{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T21:58:20Z","timestamp":1787695100484,"version":"build-2784847793"},"reference-count":21,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T00:00:00Z","timestamp":1631145600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Pomeranian University in Szczecin"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Purpose<\/jats:title>\n<jats:p>The purpose of this study was to compare the clinical characteristics and the survival of <jats:italic>CHEK2<\/jats:italic> mutation positive and <jats:italic>CHEK2<\/jats:italic> mutation negative patients diagnosed with bladder or kidney cancer.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Materials and methods<\/jats:title>\n<jats:p>1016 patients with bladder and 402 cases with kidney cancer and 8302 controls were genotyped for four <jats:italic>CHEK2<\/jats:italic> variants: 1100delC, del5395, IVS2+1G&gt;A and I157T. Predictors of survival were determined among <jats:italic>CHEK2<\/jats:italic> pathogenic variant carriers using the Cox proportional hazards model. The median follow-up was 17.5 years. Covariates included age (\u226460; &gt;61 years), sex (female; male), clinical characteristics (stage: TNM, grade, histopathological type), smoking status (non-smoking; smoking) and cancer family history (negative; positive).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>We found no impact of <jats:italic>CHEK2<\/jats:italic> mutations on bladder or kidney cancer survival. However, we observed a possible increased survival in the subgroup of patients with stage T1 bladder cancer with <jats:italic>CHEK2<\/jats:italic> mutations but this did not meet statistical significance (HR = 0.14; 95% CI 0.02\u20131.04; p = 0.055). Moreover, we observed that the missense mutations were more frequent in the low grade invasive bladder cancer patient group (OR = 7.9; 95% CI 1.50\u201342.1; p = 0.04) and in patients with bladder cancer with stage Ta (OR = 2.4; 95% CI 1.30\u20134.55; p = 0.006). The different results where missense mutations occurs less often we observed among patients with high grade invasive bladder cancer (OR = 0.12; 95% CI 0.02\u20130.66; p = 0.04) and those with stage T1 disease (OR = 0.2; 95% CI 0.07\u20130.76; p = 0.01). Our investigations revealed that any mutation in <jats:italic>CHEK2<\/jats:italic> occurs more often among patients with stage Ta bladder cancer (OR = 2.0; 95% CI 1.19\u20133.47; p = 0.01) and less often in patients with stage T1 disease (OR = 0.31; 95% CI 0.12\u20130.78; p = 0.01). In the kidney cancer patients, truncating mutations were present more often in the group with clear cell carcinoma GII (OR = 8.0; 95% CI 0.95\u201367.7; p = 0.05). The 10-year survival for all <jats:italic>CHEK2<\/jats:italic> mutation carriers with bladder cancer was 33% and for non-carriers 11% (<jats:italic>p<\/jats:italic> = 0.15). The 10-year survival for <jats:italic>CHEK2<\/jats:italic> mutation carriers with kidney cancer 34% and for non-carriers 20% (<jats:italic>p<\/jats:italic> = 0.5).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p><jats:italic>CHEK2<\/jats:italic> mutations were not associated with any change in bladder or kidney cancer survival regardless of their age, sex, smoking status and family history. We observed a potentially protective effect of <jats:italic>CHEK2<\/jats:italic> mutations on survival for patients with stage T1 bladder cancer. <jats:italic>CHEK2<\/jats:italic> missense mutations were more common among patients with low grade invasive bladder cancer and in patients with stage Ta diease. The frequencies of the I157T <jats:italic>CHEK2<\/jats:italic> pathogenic variant were less in patients with high grade invasive bladder cancer and those with stage T1 disease. Among patients with bladder cancer with stage Ta disease, the OR for any mutation in <jats:italic>CHEK2<\/jats:italic> was 2.0 but for those with stage T1 disease, the OR was 0.3. We observed truncating <jats:italic>CHEK2<\/jats:italic> mutations were associated with kidney cancer patients with GII clear cell carcinoma.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0257132","type":"journal-article","created":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T17:57:31Z","timestamp":1631210251000},"page":"e0257132","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Survival of bladder or renal cancer in patients with CHEK2 mutations"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5143-6387","authenticated-orcid":true,"given":"El\u017cbieta","family":"Z\u0142owocka-Per\u0142owska","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadeusz","family":"D\u0119bniak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcin","family":"S\u0142ojewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3910-649X","authenticated-orcid":true,"given":"Thierry","family":"van de Wetering","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"To\u0142oczko-Grabarek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cezary","family":"Cybulski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodney J.","family":"Scott","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Lubi\u0144ski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,9,9]]},"reference":[{"issue":"6","key":"pone.0257132.ref001","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1086\/426403","article-title":"CHEK2 is a multiorgan cancer susceptibility gene","volume":"75","author":"C Cybulski","year":"2004","journal-title":"Am J Hum Genet"},{"key":"pone.0257132.ref002","author":"Elzbieta Zlowocka-Perlowska","journal-title":"CHEK2 Alleles Predispose to Renal Cancer in Poland Affiliations + expand"},{"issue":"1","key":"pone.0257132.ref003","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s10549-006-9320-y","article-title":"A deletion in CHEK2 of 5,395 bp predisposes to breast cancer in Poland","volume":"102","author":"C Cybulski","year":"2007","journal-title":"Breast Cancer Res Treat"},{"issue":"3","key":"pone.0257132.ref004","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1002\/ijc.23099","article-title":"Germline mutations in the CHEK2 kinase gene are associated with an increased risk of bladder cancer","volume":"122","author":"E Z\u0142owocka","year":"2008","journal-title":"Int J Cancer"},{"key":"pone.0257132.ref005","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1086\/346094","article-title":"Mutations in CHEK2 associated with prostate cancer risk","volume":"72","author":"X Dong","year":"2003","journal-title":"Am J Hum Genet"},{"key":"pone.0257132.ref006","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1086\/421251","article-title":"CHEK2*1100delC and susceptibility to breast cancer: a collaborative analysis involving 10,860 breast cancer cases and 9,065 controls from 10 studies","volume":"74","author":"CHEK2 Breast Cancer Case-Control Consortium","year":"2004","journal-title":"Am J Hum Genet"},{"key":"pone.0257132.ref007","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":"C Cybulski","year":"2004","journal-title":"Cancer Res"},{"issue":"3","key":"pone.0257132.ref008","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1002\/ijc.29426","article-title":"CHEK2 mutations and the risk of papillary thyroid cancer","volume":"137","author":"M 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Cancer"},{"key":"pone.0257132.ref012","article-title":"An inherited NBN mutation is associated with poor prognosis prostate cancer","volume":"13","author":"C Cybulski","year":"2012","journal-title":"Br J Cancer"},{"key":"pone.0257132.ref013","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":"C Cybulski","year":"2011","journal-title":"J Clin Oncol"},{"issue":"3","key":"pone.0257132.ref014","first-page":"115","article-title":"CHEK2 germline mutations correlate with recurrence rate in patients with superficial bladder cancer","volume":"54","author":"M S\u0142ojewski","year":"2008","journal-title":"Ann Acad Med Stetin"},{"issue":"3","key":"pone.0257132.ref015","doi-asserted-by":"crossref","first-page":"1625","DOI":"10.1007\/s12253-019-00745-7","article-title":"Loss of CHEK2 Predicts Progression in Stage pT1 Non-Muscle-Invasive Bladder Cancer (NMIBC)","volume":"26","author":"PJ Spachmann","year":"2020","journal-title":"Pathol Oncol Res"},{"issue":"9","key":"pone.0257132.ref016","first-page":"1228","volume":"4","author":"MI Carlo","year":"2018","journal-title":"Prevalence of Germline Mutations in Cancer Susceptibility Genes in Patients With Advanced Renal Cell Carcinoma"},{"key":"pone.0257132.ref017","doi-asserted-by":"crossref","first-page":"33542","DOI":"10.1038\/srep33542","article-title":"Rare variants in BRCA2 and CHEK2 are associated withthe risk of urinary tract cancers","volume":"6","author":"Y Ge","year":"2016","journal-title":"Sci Rep"},{"issue":"1","key":"pone.0257132.ref018","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1186\/s13058-016-0758-5","article-title":"Patient survival and tumor characteristics associated with CHEK2:p.I157T - findings from the Breast Cancer Association Consortium. 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An inherited NBN mutation is associated with poor prognosis prostate cancer","volume":"108","author":"C Cybulski","year":"2013","journal-title":"Br J Cancer"},{"issue":"6","key":"pone.0257132.ref021","doi-asserted-by":"crossref","first-page":"1385","DOI":"10.1158\/1078-0432.CCR-19-0224","article-title":"Germline DNA Sequencing Reveals Novel Mutations Predictive of Overall Survival in a Cohort of Patients with Pancreatic Cancer","volume":"26","author":"JB Goldstein","year":"2020","journal-title":"Clin Cancer Res"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0257132","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T17:57:58Z","timestamp":1631210278000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0257132"}},"subtitle":[],"editor":[{"given":"Alvaro","family":"Galli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,9,9]]},"references-count":21,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9,9]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0257132","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,9]]}}}