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Article: Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer

TitleWhole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer
Authors
Issue Date2014
Citation
Nature Genetics, 2014, v. 46, n. 6, p. 573-582 How to Cite?
AbstractGastric cancer is a heterogeneous disease with diverse molecular and histological subtypes. We performed whole-genome sequencing in 100 tumor-normal pairs, along with DNA copy number, gene expression and methylation profiling, for integrative genomic analysis. We found subtype-specific genetic and epigenetic perturbations and unique mutational signatures. We identified previously known (TP53, ARID1A and CDH1) and new (MUC6, CTNNA2, GLI3, RNF43 and others) significantly mutated driver genes. Specifically, we found RHOA mutations in 14.3% of diffuse-type tumors but not in intestinal-type tumors (P < 0.001). The mutations clustered in recurrent hotspots affecting functional domains and caused defective RHOA signaling, promoting escape from anoikis in organoid cultures. The top perturbed pathways in gastric cancer included adherens junction and focal adhesion, in which RHOA and other mutated genes we identified participate as key players. These findings illustrate a multidimensional and comprehensive genomic landscape that highlights the molecular complexity of gastric cancer and provides a road map to facilitate genome-guided personalized therapy. © 2014 Nature America, Inc.
Persistent Identifierhttp://hdl.handle.net/10722/207125
ISSN
2015 Impact Factor: 31.616
2015 SCImago Journal Rankings: 23.762

 

DC FieldValueLanguage
dc.contributor.authorWang, Kai-
dc.contributor.authorYuen, Siu Tsan-
dc.contributor.authorXu, Jiangchun-
dc.contributor.authorLee, Siupo-
dc.contributor.authorYan, Helen H N-
dc.contributor.authorShi, Stephanie-
dc.contributor.authorSiu, Hoicheong-
dc.contributor.authorDeng, Shibing-
dc.contributor.authorChu, Kent Man-
dc.contributor.authorLaw, Simon Ying Kit-
dc.contributor.authorChan, Kokhoe-
dc.contributor.authorChan, Annie Shuk Yee-
dc.contributor.authorTsui, Waiyin-
dc.contributor.authorHo, Siulun-
dc.contributor.authorChan, Anthony Kin Wang-
dc.contributor.authorMan, Jonathan L K-
dc.contributor.authorFoglizzo, Valentina-
dc.contributor.authorNg, Mankin-
dc.contributor.authorChan, April S.-
dc.contributor.authorChing, Wilson Yik Pang-
dc.contributor.authorCheng, Grace H W-
dc.contributor.authorXie, Tao-
dc.contributor.authorFernández, Julio Raúl-
dc.contributor.authorLi, Vivian-
dc.contributor.authorClevers, Hans C.-
dc.contributor.authorRejto, Paul A.-
dc.contributor.authorMao, Mao-
dc.contributor.authorLeung, Suet Yi-
dc.date.accessioned2014-12-09T04:31:27Z-
dc.date.available2014-12-09T04:31:27Z-
dc.date.issued2014-
dc.identifier.citationNature Genetics, 2014, v. 46, n. 6, p. 573-582-
dc.identifier.issn1061-4036-
dc.identifier.urihttp://hdl.handle.net/10722/207125-
dc.description.abstractGastric cancer is a heterogeneous disease with diverse molecular and histological subtypes. We performed whole-genome sequencing in 100 tumor-normal pairs, along with DNA copy number, gene expression and methylation profiling, for integrative genomic analysis. We found subtype-specific genetic and epigenetic perturbations and unique mutational signatures. We identified previously known (TP53, ARID1A and CDH1) and new (MUC6, CTNNA2, GLI3, RNF43 and others) significantly mutated driver genes. Specifically, we found RHOA mutations in 14.3% of diffuse-type tumors but not in intestinal-type tumors (P < 0.001). The mutations clustered in recurrent hotspots affecting functional domains and caused defective RHOA signaling, promoting escape from anoikis in organoid cultures. The top perturbed pathways in gastric cancer included adherens junction and focal adhesion, in which RHOA and other mutated genes we identified participate as key players. These findings illustrate a multidimensional and comprehensive genomic landscape that highlights the molecular complexity of gastric cancer and provides a road map to facilitate genome-guided personalized therapy. © 2014 Nature America, Inc.-
dc.languageeng-
dc.relation.ispartofNature Genetics-
dc.titleWhole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/ng.2983-
dc.identifier.pmid24816253-
dc.identifier.scopuseid_2-s2.0-84901680089-
dc.identifier.hkuros229280-
dc.identifier.hkuros231873-
dc.identifier.volume46-
dc.identifier.issue6-
dc.identifier.spage573-
dc.identifier.epage582-
dc.identifier.eissn1546-1718-

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