{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T07:24:52Z","timestamp":1767857092356,"version":"3.49.0"},"reference-count":24,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T00:00:00Z","timestamp":1666828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"German Cancer Aid"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Germline pathogenic and likely pathogenic (P\/LP) variants in CHEK2 have been associated with increased prostate cancer (PrCa) risk. Our objective was to analyze their occurrence in Croatian PrCa men and to evaluate the clinical characteristics of P\/LP variant carriers. Therefore, we analyzed CHEK2 in 150 PrCa patients unselected for age of onset, family history of PrCa or clinical outcome, and the frequency of identified variants was compared to findings in 442 cancer-free men, of Croatian ancestry. We identified four PrCa cases harboring a P\/LP variant in CHEK2 (4\/150, 2.67%), which reached a statistical significance (p = 0.004) as compared to the control group. Patients with P\/LP variants in CHEK2 developed PrCa almost 9 years earlier than individuals with CHEK2 wild-type alleles (8.9 years; p = 0.0198) and had an increased risk for lymph node involvement (p = 0.0047). No association was found between CHEK2 status and further clinical characteristics, including the Gleason score, occurrence of aggressive PrCa, the tumor or metastasis stage. However, carriers of the most common P\/LP CHEK2 variant, the c.1100delC, p.Thr367Metfs15*, had a significantly higher Gleason score (p = 0.034), risk for lymph node involvement (p = 0.0001), and risk for developing aggressive PrCa (p = 0.027). Thus, in a Croatian population, CHEK2 P\/LP variant carriers were associated with increased risk for early onset prostate cancer, and carriers of the c.1100delC, p.Thr367Metfs15* had increased risk for aggressive PrCa.<\/jats:p>","DOI":"10.3390\/genes13111955","type":"journal-article","created":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T04:35:17Z","timestamp":1666845317000},"page":"1955","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Comprehensive Clinical and Genetic Analysis of CHEK2 in Croatian Men with Prostate Cancer"],"prefix":"10.3390","volume":"13","author":[{"given":"Kira","family":"Kirchner","sequence":"first","affiliation":[{"name":"Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marija","family":"Gamulin","sequence":"additional","affiliation":[{"name":"Department of Oncology, University Hospital Center Zagreb, University of Zagreb School of Medicine, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0895-5691","authenticated-orcid":false,"given":"Tomislav","family":"Kulis","sequence":"additional","affiliation":[{"name":"Department of Urology, University Hospital Centre Zagreb, University of Zagreb School of Medicine, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bianca","family":"Sievers","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zeljko","family":"Kastelan","sequence":"additional","affiliation":[{"name":"Department of Urology, University Hospital Centre Zagreb, University of Zagreb School of Medicine, 10000 Zagreb, Croatia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4496-244X","authenticated-orcid":false,"given":"Davor","family":"Lessel","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1093\/jmcb\/mju045","article-title":"CHK2 kinase in the DNA damage response and beyond","volume":"6","author":"Zannini","year":"2014","journal-title":"J. Mol. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1001\/jamaoncol.2018.6477","article-title":"Association of Inherited Pathogenic Variants in Checkpoint Kinase 2 (CHEK2) With Susceptibility to Testicular Germ Cell Tumors","volume":"5","author":"AlDubayan","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3747","DOI":"10.1200\/JCO.2010.34.0778","article-title":"Risk of breast cancer in women with a CHEK2 mutation with and without a family history of breast cancer","volume":"29","author":"Cybulski","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2546","DOI":"10.1016\/j.ejca.2011.03.025","article-title":"Meta-analysis of CHEK2 1100delC variant and colorectal cancer susceptibility","volume":"47","author":"Xiang","year":"2011","journal-title":"Eur. J. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1086\/346094","article-title":"Mutations in CHEK2 Associated with Prostate Cancer Risk","volume":"72","author":"Dong","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1038\/bjc.2012.486","article-title":"An inherited NBN mutation is associated with poor prognosis prostate cancer","volume":"108","author":"Cybulski","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1056\/NEJMoa1603144","article-title":"Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer","volume":"375","author":"Pritchard","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2091","DOI":"10.1056\/NEJMoa1911440","article-title":"Olaparib for Metastatic Castration-Resistant Prostate Cancer","volume":"382","author":"Mateo","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1001\/jama.2017.11137","article-title":"Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing","volume":"318","author":"Mandelker","year":"2017","journal-title":"JAMA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2142","DOI":"10.1002\/ijc.33024","article-title":"Rare germline genetic variants and risk of aggressive prostate cancer","volume":"147","author":"MacInnis","year":"2020","journal-title":"Int. J. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1093\/carcin\/bgs218","article-title":"Replication of genetic susceptibility loci for testicular germ cell cancer in the Croatian population","volume":"33","author":"Lessel","year":"2012","journal-title":"Carcinogenesis"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1136\/jmg.2006.044974","article-title":"A large germline deletion in the Chek2 kinase gene is associated with an increased risk of prostate cancer","volume":"43","author":"Cybulski","year":"2006","journal-title":"J. Med. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1002\/pros.23505","article-title":"A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer","volume":"78","author":"Wu","year":"2018","journal-title":"Prostate"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21551","article-title":"Cancer statistics, 2019","volume":"69","author":"Siegel","year":"2019","journal-title":"CA Cancer J. Clin."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1001\/jama.2015.17703","article-title":"Familial Risk and Heritability of Cancer Among Twins in Nordic Countries","volume":"315","author":"Mucci","year":"2016","journal-title":"JAMA J. Am. Med. Assoc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/s41588-020-00748-0","article-title":"Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction","volume":"53","author":"Conti","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.ucl.2021.04.003","article-title":"Germline Testing for Prostate Cancer Prognosis","volume":"48","author":"Helfand","year":"2021","journal-title":"Urol. Clin. N. Am."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2677","DOI":"10.1158\/0008-5472.CAN-04-0341","article-title":"A Novel Founder CHEK2 Mutation is Associated with Increased Prostate Cancer Risk","volume":"64","author":"Cybulski","year":"2004","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1038\/sj.bjc.6601425","article-title":"CHEK2 variants associate with hereditary prostate cancer","volume":"89","author":"Ikonen","year":"2003","journal-title":"Br. J. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Rantapero, T., Wahlfors, T., K\u00e4hler, A., Hultman, C., Lindberg, J., Tammela, T.L.J., Nykter, M., Schleutker, J., and Wiklund, F. (2020). Inherited DNA Repair Gene Mutations in Men with Lethal Prostate Cancer. Genes, 11.","DOI":"10.3390\/genes11030314"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Brand\u00e3o, A., Paulo, P., Maia, S., Pinheiro, M., Peixoto, A., Cardoso, M., Silva, M.P., Santos, C., Eeles, R.A., and Kote-Jarai, Z. (2020). The CHEK2 Variant C.349A>G Is Associated with Prostate Cancer Risk and Carriers Share a Common Ancestor. Cancers, 12.","DOI":"10.3390\/cancers12113254"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"109","DOI":"10.3325\/cmj.2012.53.109","article-title":"Trends in prostate cancer incidence and mortality in Croatia, 1988 to 2008","volume":"53","author":"Krhen","year":"2012","journal-title":"Croat. Med. J."},{"key":"ref_23","first-page":"27","article-title":"Epidemiology of Prostate Cancer in Croatia\u2014Situation and Perspectives","volume":"57","author":"Reljic","year":"2018","journal-title":"Acta Clin. Croat"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1002\/pros.23739","article-title":"Germline genetic testing for inherited prostate cancer in practice: Implications for genetic testing, precision therapy, and cascade testing","volume":"79","author":"Giri","year":"2019","journal-title":"Prostate"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/11\/1955\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:03:42Z","timestamp":1760144622000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/11\/1955"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,27]]},"references-count":24,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["genes13111955"],"URL":"https:\/\/doi.org\/10.3390\/genes13111955","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,27]]}}}