrounding the CHEK2 gene (digital droplet PCR).Results. The frequency of the LOH phenomenon in the studied cohort reached 27/50 (54%). Loss of heterozygosity was observed in 10/19 (52.6%) CHEK2 1000delC-associated, 6/12 (50%) CHEK2 IVS2+1G>A-associated, and 11/19 (57.9%) CHEK2 del5395-associated tumors. In one carcinoma from a carrier of the CHEK2 IVS2+1G>A alteration, the loss of mutated allele was confirmed. The main clinical and pathological characteristics were compared between tumors with loss and retention of heterozygosity. This comparison did not reveal any significant differences.Conclusion. Loss of heterozygosity is observed in about half of breast carcinomas arising in CHEK2 mutation carriers; the frequency of this phenomenon does not differ between three types of CHEK2 genetic defects.
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