Application of Multigene Panels Testing for Hereditary Cancer Syndromes.

BACKGROUND: Approximately 5-10% of all cancers are associated with hereditary cancer predisposition syndromes (HCPS). Early identification of HCPS is facilitated by widespread use of next-generation sequencing (NGS) and brings significant benefits to both the patient and their relatives. This study aims to evaluate the landscape of genetic variants in patients with personal and/or family history of cancer using NGS-based multigene panel testing. MATERIALS AND METHODS: The study cohort included 1117 probands from Russia: 1060 (94.9%) patients with clinical signs of HCPS and 57 (5.1%) healthy individuals with family history of cancer. NGS analysis of 76 HCPS genes was performed using a custom Roche NimbleGen enrichment panel. RESULTS: Pathogenic/likely pathogenic variants were identified in 378 of 1117 individuals (33.8%). The predominant number (59.8%) of genetic variants was identified in BRCA1/BRCA2 genes. CHEK2 was the second most commonly altered gene with a total of 28 (7.4%) variants, and 124 (32.8%) genetic variants were found in other 35 cancer-associated genes with variable penetrance. CONCLUSIONS: Multigene panel testing allows for a differential diagnosis and identification of high-risk group for oncological diseases. Our results demonstrate that inclusion of non-coding gene regions into HCPS gene panels is highly important for the identification of rare spliceogenic variants with high penetrance.

Association of SNPs of CD40 gene with multiple sclerosis in Russians.

Multiple sclerosis (MS) is a serious, incurable neurological disease. In 2009, the ANZgene studies detected the suggestive association of located upstream of CD40 gene in chromosome 20q13 (p = 1.3×10(-7)). Identification of the causal variant(s) in the CD40 locus leads to a better understanding of the mechanism underlying the development of autoimmune pathologies. We determined the genotypes of rs6074022, rs1883832, rs1535045, and rs11086996 in patients with MS (n = 1684) and in the control group (n = 879). Two SNPs were significantly associated with MS: rs6074022 (additive model C allele OR = 1.27, 95% CI = [1.12-1.45], p = 3×10(-4)) and rs1883832 (additive model T allele OR = 1.20, 95% CI = [1.05-1.38], p = 7×10(-3)). In the meta-analysis of our results and the results of four previous studies, we obtain the association p-value of 2.34×10(-12), which confirmed the association between MS and rs6074022 at a genome-wide significant level. Next, we demonstrated that the model including rs6074022 only sufficiently described the association. From our analysis, we can speculate that the association between rs1883832 and MS was induced by LD, whereas rs6074022 was a marker in stronger LD with the functional variant or was the functional variant itself. Our results indicated that the functional variants were located in the upstream region of the gene CD40 and were in higher LD with rs6074022 than LD with rs1883832.

Polymorphic locus rs10492972 of the KIF1B gene association with multiple sclerosis in Russia: case control study.

Axonal degeneration is responsible for the progression of the irreversible destruction caused by multiple sclerosis (MS) resulting ultimately in permanent disability. The KIF1B protein, a member of the kinesin family, is necessary for axon growth and myelination in vertebrates. In the recent paper, Aulchenko et al. suggested that the rs10492972[C] variant of KIF1B increases susceptibility to MS, but three following replication study didn't confirm this association. We studied the association of the polymorphic locus rs10492972 present in the KIF1B gene with genetic predisposition and its occurrence in clinical presentations of MS patients resident in western Siberia and the Sakha Republic (Yakutia), Russia. rs10492972 has been genotype in 833 samples of MS patient and 689 healthy controls. Distribution of rs10492972 genotypes corresponded with a Hardy-Weinberg distribution in both the MS patient and control groups, with the frequency of the C allele being the same in both groups (33%). Frequencies of occurrence of the genotypes were not shown to be associated with different disease courses or other characteristics of the disease, such as age at onset or duration. A complete meta-analysis of all analogous studies published to date showed that the protective effect of the rs10492972[C] allele is statistically significant (OR=0.95, C.I.95% [0.90-0.99], p=0.02).