{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T17:45:22Z","timestamp":1778780722101,"version":"3.51.4"},"reference-count":46,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T00:00:00Z","timestamp":1632182400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Collaborative Research Fund","award":["C7031.15G"],"award-info":[{"award-number":["C7031.15G"]}]},{"name":"Seed Fund for Basic Research from the University of Hong Kong","award":["201611159317"],"award-info":[{"award-number":["201611159317"]}]},{"name":"General Research Fund","award":["17118517"],"award-info":[{"award-number":["17118517"]}]},{"name":"Asian Fund for Cancer Research","award":["Not applicable"],"award-info":[{"award-number":["Not applicable"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Unbiased whole-exome sequencing approaches in familial esophageal squamous cell carcinoma (ESCC) initially prioritized RAD50 as a candidate cancer predisposition gene. The combined study with 3289 Henan individuals from Northern China identified two pathogenic RAD50 protein truncation variants, p.Q672X and a recurrent p.K722fs variant at the zinc hook domain significantly conferring increased familial ESCC risk. Effects of ~10-fold higher familial ESCC risk were observed, when compared to East Asians from the gnomAD database. Functional characterization suggested that the RAD50Q672X mutation contributes a dominant-negative effect in DNA repair of double-stranded breaks. Overexpression of the RAD50Q672X and RAD50L1264F missense mutation also sensitized cell death upon replication stress stimuli induced by formaldehyde treatment and the CHK1 inhibitor, AZD7762. Our study suggested the novel insight of the potential for synthetic lethal therapeutic options for RAD50Q672X and the East-Asian-specific RAD50L1264F variants and CHK1 inhibitors. Our study also suggested the association of RAD50 LOF variants in the zinc hook domain with a higher risk of familial ESCC in Chinese.<\/jats:p>","DOI":"10.3390\/cancers13184715","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T08:04:23Z","timestamp":1632211463000},"page":"4715","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["RAD50 Loss of Function Variants in the Zinc Hook Domain Associated with Higher Risk of Familial Esophageal Squamous Cell Carcinoma"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7997-331X","authenticated-orcid":false,"given":"Josephine Mun Yee","family":"Ko","sequence":"first","affiliation":[{"name":"Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3001-3112","authenticated-orcid":false,"given":"Shiu Yeung","family":"Lam","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7978-4028","authenticated-orcid":false,"given":"Lvwen","family":"Ning","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8015-6050","authenticated-orcid":false,"given":"Annie Wai Yeeng","family":"Chai","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0990-1035","authenticated-orcid":false,"given":"Lisa Chan","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheyne Sta Ana","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carissa Wing Yan","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2559-3626","authenticated-orcid":false,"given":"Maria Li","family":"Lung","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. 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