Hidden burden of chronic non-communicable diseases. Part 2: prevalence of germline variants associated with cancers among residents of the Russian Federation

Introduction. Cancer is a leading cause of mortality worldwide. Hereditary (germline) mutations in cancer predisposition genes significantly contribute to oncogenesis (accounting for 3–12.6% of adult cases). Identifying carriers of pathogenic/likely pathogenic (P/LP) variants is crucial for cancer prevention and its early detection. Large-scale data on the prevalence of such variants in the general population of the Russian Federation, essential for healthcare resource planning, have been extremely limited until now.

Objective. To assess the prevalence and spectrum of pathogenic and likely pathogenic germline variants in genes associated with cancer risk in a Russian population cohort.

Materials and methods. An analysis of whole-genome sequencing data from 116,794 participants (a representative sample of the adult population from 86 federal subjects of the Russian Federation) was conducted. The search for P/LP variants in cancer-associated genes was performed based on the ClinVar database. Variant annotation was carried out considering the level of evidence. Statistical analysis was performed using Python (v3.9.12).

Results. P/LP variants were identified in 26 cancer-associated genes among 2643 participants (2.26%). The most frequent variant was rs36053993 (MUTYH, 0.28%), with its frequency in the Russian Federation being lower than in global databases (ALFA, gnomAD). Level A variants (only those with the “reviewed by expert panel” level of evidence) were carried by 0.8% of individuals collectively. Level B variants (those with the “reviewed by expert panel” and “criteria provided, multiple submitters, no conflicts” levels of evidence) were carried by 2.08%. The inclusion of less reliable evidence levels (C, D) increased this proportion only marginally, to 2.26%. A statistically significant decrease in the proportion of carriers of Level A variants with age was observed (p = 0.007), while the overall proportion of P/LP variant carriers decreased only slightly (p = 0.17). Substantial geographical variability in prevalence was identified, ranging from 865 (Bashkortostan) to 6250 (Chechnia) variants per 100,000 population. In Moscow, the prevalence was 2340 per 100,000.

Conclusions. The study revealed a significant “hidden burden” of P/LP oncogenic germline variant carriers (2.26%) in the Russian population. The primary burden is attributed to variants with a high level of evidence (Level B). The substantial variability in prevalence across regions of the Russian Federation necessitates a differentiated approach to healthcare resource planning. The data obtained substantiate the need for implementing genetic screening programs (especially for individuals with a family history) and enhanced oncological surveillance for carriers. This represents a strategic direction for reducing cancer incidence and mortality in high genetic risk groups within the Russian Federation.

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