urmjУральский медицинский журналUral Medical Journal2949-4389Ural State Medical University10.52420/2071-5943-2023-22-3-126-136urmj-1272Research ArticleЛитературные обзоры | Literature reviewsLiterature reviewsГерминальные мутации в генах PALB2 и CHEK2 и наследственный ракGermline mutations in the PALB2 and CHEK2 genes and hereditary cancerhttps://orcid.org/0000-0003-2607-2777ГолотюкМ. А.GolotyukM. A.

Марина Анатольевна Голотюк – научный сотрудник

Екатеринбург

Marina A. Golotyuk – Researcher

Ekaterinburg

79041615797@ya.ruhttps://orcid.org/0000-0002-5813-6758БережнойА. А.BerezhnojA. A.

Артем Андреевич Бережной – научный сотрудник

Екатеринбург

Artem A. Bereznoi – Researcher

Ekaterinburg

aberezhnoy55@gmail.comhttps://orcid.org/0000-0001-6212-0495КазанцеваН. В.KazancevaN. V.

Наталья Владимировна Казанцева – заведующая патологоанатомическим отделением

Екатеринбург

Natalia V. Kazanceva – Head of Pathology Department

Ekaterinburg

nvkazantseva@mail.ruДорофеевА. В.DorofeevA. V.

Александр Владимирович Дорофеев – доктор медицинских наук

Екатеринбург

Alexander V. Dorofeev – Doctor of Science (Medicine)

Ekaterinburg

avdonco@gmail.comБорзуноваТ. И.BorzunovaT. I.

Татьяна Игоревна Борзунова – студентка

Екатеринбург

Tatiana I. Borzunovа – Student

Ekaterinburg

tan.borzunova@gmail.comСвердловский областной онкологический диспансер; Институт медицинских клеточных технологийРоссияSverdlovsk Regional Oncology Center; Institute of Medical Cell TechnologiesRussian FederationСвердловский областной онкологический диспансер; Институт медицинских клеточных технологий; Уральский государственный медицинский университетРоссияSverdlovsk Regional Oncology Center; Institute of Medical Cell Technologies; Ural State Medical UniversityRussian FederationУральский государственный медицинский университетРоссияUral State Medical UniversityRussian Federation202330062023223126136Copyright © Голотюк М.А., Бережной А.А., Казанцева Н.В., Дорофеев А.В., Борзунова Т.И., 20232023Голотюк М.А., Бережной А.А., Казанцева Н.В., Дорофеев А.В., Борзунова Т.И.Golotyuk M.A., Berezhnoj A.A., Kazanceva N.V., Dorofeev A.V., Borzunova T.I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.umjusmu.ru/jour/article/view/1272Введение

Введение. Не менее 3 % всех случаев рака связаны с наследственными изменениями в генах предрасположенности к злокачественным новообразованиям. Помимо широко известных генов BRCA1,2, в рутинную диагностику внедряются и другие гены, участвующие наравне с BRCA1,2 в системе репарации ДНК и поддержании целостности генома, такие как PALB2, CHEK2. В этом обзоре мы представляем актуальную информацию из последних исследований о строении и функции генов PALB2 и CHEK2, и диагностике мутаций в этих генах, а также об их клиническом значении. Цель работы – актуализация и систематизация данных о генах PALB2 и CHEK2 для лучшего понимания их значения в канцерогенезе, сопряженных с ними рисков развития злокачественных новообразований, профилактики и тактики лечения носителей мутаций.

Материалы и методы

Материалы и методы. Проведен поиск в базах данных PubMed, Google Scholar, Cyberleninka. Критериями включения статей были новизна и актуальность данных, соответствие тематики обзора. На основании этого было выбрано 79 литературных источников.

Результаты и обсуждение

Результаты и обсуждение. Мутации в гене PALB2 распространены в 0,5 до 2,1 % случаев рака и ассоциированы с повышенным риском развития рака молочной железы (52,8 % к 80 годам), а также рака яичников (5 %), поджелудочной железы (2,8 %). Частота изменений в гене CHEK2 достигает 5 % и сопряжена с риском развития рака молочной железы (до 40 % к 80 годам) и колоректальным раком. В ходе многочисленных исследований отмечается взаимосвязь наличия мутаций в этих генах и развития рака предстательной железы, легкого, почки и меланомы.

Заключение

Заключение. Более полное понимание спектра генетической предрасположенности и определение геноспецифических рисков рака может привести к улучшению скрининга, профилактики и терапевтических стратегий для пациентов с наследственным раком и их семей.

Introduction

Introduction. At least 3% of all cancer cases are associated with hereditary changes in genes predisposing to malignant neoplasms. In addition to the widely known BRCA1,2 genes, other genes involved equally with BRCA1,2 in the DNA repair system and maintenance of genome integrity, such as PALB2, CHEK2, are being introduced into routine diagnosis. In this review we present current information from recent studies on the structure and function of PALB2 and CHEK2 genes, and the diagnosis of mutations in these genes, as well as their clinical significance.

The purpose of this work was to update and systematize the data on PALB2 and CHEK2 genes in order to better understand their significance in carcinogenesis, associated risks of malignant neoplasms, prevention and treatment tactics for mutation carriers.

Materials and methods

Materials and methods. PubMed, Google Scholar, Cyberleninka databases were searched. The criteria for inclusion of articles were the novelty and relevance of the data, compliance to the topic of the review. Based on this, 79 literary sources were selected.

Results and discussion

Results and discussion. Mutations in the PALB2 gene are common in 0.5 to 2.1 % of cancer cases and are associated with an increased risk of breast cancer (52.8 % by age 80), as well as ovarian cancer (5 %), pancreatic cancer (2.8 %). The frequency of changes in the CHEK2 gene reaches 5 % and is associated with a risk of breast cancer (up to 40 % by age 80) and colorectal cancer. Numerous studies have shown that mutations in these genes are associated with prostate, lung, kidney, and melanoma cancers.

Conclusion

Conclusion. A better understanding of the spectrum of genetic predisposition and identification of genespecific cancer risks could lead to improved screening, prevention, and therapeutic strategies for patients with hereditary cancer and their families.

наследственный ракнаследственные мутациисиндром наследственного рака молочной железы и яичниковгены репарации ДНКPALB2CHEK2hereditary cancerhereditary mutationshereditary breast and ovarian cancer syndromeDNA repair genesPALB2CHEK2ReferencesRahman N. Realizing the promise of cancer predisposition genes. Nature. 2014;505(7483):302−308. https://doi.org/10.1038/nature12981.Rahman N. Realizing the promise of cancer predisposition genes. Nature. 2014;505(7483):302−308. https://doi.org/10.1038/nature12981.Turnbull C, Sud A, Houlston RS. Cancer genetics, precision prevention and a call to action. Nat Genet. 2018;50(9):1212−1218. https://doi.org/10.1038/s41588-018-0202-0.Turnbull C, Sud A, Houlston RS. Cancer genetics, precision prevention and a call to action. Nat Genet. 2018;50(9):1212−1218. https://doi.org/10.1038/s41588-018-0202-0.Xia B, Sheng Q, Nakanishi K et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006;22(6):719−729. https://doi.org/10.1016/j.molcel.2006.05.022.Xia B, Sheng Q, Nakanishi K et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell. 2006;22(6):719−729. https://doi.org/10.1016/j.molcel.2006.05.022.Zhang F, Ma J, Wu J et al. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr Biol. 2009;19(6):524–529. https://doi.org/10.1016/j.cub.2009.02.018.Zhang F, Ma J, Wu J et al. PALB2 links BRCA1 and BRCA2 in the DNA-damage response. Curr Biol. 2009;19(6):524–529. https://doi.org/10.1016/j.cub.2009.02.018.Ducy M, Sesma-Sanz L, Guitton-Sert L et al. The Tumor Suppressor PALB2: Inside Out. Trends Biochem Sci. 2019;44(3):226−240. https://doi.org/10.1016/j.tibs.2018.10.008.Ducy M, Sesma-Sanz L, Guitton-Sert L et al. The Tumor Suppressor PALB2: Inside Out. Trends Biochem Sci. 2019;44(3):226−240. https://doi.org/10.1016/j.tibs.2018.10.008.Simhadri S, Vincelli G, Huo Y et al. PALB2 connects BRCA1 and BRCA2 in the G2/M checkpoint response. Oncogene. 2019;38(10):1585−1596. https://doi.org/10.1038/s41388-018-0535-2.Simhadri S, Vincelli G, Huo Y et al. PALB2 connects BRCA1 and BRCA2 in the G2/M checkpoint response. Oncogene. 2019;38(10):1585−1596. https://doi.org/10.1038/s41388-018-0535-2.Reid S, Schindler D, Hanenberg H et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet. 2007;39(2):162−164. https://doi.org/10.1038/ng1947.Reid S, Schindler D, Hanenberg H et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet. 2007;39(2):162−164. https://doi.org/10.1038/ng1947.Rahman N, Seal S, Thompson D et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007;39(2):165−167. https://doi.org/10.1038/ng1959.Rahman N, Seal S, Thompson D et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007;39(2):165−167. https://doi.org/10.1038/ng1959.Yang X, Leslie G, Doroszuk A et al. Cancer risks associated with germline PALB2 pathogenic variants: an international study of 524 families. J Clin Oncol. 2020;38(7):674−685. https://doi.org/10.1200/JCO.19.01907.Yang X, Leslie G, Doroszuk A et al. Cancer risks associated with germline PALB2 pathogenic variants: an international study of 524 families. J Clin Oncol. 2020;38(7):674−685. https://doi.org/10.1200/JCO.19.01907.Erkko H, Xia B, Nikkilä J et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature. 2007;446(7133):316–319. https://doi.org/10.1038/nature05609.Erkko H, Xia B, Nikkilä J et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature. 2007;446(7133):316–319. https://doi.org/10.1038/nature05609.Dansonka-Mieszkowska A, Kluska A, Moes J et al. A novel germline PALB2 deletion in Polish breast and ovarian cancer patients. BMC Med Genet. 2010;11:20. https://doi.org/10.1186/1471-2350-11-20.Dansonka-Mieszkowska A, Kluska A, Moes J et al. A novel germline PALB2 deletion in Polish breast and ovarian cancer patients. BMC Med Genet. 2010;11:20. https://doi.org/10.1186/1471-2350-11-20.Bogdanova N, Sokolenko AP, Iyevleva AG et al. PALB2 mutations in German and Russian patients with bilateral breast cancer. Breast Cancer Res Treat. 2011;126(2):545−550. https://doi.org/10.1007/s10549-010-1290-4.Bogdanova N, Sokolenko AP, Iyevleva AG et al. PALB2 mutations in German and Russian patients with bilateral breast cancer. Breast Cancer Res Treat. 2011;126(2):545−550. https://doi.org/10.1007/s10549-010-1290-4.Casadei S, Norquist BM, Walsh T et al. Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res. 2011;71(6):2222−2229. https://doi.org/10.1158/0008-5472.CAN-10-3958.Casadei S, Norquist BM, Walsh T et al. Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res. 2011;71(6):2222−2229. https://doi.org/10.1158/0008-5472.CAN-10-3958.Teo ZL, Park DJ, Provenzano E et al. Prevalence of PALB2 mutations in Australasian multiple-case breast cancer families. Breast Cancer Res. 2013;15(1):R17. https://doi.org/10.1186/bcr3392.Teo ZL, Park DJ, Provenzano E et al. Prevalence of PALB2 mutations in Australasian multiple-case breast cancer families. Breast Cancer Res. 2013;15(1):R17. https://doi.org/10.1186/bcr3392.Catucci I, Peterlongo P, Ciceri S et al. PALB2 sequencing in Italian familial breast cancer cases reveals a high-risk mutation recurrent in the province of Bergamo. Gen Med. 2014;16(9):688−694. https://doi.org/10.1038/gim.2014.13.Catucci I, Peterlongo P, Ciceri S et al. PALB2 sequencing in Italian familial breast cancer cases reveals a high-risk mutation recurrent in the province of Bergamo. Gen Med. 2014;16(9):688−694. https://doi.org/10.1038/gim.2014.13.Kluska A, Balabas A, Piatkowska M et al. PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland. BMC Med Genomics. 2017;10(1):14. https://doi.org/10.1186/s12920-017-0251-8.Kluska A, Balabas A, Piatkowska M et al. PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland. BMC Med Genomics. 2017;10(1):14. https://doi.org/10.1186/s12920-017-0251-8.Preobrazhenskaya EV, Shleykina AU, Gorustovich OA et al. Frequency and molecular characteristics of PALB2-associated cancers in Russian patients. Int J Cancer. 2021;148(1):203–210. https://doi.org/10.1002/ijc.33317.Preobrazhenskaya EV, Shleykina AU, Gorustovich OA et al. Frequency and molecular characteristics of PALB2-associated cancers in Russian patients. Int J Cancer. 2021;148(1):203–210. https://doi.org/10.1002/ijc.33317.Zhou J, Wang H, Fu F et al. Spectrum of PALB2 germline mutations and characteristics of PALB2-related breast cancer: Screening of 16,501 unselected patients with breast cancer and 5890 controls by next-generation sequencing. Cancer. 2020;126(14):3202−3208. https://doi.org/10.1002/cncr.32905.Zhou J, Wang H, Fu F et al. Spectrum of PALB2 germline mutations and characteristics of PALB2-related breast cancer: Screening of 16,501 unselected patients with breast cancer and 5890 controls by next-generation sequencing. Cancer. 2020;126(14):3202−3208. https://doi.org/10.1002/cncr.32905.Ng PS, Boonen RA, Wijaya E et al. Characterisation of protein-truncating and missense variants in PALB2 in 15 768 women from Malaysia and Singapore. J Med. Genet 2022;59(5):481−491. https://doi.org/10.1136/jmedgenet-2020-107471.Ng PS, Boonen RA, Wijaya E et al. Characterisation of protein-truncating and missense variants in PALB2 in 15 768 women from Malaysia and Singapore. J Med. Genet 2022;59(5):481−491. https://doi.org/10.1136/jmedgenet-2020-107471.Antoniou AC, Casadei S, Heikkinen T et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371(6):497−506. https://doi.org/10.1056/NEJMoa1400382.Antoniou AC, Casadei S, Heikkinen T et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371(6):497−506. https://doi.org/10.1056/NEJMoa1400382.Deng M, Chen HH, Zhu X et al. Prevalence and clinical outcomes of germline mutations in BRCA1/2 and PALB2 genes in 2769 unselected breast cancer patients in China. Int J Cancer. 2019;145(6):1517–1528. https://doi.org/10.1002/ijc.32184.Deng M, Chen HH, Zhu X et al. Prevalence and clinical outcomes of germline mutations in BRCA1/2 and PALB2 genes in 2769 unselected breast cancer patients in China. Int J Cancer. 2019;145(6):1517–1528. https://doi.org/10.1002/ijc.32184.Ramus SJ, Song H, Dicks E et al. Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J Natl Cancer Inst. 2015;107(11):djv214. https://doi.org/10.1093/jnci/djv214.Ramus SJ, Song H, Dicks E et al. Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J Natl Cancer Inst. 2015;107(11):djv214. https://doi.org/10.1093/jnci/djv214.Norquist BM, Harrell MI, Brady MF et al. Inherited mutations in women with ovarian carcinoma. JAMA Oncol. 2016;2(4):482–490. https://doi.org/10.1001/jamaoncol.2015.5495.Norquist BM, Harrell MI, Brady MF et al. Inherited mutations in women with ovarian carcinoma. JAMA Oncol. 2016;2(4):482–490. https://doi.org/10.1001/jamaoncol.2015.5495.Hu C, Hart SN, Polley EC et al. Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. JAMA. 2018;319(23):2401−2409. https://doi.org/10.1001/jama.2018.6228.Hu C, Hart SN, Polley EC et al. Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. JAMA. 2018;319(23):2401−2409. https://doi.org/10.1001/jama.2018.6228.Shindo K, Yu J, Suenaga M et al. Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma. J Clin Oncol. 2017;35(30):3382−3390. https://doi.org/10.1200/JCO.2017.72.3502.Shindo K, Yu J, Suenaga M et al. Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma. J Clin Oncol. 2017;35(30):3382−3390. https://doi.org/10.1200/JCO.2017.72.3502.Nicolosi P, Ledet E, Yang S et al. Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines. JAMA Oncol. 2019;5(4):523−528. https://doi.org/10.1001/jamaoncol.2018.6760.Nicolosi P, Ledet E, Yang S et al. Prevalence of germline variants in prostate cancer and implications for current genetic testing guidelines. JAMA Oncol. 2019;5(4):523−528. https://doi.org/10.1001/jamaoncol.2018.6760.Dillon KM, Bekele RT, Sztupinszki Z et al. PALB2 or BARD1 loss confers homologous recombination deficiency and PARP inhibitor sensitivity in prostate cancer. NPJ Precis Oncol. 2022;6(1):49. https://doi.org/10.1038/s41698-022-00291-7.Dillon KM, Bekele RT, Sztupinszki Z et al. PALB2 or BARD1 loss confers homologous recombination deficiency and PARP inhibitor sensitivity in prostate cancer. NPJ Precis Oncol. 2022;6(1):49. https://doi.org/10.1038/s41698-022-00291-7.Lu C, Xie M, Wendl MC et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun. 2015;6:10086. https://doi.org/10.1001/jamaoncol.2014.168.Lu C, Xie M, Wendl MC et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat Commun. 2015;6:10086. https://doi.org/10.1001/jamaoncol.2014.168.Sahasrabudhe R, Lott P, Bohorquez M et al. Germline mutations in PALB2, BRCA1, and RAD51C, which regulate DNA recombination repair, in patients with gastric cancer. Gastroenterology. 2017;152(5):983−986.e6. https://doi.org/10.1053/j.gastro.2016.12.010.Sahasrabudhe R, Lott P, Bohorquez M et al. Germline mutations in PALB2, BRCA1, and RAD51C, which regulate DNA recombination repair, in patients with gastric cancer. Gastroenterology. 2017;152(5):983−986.e6. https://doi.org/10.1053/j.gastro.2016.12.010.Vogelaar IP, van der Post RS, van Krieken JHJ et al. Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing. Eur J Hum Genet. 2017;25(11):1246−1252. https://doi.org/10.1038/ejhg.2017.138.Vogelaar IP, van der Post RS, van Krieken JHJ et al. Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing. Eur J Hum Genet. 2017;25(11):1246−1252. https://doi.org/10.1038/ejhg.2017.138.Fewings E, Larionov A, Redman J et al. Germline pathogenic variants in PALB2 and other cancer-predisposing genes in families with hereditary diffuse gastric cancer without CDH1 mutation: a whole-exome sequencing study. Lancet Gastroenterol Hepatol. 2018;3(7):489−498. https://doi.org/10.1016/S2468-1253(18)30079-7.Fewings E, Larionov A, Redman J et al. Germline pathogenic variants in PALB2 and other cancer-predisposing genes in families with hereditary diffuse gastric cancer without CDH1 mutation: a whole-exome sequencing study. Lancet Gastroenterol Hepatol. 2018;3(7):489−498. https://doi.org/10.1016/S2468-1253(18)30079-7.AlDubayan SH, Giannakis M, Moore ND et al. Inherited DNA-repair defects in colorectal cancer. Am J Hum Genet. 2018;102(3):401−414. https://doi.org/10.1016/j.ajhg.2018.01.018.AlDubayan SH, Giannakis M, Moore ND et al. Inherited DNA-repair defects in colorectal cancer. Am J Hum Genet. 2018;102(3):401−414. https://doi.org/10.1016/j.ajhg.2018.01.018.Zhang J, Tang S, Zhang C et al. Investigation of PALB2 mutation and correlation with immunotherapy biomarker in chinese non-small cell lung cancer patients. Front Oncol. 2022;11:742833. https://doi.org/10.3389/fonc.2021.742833.Zhang J, Tang S, Zhang C et al. Investigation of PALB2 mutation and correlation with immunotherapy biomarker in chinese non-small cell lung cancer patients. Front Oncol. 2022;11:742833. https://doi.org/10.3389/fonc.2021.742833.Lau B, Menzies AM, Joshua AM. Ongoing partial response at 6 months to olaparib for metastatic melanoma with somatic PALB2 mutation after failure of immunotherapy: a case report. Ann Oncol. 2021;32(2):280−282. https://doi.org/10.1016/j.annonc.2020.11.006.Lau B, Menzies AM, Joshua AM. Ongoing partial response at 6 months to olaparib for metastatic melanoma with somatic PALB2 mutation after failure of immunotherapy: a case report. Ann Oncol. 2021;32(2):280−282. https://doi.org/10.1016/j.annonc.2020.11.006.Xia B, Biswas K, Foo TK et al. Rare germline variants in PALB2 and BRCA2 in familial and sporadic chordoma. Hum Mutat 2022;43(10):1396−1407. https://doi.org/10.1002/humu.24427.Xia B, Biswas K, Foo TK et al. Rare germline variants in PALB2 and BRCA2 in familial and sporadic chordoma. Hum Mutat 2022;43(10):1396−1407. https://doi.org/10.1002/humu.24427.Tung NM, Boughey JC, Pierce LJ et al. Management of hereditary breast cancer: American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Guideline. J Clin Oncol. 2020;38(18):2080−2106. https://doi.org/10.1200/JCO.20.00299.Tung NM, Boughey JC, Pierce LJ et al. Management of hereditary breast cancer: American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Guideline. J Clin Oncol. 2020;38(18):2080−2106. https://doi.org/10.1200/JCO.20.00299.Tischkowitz M, Balmaña J, Foulkes WD et al. Management of individuals with germline variants in PALB2: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23(8):1416−1423. https://doi.org/10.1038/s41436-021-01151-8.Tischkowitz M, Balmaña J, Foulkes WD et al. Management of individuals with germline variants in PALB2: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23(8):1416−1423. https://doi.org/10.1038/s41436-021-01151-8.Goggins M, Overbeek KA, Brand R et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut. 2020;69(1):7−17. https://doi.org/10.1136/gutjnl-2019-319352.Goggins M, Overbeek KA, Brand R et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut. 2020;69(1):7−17. https://doi.org/10.1136/gutjnl-2019-319352.Blasina A, de Weyer IV, Laus MC et al. A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase. Curr Biol. 1999;9(1):1−10. https://doi.org/10.1016/s0960-9822(99)80041-4.Blasina A, de Weyer IV, Laus MC et al. A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase. Curr Biol. 1999;9(1):1−10. https://doi.org/10.1016/s0960-9822(99)80041-4.Stolarova L, Kleiblova P, Janatova M et al. CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate. Cells. 2020;9(12):2675. https://doi.org/10.3390/cells9122675.Stolarova L, Kleiblova P, Janatova M et al. CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate. Cells. 2020;9(12):2675. https://doi.org/10.3390/cells9122675.Bell DW, Varley JM, Szydlo TE et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999;286(5449):2528−2531. https://doi.org/10.1126/science.286.5449.2528.Bell DW, Varley JM, Szydlo TE et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999;286(5449):2528−2531. https://doi.org/10.1126/science.286.5449.2528.Sodha N, Houlston RS, Bullock S et al. Increasing evidence that germline mutations in CHEK2 do not cause Li-Fraumeni syndrome. Hum Mutat. 2002;20(6):460−462. https://doi.org/10.1002/humu.10136.Sodha N, Houlston RS, Bullock S et al. Increasing evidence that germline mutations in CHEK2 do not cause Li-Fraumeni syndrome. Hum Mutat. 2002;20(6):460−462. https://doi.org/10.1002/humu.10136.Cybulski C, Górski B, Huzarski T et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004;75(6):1131−1135. https://doi.org/10.1086/426403.Cybulski C, Górski B, Huzarski T et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004;75(6):1131−1135. https://doi.org/10.1086/426403.Vahteristo P, Bartkova J, Eerola H, et al. A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet. 2002;71(2):432−438. https://doi.org/10.1086/341943.Vahteristo P, Bartkova J, Eerola H, et al. A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am J Hum Genet. 2002;71(2):432−438. https://doi.org/10.1086/341943.Bermisheva MA, Takhirova ZR, Bogdanova N, Khusnutdinova EK. Frequency of CHEK2 gene mutations in breast cancer patients from Republic of Bashkortostan. Mol Biol. 2014;48:46–51. https://doi.org/10.1134/S0026893314010026.Bermisheva MA, Takhirova ZR, Bogdanova N, Khusnutdinova EK. Frequency of CHEK2 gene mutations in breast cancer patients from Republic of Bashkortostan. Mol Biol. 2014;48:46–51. https://doi.org/10.1134/S0026893314010026.Sun J, Meng H, Yao L et al. Germline mutations in cancer susceptibility genes in a large series of unselected breast cancer patients. Clin Cancer Res. 2017;23(20):6113-6119. https://doi.org/10.1158/1078-0432.CCR-16-3227.Sun J, Meng H, Yao L et al. Germline mutations in cancer susceptibility genes in a large series of unselected breast cancer patients. Clin Cancer Res. 2017;23(20):6113-6119. https://doi.org/10.1158/1078-0432.CCR-16-3227.Zeng C, Guo X, Wen W et al. Evaluation of pathogenetic mutations in breast cancer predisposition genes in population-based studies conducted among Chinese women. Breast Cancer Res Treat. 2020;181(2):465−473. https://doi.org/10.1007/s10549-020-05643-0.Zeng C, Guo X, Wen W et al. Evaluation of pathogenetic mutations in breast cancer predisposition genes in population-based studies conducted among Chinese women. Breast Cancer Res Treat. 2020;181(2):465−473. https://doi.org/10.1007/s10549-020-05643-0.Ansari N, Shahrabi S, Khosravi A et al. Prognostic significance of CHEK2 mutation in progression of breast cancer. Lab Med. 2019;50(3):e36–e41. https://doi.org/10.1093/labmed/lmz009.Ansari N, Shahrabi S, Khosravi A et al. Prognostic significance of CHEK2 mutation in progression of breast cancer. Lab Med. 2019;50(3):e36–e41. https://doi.org/10.1093/labmed/lmz009.Decker B, Allen J, Luccarini C et al. Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. J Med Genet. 2017;54(11):732−741. https://doi.org/10.1136/jmedgenet-2017-104588.Decker B, Allen J, Luccarini C et al. Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. J Med Genet. 2017;54(11):732−741. https://doi.org/10.1136/jmedgenet-2017-104588.Akdeniz D, Schmidt MK, Seynaeve CM et al. Risk factors for metachronous contralateral breast cancer: A systematic review and meta-analysis. Breast. 2019;44:1−14. https://doi.org/10.1016/j.breast.2018.11.005.Akdeniz D, Schmidt MK, Seynaeve CM et al. Risk factors for metachronous contralateral breast cancer: A systematic review and meta-analysis. Breast. 2019;44:1−14. https://doi.org/10.1016/j.breast.2018.11.005.Ansari N, Shahrabi S, Khosravi A et al. Prognostic significance of CHEK2 mutation in progression of breast cancer. Lab Med. 2019;50(3):e36−e41. https://doi.org/10.1093/labmed/lmz009.Ansari N, Shahrabi S, Khosravi A et al. Prognostic significance of CHEK2 mutation in progression of breast cancer. Lab Med. 2019;50(3):e36−e41. https://doi.org/10.1093/labmed/lmz009.Schmidt MK, Hogervorst F, van Hien R et al. Age- and tumor subtype-specific breast cancer risk estimates for CHEK2*1100delC carriers. J Clin Oncol. 2016;34(23):2750−2760. https://doi.org/10.1200/JCO.2016.66.5844.Schmidt MK, Hogervorst F, van Hien R et al. Age- and tumor subtype-specific breast cancer risk estimates for CHEK2*1100delC carriers. J Clin Oncol. 2016;34(23):2750−2760. https://doi.org/10.1200/JCO.2016.66.5844.Huszno J, Kolosza Z. Molecular characteristics of breast cancer according to clinicopathological factors. Mol Clin Oncol. 2019;11(2):192−200. https://doi.org/10.3892/mco.2019.1869.Huszno J, Kolosza Z. Molecular characteristics of breast cancer according to clinicopathological factors. Mol Clin Oncol. 2019;11(2):192−200. https://doi.org/10.3892/mco.2019.1869.Szwiec M, Tomiczek-Szwiec J, Kluźniak W et al. Genetic predisposition to male breast cancer in Poland. BMC Cancer. 2021;21(1):975. https://doi.org/10.1186/s12885-021-08718-3.Szwiec M, Tomiczek-Szwiec J, Kluźniak W et al. Genetic predisposition to male breast cancer in Poland. BMC Cancer. 2021;21(1):975. https://doi.org/10.1186/s12885-021-08718-3.Kleiblova P, Stolarova L, Krizova K et al. Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer. Int J Cancer. 2019;145(7):1782−1797. https://doi.org/10.1002/ijc.32385.Kleiblova P, Stolarova L, Krizova K et al. Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer. Int J Cancer. 2019;145(7):1782−1797. https://doi.org/10.1002/ijc.32385.Koczkowska M, Krawczynska N, Stukan M et al. Spectrum and prevalence of pathogenic variants in ovarian cancer susceptibility genes in a group of 333 patients. Cancers (Basel). 2018;10(11):442. https://doi.org/10.3390/cancers10110442.Koczkowska M, Krawczynska N, Stukan M et al. Spectrum and prevalence of pathogenic variants in ovarian cancer susceptibility genes in a group of 333 patients. Cancers (Basel). 2018;10(11):442. https://doi.org/10.3390/cancers10110442.Carter NJ, Marshall ML, Susswein LR et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018;151(3):481−488. https://doi.org/10.1016/j.ygyno.2018.09.030.Carter NJ, Marshall ML, Susswein LR et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018;151(3):481−488. https://doi.org/10.1016/j.ygyno.2018.09.030.Lilyquist J, LaDuca H, Polley E et al. Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. Gynecol Oncol. 2017;147(2):375−380. https://doi.org/10.1016/j.ygyno.2017.08.030.Lilyquist J, LaDuca H, Polley E et al. Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. Gynecol Oncol. 2017;147(2):375−380. https://doi.org/10.1016/j.ygyno.2017.08.030.Бетенева Е.И., Филиппова М.Г., Тюляндина А.С. с соавт. Высокая частота мутаций в генах brca1, BRCA2, CHEK2, NbN, BLM у больных раком яичников в российской популяции. Опухоли женской репродуктивной системы. 2014;4:51−56.Bateneva EI, Filippova MG, Tyulyandina AS et al. High rate of mutations in brca1, BRCA2, CHEK2, NbN, and BLM genes in Russian ovarian cancer patients. Tumors of the female reproductive system = Opuholi zhenskoj reproduktivnoj sistemy. 2014;4:51−56.Ogrodniczak A, Menkiszak J, Gronwald J et al. Association of recurrent mutations in BRCA1, BRCA2, RAD51C, PALB2, and CHEK2 with the risk of borderline ovarian tumor. Hered Cancer Clin Pract. 2022;20(1):11. https://doi.org/10.1186/s13053-022-00218-0.Ogrodniczak A, Menkiszak J, Gronwald J et al. Association of recurrent mutations in BRCA1, BRCA2, RAD51C, PALB2, and CHEK2 with the risk of borderline ovarian tumor. Hered Cancer Clin Pract. 2022;20(1):11. https://doi.org/10.1186/s13053-022-00218-0.Wieme G, Kral J, Rosseel T et al. Prevalence of germline pathogenic variants in cancer predisposing genes in Czech and Belgian pancreatic cancer patients. Cancers (Basel). 2021;13(17):4430. https://doi.org/10.3390/cancers13174430.Wieme G, Kral J, Rosseel T et al. Prevalence of germline pathogenic variants in cancer predisposing genes in Czech and Belgian pancreatic cancer patients. Cancers (Basel). 2021;13(17):4430. https://doi.org/10.3390/cancers13174430.Dong X, Wang L, Taniguchi K et al. Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet. 2003;72(2):270−280. https://doi.org/10.1086/346094.Dong X, Wang L, Taniguchi K et al. Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet. 2003;72(2):270−280. https://doi.org/10.1086/346094.Isaacsson Velho P, Silberstein JL, Markowski MC et al. Intraductal/ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer. Prostate. 2018;78(5):401−407. https://doi.org/10.1002/pros.23484.Isaacsson Velho P, Silberstein JL, Markowski MC et al. Intraductal/ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer. Prostate. 2018;78(5):401−407. https://doi.org/10.1002/pros.23484.Wu Y, Yu H, Zheng SL et al. A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer. Prostate. 2018;78(8):607−615. https://doi.org/10.1002/pros.23505.Wu Y, Yu H, Zheng SL et al. A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer. Prostate. 2018;78(8):607−615. https://doi.org/10.1002/pros.23505.Ged Y, Chaim JL, DiNatale RG et al. DNA damage repair pathway alterations in metastatic clear cell renal cell carcinoma and implications on systemic therapy. J Immunother Cancer. 2020;8(1):e000230. https://doi.org/10.1136/jitc-2019-000230.Ged Y, Chaim JL, DiNatale RG et al. DNA damage repair pathway alterations in metastatic clear cell renal cell carcinoma and implications on systemic therapy. J Immunother Cancer. 2020;8(1):e000230. https://doi.org/10.1136/jitc-2019-000230.Carlo MI, Mukherjee S, Mandelker D et al. Prevalence of germline mutations in cancer susceptibility genes in patients with advanced renal cell carcinoma. JAMA Oncol. 2018;4(9):1228−1235. https://doi.org/10.1001/jamaoncol.2018.1986.Carlo MI, Mukherjee S, Mandelker D et al. Prevalence of germline mutations in cancer susceptibility genes in patients with advanced renal cell carcinoma. JAMA Oncol. 2018;4(9):1228−1235. https://doi.org/10.1001/jamaoncol.2018.1986.Pekova B, Dvorakova S, Sykorova V et al. Somatic genetic alterations in a large cohort of pediatric thyroid nodules. Endocr Connect. 2019;8(6):796−805. https://doi.org/10.1530/EC-19-0069.Pekova B, Dvorakova S, Sykorova V et al. Somatic genetic alterations in a large cohort of pediatric thyroid nodules. Endocr Connect. 2019;8(6):796−805. https://doi.org/10.1530/EC-19-0069.Zhao Y, Yu T, Chen L et al. A Germline CHEK2 mutation in a family with papillary thyroid cancer. Thyroid. 2020;30(6):924−930. https://doi.org/10.1089/thy.2019.0774.Zhao Y, Yu T, Chen L et al. A Germline CHEK2 mutation in a family with papillary thyroid cancer. Thyroid. 2020;30(6):924−930. https://doi.org/10.1089/thy.2019.0774.Federico AD, Gelsomino F, De Biase D, Ardizzoni A. Should we test cancer susceptibility genes in routinely used multigene panels? A case of synchronous lung adenocarcinoma and breast cancer associated with germline CHEK2 mutation. Clin Lung Cancer. 2022;23(4):e283−e284. https://doi.org/10.1016/j.cllc.2021.09.011.Federico AD, Gelsomino F, De Biase D, Ardizzoni A. Should we test cancer susceptibility genes in routinely used multigene panels? A case of synchronous lung adenocarcinoma and breast cancer associated with germline CHEK2 mutation. Clin Lung Cancer. 2022;23(4):e283−e284. https://doi.org/10.1016/j.cllc.2021.09.011.Mastronikolis S, Adamopoulou M, Papouliakos S et al. Mutational landscape in uveal melanoma. J BUON. 2021;26(4):1194−1197.Mastronikolis S, Adamopoulou M, Papouliakos S et al. Mutational landscape in uveal melanoma. J BUON. 2021;26(4):1194−1197.Stubbins RJ, Korotev S, Godley LA. Germline CHEK2 and ATM variants in myeloid and other hematopoietic malignancies. Curr Hematol Malig Rep. 2022;17(4):94−104. https://doi.org/10.1007/s11899-022-00663-7.Stubbins RJ, Korotev S, Godley LA. Germline CHEK2 and ATM variants in myeloid and other hematopoietic malignancies. Curr Hematol Malig Rep. 2022;17(4):94−104. https://doi.org/10.1007/s11899-022-00663-7.Wood ME, McKinnon W, Garber J. Risk for breast cancer and management of unaffected individuals with non-BRCA hereditary breast cancer. Breast J. 2020;26(8):1528−1534. https://doi.org/10.1111/tbj.13969.Wood ME, McKinnon W, Garber J. Risk for breast cancer and management of unaffected individuals with non-BRCA hereditary breast cancer. Breast J. 2020;26(8):1528−1534. https://doi.org/10.1111/tbj.13969.Tung NM, Robson ME, Ventz S, et al. TBCRC 048: Phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol. 2020;38(36):4274−4282. https://doi.org/10.1200/JCO.20.02151.Tung NM, Robson ME, Ventz S, et al. TBCRC 048: Phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol. 2020;38(36):4274−4282. https://doi.org/10.1200/JCO.20.02151.Angius G, Tomao S, Stati V et al. Prexasertib, a checkpoint kinase inhibitor: from preclinical data to clinical development. Cancer Chemother Pharmacol. 2020;85(1):9−20. https://doi.org/10.1007/s00280-019-03950-y.Angius G, Tomao S, Stati V et al. Prexasertib, a checkpoint kinase inhibitor: from preclinical data to clinical development. Cancer Chemother Pharmacol. 2020;85(1):9−20. https://doi.org/10.1007/s00280-019-03950-y.

The authors declare that there are no conflicts of interest present.