Diagnostics of hereditary cancer syndromes by ngs. A database creation experience

Abstract

Background: More than 500 thousand new cases of malignant neoplasms are registered annually in the Russian Federation, of which more than 50 thousand new cases are due to hereditary forms. Improving the diagnosis of these diseases will make it possible to detect tumors at the early stages and take timely preventive and therapeutic measures.

Aims: Creation of a database and development of a software for the NGS data analysis for the prevention and early diagnosis of hereditary forms of oncological diseases.

Methods: The present study used 636 DNA samples obtained from cancer patients with a high hereditary risk or a burdened family history. DNA was isolated from blood lymphocytes. DNA libraries were prepared with a KAPA Target Enrichment Panel (Roche). The panel included probes for targeted enrichment of the coding region of 44 genes. NGS was performed on the MiSeq platform (Illumina).

Results: We identified 65 pathogenic/ probably pathogenic nucleotide sequence variants in 96 patients in the ATM, BLM, BRCA1, BRCA2, CHEK2, EPCAM, MEN1, MLH1, MSH2, MSH3, MSH6, MUTYH, PALB2, TP53 genes. We also identified 2858 nucleotide sequence variants of unknown clinical significance. Conclusions: We have created a local database that contains both genetic variants and clinical and anamnestic data. The database contains 4763 nucleotide sequence variants at the moment, among which 2522 are unique variants identified in a single patient.

Keywords

neoplastic syndromes / hereditary / high-throughput nucleotide sequencing / databases / genetic

References

[1] Имянитов Е.Н. Общие представления о наследственных опухолевых синдромах // Практическая онкология. 2014. Т. 15, № 3. С. 101–106. [Imyanitov EN. General ideas about hereditary tumor syndromes. Practical Oncology. 2014;15(3):101–106. (In Russ).]

[2] Biller LH, Syngal S, Yurgelun MB. Recent advances in Lynch syndrome. Fam Cancer. 2019;18(2):211–219. doi: 10.1007/s10689-018-00117-1

[3] Haraldsdottir S, Rafnar F, Frankel WL, et al. Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2. Nat Commun. 2017;8(1):14755. doi: 10.1038/ncomms14755

[4] Felix GE, Abe-Sandes C, Machado-Lopes TM, et al. Germline mutations in BRCA1, BRCA2, CHEK2 and TP53 in patients at high-risk for HBOC: characterizing a Northeast Brazilian Population. Hum Genome Var. 2014;1:14012. doi: 10.1038/hgv.2014.12

[5] Kwong A, Shin VY, Ho JC, et al. Comprehensive spectrum of BRCA1 and BRCA2 deleterious mutations in breast cancer in Asian countries. J Med Genet. 2016;53(1):15–23. doi: 10.1136/jmedgenet-2015-103132

[6] Rosenthal ET, Bernhisel R, Brown K, et al. Clinical testing with a panel of 25 genes associated with increased cancer risk results in a significant increase in clinically significant findings across a broad range of cancer histories. Cancer Genet. 2017; 218-219:58–68. doi: 10.1016/j.cancergen.2017.09.003

[7] Никитин А.Г., Бровкина О.И., Ходырев Д.С., и др. Опыт создания публичной базы данных мутаций oncoBRCA: биоинформационные проблемы и решения // Клиническая практика. 2020. Т. 11, № 1. С. 21–29. [Nikitin AG, Brovkina OI, Khodyrev DS, et al. The experience of creating a public database of oncoBRCA mutations: bioinformatic problems and solutions. Journal of Clinical Practice. 2020;11(1):21–29. (In Russ).] doi: 10.17816/clinpract25860

Funding

Государственное заданиеState assignment(388-00102-20-01/388-00154-21-00)

RIGHTS & PERMISSIONS

Abramov I.S., Lisitsa T.S., Stroganova A.M., Ryabaya O.O., Danishevich A.M., Khakhina A.O., Zakamornaya A.I., Matsvay A.D., Shipulin G.A.