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Article: BRCA2 loss‐of‐function germline mutations are associated with esophageal squamous cell carcinoma risk in Chinese

TitleBRCA2 loss‐of‐function germline mutations are associated with esophageal squamous cell carcinoma risk in Chinese
Authors
KeywordsEsophageal cancer susceptibility gene
Synthetic lethality
Chinese
BRCA2
Loss‐of‐function mutations
Issue Date2020
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/journal/29331/home
Citation
International Journal of Cancer, 2020, v. 146 n. 4, p. 1042-1051 How to Cite?
AbstractEsophageal squamous cell carcinoma (ESCC) occurs with highest frequency in China with over 90% mortality, highlighting the need for early detection and improved treatment strategies. We aimed to identify ESCC cancer predisposition gene(s). Our study included 4,517 individuals. The discovery phase using whole‐exome sequencing (WES) included 186 familial ESCC patients from high‐risk China. Targeted gene sequencing validation of 598 genes included 3,289 Henan and 1,228 moderate‐risk Hong Kong Chinese. A WES approach identified BRCA2 loss‐of‐function (LOF) mutations in 3.23% (6/186) familial ESCC patients compared to 0.21% (9/4300) in the ExAC East Asians (odds ratio [OR] = 15.89, p = 2.48 × 10−10). BRCA2 LOF mutation frequency in the combined Henan cohort has significantly higher prevalence (OR = 10.55, p = 0.0035). Results were independently validated in an ESCC Hong Kong cohort (OR = 10.64, p = 0.022). One Hong Kong pedigree was identified to carry a BRCA2 LOF mutation. BRCA2 inactivation in ESCC was via germline LOF mutations and wild‐type somatic allelic loss via loss of heterozygosity. Gene‐based association analysis, including LOF mutations and rare deleterious missense variants defined with combined annotation dependent depletion score ≥30, confirmed the genetic predisposition role of BRCA2 (OR = 9.50, p = 3.44 × 10−5), and provided new evidence for potential association of ESCC risk with DNA repair genes (POLQ and MSH2), inflammation (TTC39B) and angiogenesis (KDR). Our findings are the first to provide compelling evidence of the role of BRCA2 in ESCC genetic susceptibility in Chinese, suggesting defective homologous recombination is an underlying cause in ESCC pathogenesis, which is amenable to therapeutic options based on synthetic lethality approaches such as targeting BRCA2 with PARP1 inhibitors in ESCC.
Persistent Identifierhttp://hdl.handle.net/10722/273858
ISSN
2019 Impact Factor: 5.145
2015 SCImago Journal Rankings: 2.657
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorKo, JMY-
dc.contributor.authorNing, L-
dc.contributor.authorZhao, XK-
dc.contributor.authorChai, AWY-
dc.contributor.authorLei, LC-
dc.contributor.authorChoi, SSA-
dc.contributor.authorTao, L-
dc.contributor.authorLaw, S-
dc.contributor.authorKwong, A-
dc.contributor.authorLee, NPY-
dc.contributor.authorChan, KT-
dc.contributor.authorLo, A-
dc.contributor.authorSong, X-
dc.contributor.authorChen, PN-
dc.contributor.authorChang, YL-
dc.contributor.authorWang, LD-
dc.contributor.authorLung, ML-
dc.date.accessioned2019-08-18T14:50:02Z-
dc.date.available2019-08-18T14:50:02Z-
dc.date.issued2020-
dc.identifier.citationInternational Journal of Cancer, 2020, v. 146 n. 4, p. 1042-1051-
dc.identifier.issn0020-7136-
dc.identifier.urihttp://hdl.handle.net/10722/273858-
dc.description.abstractEsophageal squamous cell carcinoma (ESCC) occurs with highest frequency in China with over 90% mortality, highlighting the need for early detection and improved treatment strategies. We aimed to identify ESCC cancer predisposition gene(s). Our study included 4,517 individuals. The discovery phase using whole‐exome sequencing (WES) included 186 familial ESCC patients from high‐risk China. Targeted gene sequencing validation of 598 genes included 3,289 Henan and 1,228 moderate‐risk Hong Kong Chinese. A WES approach identified BRCA2 loss‐of‐function (LOF) mutations in 3.23% (6/186) familial ESCC patients compared to 0.21% (9/4300) in the ExAC East Asians (odds ratio [OR] = 15.89, p = 2.48 × 10−10). BRCA2 LOF mutation frequency in the combined Henan cohort has significantly higher prevalence (OR = 10.55, p = 0.0035). Results were independently validated in an ESCC Hong Kong cohort (OR = 10.64, p = 0.022). One Hong Kong pedigree was identified to carry a BRCA2 LOF mutation. BRCA2 inactivation in ESCC was via germline LOF mutations and wild‐type somatic allelic loss via loss of heterozygosity. Gene‐based association analysis, including LOF mutations and rare deleterious missense variants defined with combined annotation dependent depletion score ≥30, confirmed the genetic predisposition role of BRCA2 (OR = 9.50, p = 3.44 × 10−5), and provided new evidence for potential association of ESCC risk with DNA repair genes (POLQ and MSH2), inflammation (TTC39B) and angiogenesis (KDR). Our findings are the first to provide compelling evidence of the role of BRCA2 in ESCC genetic susceptibility in Chinese, suggesting defective homologous recombination is an underlying cause in ESCC pathogenesis, which is amenable to therapeutic options based on synthetic lethality approaches such as targeting BRCA2 with PARP1 inhibitors in ESCC.-
dc.languageeng-
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www3.interscience.wiley.com/journal/29331/home-
dc.relation.ispartofInternational Journal of Cancer-
dc.rightsThis is the peer reviewed version of the following article: International Journal of Cancer, 2020, v. 146 n. 4, p. 1042-1051, which has been published in final form at https://doi.org/10.1002/ijc.32619. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions-
dc.subjectEsophageal cancer susceptibility gene-
dc.subjectSynthetic lethality-
dc.subjectChinese-
dc.subjectBRCA2-
dc.subjectLoss‐of‐function mutations-
dc.titleBRCA2 loss‐of‐function germline mutations are associated with esophageal squamous cell carcinoma risk in Chinese-
dc.typeArticle-
dc.identifier.emailKo, JMY: joko@hku.hk-
dc.identifier.emailNing, L: lvwen@hku.hk-
dc.identifier.emailTao, L: taolihua@hku.hk-
dc.identifier.emailKwong, A: avakwong@hku.hk-
dc.identifier.emailLee, NPY: nikkilee@hku.hk-
dc.identifier.emailChan, KT: ktchan66@hku.hk-
dc.identifier.emailLung, ML: mlilung@hku.hk-
dc.identifier.authorityKo, JMY=rp02011-
dc.identifier.authorityKwong, A=rp01734-
dc.identifier.authorityLee, NPY=rp00263-
dc.identifier.authorityLung, ML=rp00300-
dc.description.naturepostprint-
dc.identifier.doi10.1002/ijc.32619-
dc.identifier.pmid31396961-
dc.identifier.scopuseid_2-s2.0-85071772881-
dc.identifier.hkuros301611-
dc.identifier.hkuros304484-
dc.identifier.hkuros311772-
dc.identifier.volume146-
dc.identifier.issue4-
dc.identifier.spage1042-
dc.identifier.epage1051-
dc.identifier.isiWOS:000483654400001-
dc.publisher.placeUnited States-

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