{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T04:00:37Z","timestamp":1789790437458,"version":"4.0.1"},"reference-count":34,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["K01 CA237875"],"award-info":[{"award-number":["K01 CA237875"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Genetic Epidemiology Risk Assessment Program for Pancreatic Cancer honoring Dr. Gloria Petersen"},{"name":"The Intramural Research Program of the National Institutes of Health (NIH)."}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Pancreatic ductal adenocarcinoma (PDAC) remains a highly fatal malignancy due partly to treatment resistance in many patients. We previously identified a functional germline deletion overlapping exon 6 of\n                      <jats:italic>CTRB2<\/jats:italic>\n                      (CTRB2ex6) at a PDAC genome-wide risk locus on chr16q23.1. This variant leads to a nonfunctional truncated chymotrypsin protein that accumulates intracellularly and induces endoplasmic reticulum stress. Here, we performed a retrospective study to determine whether CTRB2ex6 deletions are associated with response to chemotherapy, time to cancer progression, or overall survival (OS) in PDAC patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The study included\n                      <jats:italic>CTRB2<\/jats:italic>\n                      genotype data from two independent PDAC cohorts (Cohort 1: n\u2009=\u2009633; Cohort 2: n\u2009=\u20093,896). We examined associations between CTRB2ex6 deletion status and OS and time-to-progression (TTP) using Cox proportional hazard modeling. TTP was also evaluated in a subset of chemotherapy-treated patients in Cohort 1 (n\u2009=\u2009263) to determine the impact of CTRB2ex6 deletion status on chemotherapy response.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      CTRB2ex6 deletions were found in 20% of patients in both cohorts combined (19% in Cohort 1, and 21% in Cohort 2). No significant difference was observed in OS by\n                      <jats:italic>CTRB2<\/jats:italic>\n                      deletion status in either cohort (Cohort 1: HR\u2009=\u20090.95,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.60; Cohort 2: HR\u2009=\u20091.04,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.43). Among chemotherapy-treated patients in Cohort 1,\n                      <jats:italic>CTRB2<\/jats:italic>\n                      deletion carriers had a longer median TTP (20.4 vs. 12 months), though this was not statistically significant (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.49). Homozygous deletion carriers had the longest TTP (70 months).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      No clinical impact on chemotherapy response or OS was observed by\n                      <jats:italic>CTRB2<\/jats:italic>\n                      deletion status. Further studies are needed to identify reliable biomarkers of therapy response in PDAC.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0343022","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T18:28:34Z","timestamp":1771525714000},"page":"e0343022","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Alterations in the CTRB2 gene and response to chemotherapy in pancreatic cancer"],"prefix":"10.1371","volume":"21","author":[{"given":"Khalid","family":"Jazieh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5988-0135","authenticated-orcid":true,"given":"Erin 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Ohhashi","year":"2008","journal-title":"Anticancer Res"},{"issue":"7579","key":"pone.0343022.ref007","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/nature16064","article-title":"Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer","volume":"527","author":"X Zheng","year":"2015","journal-title":"Nature"},{"issue":"4","key":"pone.0343022.ref008","doi-asserted-by":"crossref","first-page":"2137","DOI":"10.3390\/cancers6042137","article-title":"Desmoplasia and chemoresistance in pancreatic cancer","volume":"6","author":"M Schober","year":"2014","journal-title":"Cancers (Basel)"},{"key":"pone.0343022.ref009","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.canlet.2020.07.041","article-title":"Hypoxia: Friend or Foe for drug delivery in Pancreatic Cancer","volume":"492","author":"VM Shah","year":"2020","journal-title":"Cancer 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Pancreatic adenocarcinoma (version 2.2025). https:\/\/www.nccn.org\/guidelines\/guidelines-detail?category=1&id=1455. Accessed 2025 September 6."},{"issue":"10","key":"pone.0343022.ref012","first-page":"1852","article-title":"A 584 bp deletion in CTRB2 inhibits chymotrypsin B2 activity and secretion and confers risk of pancreatic cancer. 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Proteomics"},{"issue":"3","key":"pone.0343022.ref019","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1093\/jnci\/djx272","article-title":"Risk of different cancers among first-degree relatives of pancreatic cancer patients: influence of probands\u2019 susceptibility gene mutation status","volume":"111","author":"SO Antwi","year":"2019","journal-title":"J Natl Cancer Inst"},{"issue":"7","key":"pone.0343022.ref020","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1158\/1055-9965.EPI-19-1597","article-title":"Leukocyte telomere length and its interaction with germline variation in telomere-related genes in relation to pancreatic adenocarcinoma risk","volume":"29","author":"SO Antwi","year":"2020","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"issue":"11","key":"pone.0343022.ref021","first-page":"1583","article-title":"Exposure to environmental chemicals and heavy metals, and risk of pancreatic cancer","volume":"26","author":"SO Antwi","year":"2015","journal-title":"Cancer Causes Control"},{"issue":"1","key":"pone.0343022.ref022","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1038\/s41467-018-02942-5","article-title":"Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer","volume":"9","author":"AP Klein","year":"2018","journal-title":"Nat Commun"},{"issue":"9","key":"pone.0343022.ref023","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1158\/1055-9965.EPI-23-0453","article-title":"Genetic Susceptibility to Nonalcoholic Fatty Liver Disease and Risk for Pancreatic Cancer: Mendelian Randomization","volume":"32","author":"SD King","year":"2023","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"issue":"2","key":"pone.0343022.ref024","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1158\/1055-9965.EPI-21-0745","article-title":"Influence of cancer susceptibility gene mutations and ABO blood group of pancreatic cancer probands on concomitant risk to first-degree relatives","volume":"31","author":"SO Antwi","year":"2022","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"issue":"1","key":"pone.0343022.ref025","doi-asserted-by":"crossref","DOI":"10.1212\/NXG.0000000000200120","article-title":"Machine learning models of polygenic risk for enhanced prediction of alzheimer disease endophenotypes","volume":"10","author":"NB Gunter","year":"2024","journal-title":"Neurol Genet"},{"issue":"9","key":"pone.0343022.ref026","doi-asserted-by":"crossref","first-page":"2701","DOI":"10.1038\/s41380-024-02530-8","article-title":"Clinical and genetic contributions to medical comorbidity in bipolar disorder: a study using electronic health records-linked biobank data","volume":"29","author":"JA Sanchez-Ruiz","year":"2024","journal-title":"Mol Psychiatry"},{"issue":"1","key":"pone.0343022.ref027","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/s41588-020-00756-0","article-title":"Efficient phasing and imputation of low-coverage sequencing data using large reference panels","volume":"53","author":"S Rubinacci","year":"2021","journal-title":"Nat Genet"},{"issue":"2","key":"pone.0343022.ref028","doi-asserted-by":"crossref","DOI":"10.1093\/gigascience\/giab008","article-title":"Twelve years of SAMtools and BCFtools","volume":"10","author":"P Danecek","year":"2021","journal-title":"Gigascience"},{"issue":"2","key":"pone.0343022.ref029","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1002\/humu.22240","article-title":"Mechanisms of formation of structural variation in a fully sequenced human genome","volume":"34","author":"AWC Pang","year":"2013","journal-title":"Hum Mutat"},{"issue":"19","key":"pone.0343022.ref030","doi-asserted-by":"crossref","first-page":"4932","DOI":"10.3390\/cancers13194932","article-title":"The heterogeneity of the tumor microenvironment as essential determinant of development, progression and therapy response of pancreatic cancer","volume":"13","author":"Group Young Researchers In 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pancreatitis","volume":"67","author":"J Rosendahl","year":"2018","journal-title":"Gut"},{"issue":"23","key":"pone.0343022.ref034","doi-asserted-by":"crossref","first-page":"4283","DOI":"10.1111\/febs.12018","article-title":"Determinants of chymotrypsin C cleavage specificity in the calcium-binding loop of human cationic trypsinogen","volume":"279","author":"A Szab\u00f3","year":"2012","journal-title":"Febs j"}],"container-title":["PLOS 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