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Article: Clinical Outcome-Related Mutational Signatures Identified by Integrative Genomic Analysis in Nasopharyngeal Carcinoma

TitleClinical Outcome-Related Mutational Signatures Identified by Integrative Genomic Analysis in Nasopharyngeal Carcinoma
Authors
Issue Date2020
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://clincancerres.aacrjournals.org/
Citation
Clinical Cancer Research, 2020, v. 26 n. 24, p. 6494-6504 How to Cite?
AbstractPurpose: Investigation of biological mechanisms underlying genetic alterations in cancer can assist the understanding of etiology and identify the potential prognostic biomarkers. Experimental Design: We performed an integrative genomic analysis for a total of 731 nasopharyngeal carcinoma cases from five independent nasopharyngeal carcinoma cohorts to identify the genetic events associated with clinical outcomes. Results: In addition to the known mutational signatures associated with aging, APOBEC and mismatch repair (MMR), a new signature for homologous recombination deficiency (BRCAness) was discovered in 64 of 216 (29.6%) cases in the discovery set including three cohorts. This signature appeared more frequently in the recurrent and metastatic tumors and significantly correlated with shorter overall survival (OS) in the primary tumors. Independent prognostic value of MMR and BRCAness signatures was revealed by multivariable Cox analysis after adjustment for clinical parameters and stratification by studies. The cases with both signatures had much worse clinical outcome than those without these signatures [hazard ratio (HR), 12.4; P = 0.002]. This correlation was confirmed in the validation set (HR, 8.9; P = 0.003). The BRCAness signature is highly associated with BRCA2 pathogenic germline or somatic alterations (7.8% vs. 0%; P = 0.002). Targeted sequencing results from a prospective nasopharyngeal carcinoma cohort (N = 402) showed that the cases carrying BRCA2 germline rare variants are more likely to have poor OS and progression-free survival. Conclusions: Our study highlights importance of defects of DNA repair machinery in nasopharyngeal carcinoma pathogenesis and their prognostic values for clinical implications. These signatures will be useful for patient stratification to evaluate conventional and new treatment for precision medicine in nasopharyngeal carcinoma.
Persistent Identifierhttp://hdl.handle.net/10722/289665
ISSN
2020 Impact Factor: 12.531
2020 SCImago Journal Rankings: 5.427
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorDai, W-
dc.contributor.authorChung, DLS-
dc.contributor.authorChow, LKY-
dc.contributor.authorYu, VZ-
dc.contributor.authorLei, LC-
dc.contributor.authorLeong, MML-
dc.contributor.authorChan, CKC-
dc.contributor.authorKo, JMY-
dc.contributor.authorLung, ML-
dc.date.accessioned2020-10-22T08:15:44Z-
dc.date.available2020-10-22T08:15:44Z-
dc.date.issued2020-
dc.identifier.citationClinical Cancer Research, 2020, v. 26 n. 24, p. 6494-6504-
dc.identifier.issn1078-0432-
dc.identifier.urihttp://hdl.handle.net/10722/289665-
dc.description.abstractPurpose: Investigation of biological mechanisms underlying genetic alterations in cancer can assist the understanding of etiology and identify the potential prognostic biomarkers. Experimental Design: We performed an integrative genomic analysis for a total of 731 nasopharyngeal carcinoma cases from five independent nasopharyngeal carcinoma cohorts to identify the genetic events associated with clinical outcomes. Results: In addition to the known mutational signatures associated with aging, APOBEC and mismatch repair (MMR), a new signature for homologous recombination deficiency (BRCAness) was discovered in 64 of 216 (29.6%) cases in the discovery set including three cohorts. This signature appeared more frequently in the recurrent and metastatic tumors and significantly correlated with shorter overall survival (OS) in the primary tumors. Independent prognostic value of MMR and BRCAness signatures was revealed by multivariable Cox analysis after adjustment for clinical parameters and stratification by studies. The cases with both signatures had much worse clinical outcome than those without these signatures [hazard ratio (HR), 12.4; P = 0.002]. This correlation was confirmed in the validation set (HR, 8.9; P = 0.003). The BRCAness signature is highly associated with BRCA2 pathogenic germline or somatic alterations (7.8% vs. 0%; P = 0.002). Targeted sequencing results from a prospective nasopharyngeal carcinoma cohort (N = 402) showed that the cases carrying BRCA2 germline rare variants are more likely to have poor OS and progression-free survival. Conclusions: Our study highlights importance of defects of DNA repair machinery in nasopharyngeal carcinoma pathogenesis and their prognostic values for clinical implications. These signatures will be useful for patient stratification to evaluate conventional and new treatment for precision medicine in nasopharyngeal carcinoma.-
dc.languageeng-
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://clincancerres.aacrjournals.org/-
dc.relation.ispartofClinical Cancer Research-
dc.titleClinical Outcome-Related Mutational Signatures Identified by Integrative Genomic Analysis in Nasopharyngeal Carcinoma-
dc.typeArticle-
dc.identifier.emailDai, W: weidai2@hku.hk-
dc.identifier.emailYu, VZ: zvyu@hku.hk-
dc.identifier.emailChan, CKC: biocandy@hku.hk-
dc.identifier.emailKo, JMY: joko@hku.hk-
dc.identifier.emailLung, ML: mlilung@hku.hk-
dc.identifier.authorityDai, W=rp02146-
dc.identifier.authorityYu, VZ=rp02756-
dc.identifier.authorityKo, JMY=rp02011-
dc.identifier.authorityLung, ML=rp00300-
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1158/1078-0432.CCR-20-2854-
dc.identifier.pmid32988965-
dc.identifier.scopuseid_2-s2.0-85100631832-
dc.identifier.hkuros315942-
dc.identifier.volume26-
dc.identifier.issue24-
dc.identifier.spage6494-
dc.identifier.epage6504-
dc.identifier.isiWOS:000606533000013-
dc.publisher.placeUnited States-
dc.identifier.issnl1078-0432-

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