Structure of germline pathogenic variants associated with hereditary cancer syndromes in patients with malignant neoplasms from the Yamalo-Nenets Autonomous Okrug based on whole-genome sequencing results

Introduction: Hereditary cancer syndromes (HCS) represent a group of genetically determined diseases where the risk of developing various types of tumors is significantly higher compared to the general population. Iden tifying germline pathogenic variants (PVs) associated with an increased risk of tumor formation is crucial for prevention, diagnosis, and treatment of patients. Scientific studies conducted on Russian patients with malignant neoplasms (MNs) will help to identify genetic markers of HCS that are specific to different ethnic groups and patient samples.

Aim: To analyze the results of whole-genome sequencing (WGS) of 500 patients with MNs from the Yamalo-Nenets Autonomous Okrug (YNAO) and to identify germline variants associated with the development of HCS in oncology patients, along with a description of the structure and frequency of the genetic variants obtained.

Methods: Since 2021, unique scientific projects aimed at identifying genetic variants associated with HCS have been implemented in YNAO using WGS. This study included 500 patients with MNs meeting at least one of the following criteria: 1) early age at onset of MN; 2) multiple primary MNs; 3) certain histological and immunohisto chemical characteristics of MNs; 4) a significant family cancer history. Whole-genome sequencing of DNA isolated from peripheral blood lymphocytes was performed.

Results: WGS results demonstrated that 83 out of 500 patients with MNs were found to have PVs in genes associ ated with carcinogenesis, accounting for 16.6 %. This article presents the structure of the identified PVs in groups of patients with breast and ovarian cancers, patients with colorectal cancer and endometrial cancer, as well as in a heterogeneous group of patients with various tumor types.

Conclusion: We have published the WGS results from YNAO for the first time and analyzed the structure of the obtained genetic variants in oncology patients. Research on the genetic characteristics of the patients from YNAO not only helps to identify patients at increased risk of developing cancer, providing them with preventive measures and effective treatment but also generates unique scientific information necessary for the development and adap tation of molecular genetic tests considering the sample’s peculiarities and international experience.

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