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Conference Paper: Nasopharyngeal carcinoma molecular subgroups for somatic copy number alterations (SCNAs)

TitleNasopharyngeal carcinoma molecular subgroups for somatic copy number alterations (SCNAs)
Authors
Issue Date2020
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
Proceedings of the 111th Annual Meeting of the American Association for Cancer Research (AACR), Virtual Meeting II, 22-24 June 2020. In Cancer Research, 2020, v. 80 n. 16, Suppl., abstract no. 4734 How to Cite?
AbstractBackground: Investigation of biological mechanisms underlying genetic alterations in cancer can assist the understanding of the inter-patient heterogeneity and identify new therapeutic targets. Although multiple genomic studies have been carried out in nasopharyngeal carcinoma (NPC), the detailed mechanisms underlying these genetic alterations and NPC pathogenesis remain unclear. Aims: We aim to identify the additional genetic events driving tumorigenesis by increasing the statistical power to distinguish the infrequent driver events from passengers, gain insights in the mechanisms underlying genetic alterations and evaluate their prognostic value for overall survival. Our ultimate goal is to identify potential new therapeutic targets for NPC treatment. Methods: We performed an integrative genomic and transcriptomic analysis for a total of 216 NPC cases from three genomics studies to catalogue the somatic mutational signatures, somatic copy number alterations (SCNAs) and gene expression changes in NPC. Results: Three clusters with distinct SCNA patterns were uncovered. Cluster 1 (SCNA-L-gain), accounting for 66.7% of total cases, has consistent CN loss in chromosomes 3, 14 and 16, which are typical SCNAs in NPC; Cluster 2 (SCNA-M-gain, 8.2%) is characterized as a moderate level of CN gain involved in selected chromosomes 17, 19 and 22. Strikingly, Cluster 3 (SCNA-H-gain, 25.1%) has extensive CN gains across the genome with regional loss near telomeres in several chromosomes. Noticeably, a new mutational signature relevant to the deficiency of the homologous recombination (HR) repair pathway (BRCAness) was discovered in a subset of NPC cases (29.6%). The survival analysis indicates that this mutational signature is significantly associated with shorter overall survival after adjustment for stage, gender and age and stratification by studies (P=0.018, HR=2.2, 95% CI 1.1-4.4). All the cases harboring the pathogenic BRCA2 germline and somatic mutations carry this mutational signature, but only account for 7.8% of such cases. A strong BRCAness signature is more frequently found in the SCNA-H-gain cluster (P=0.012), indicating HR deficiency may play a role for genomic instability in this subset of NPC patients. Conclusions: In NPC, there is a molecular subtype with extensively high copy number gain and a strong BRCAness signature. Discovery of this molecular subtype supports prospective clinical trials investigating agents, such as PARP inhibitor, to target this subset of patients. Acknowledgements: This study was funded by the Hong Kong Research Grants Council grant (AoE/M-06/08) to MLL
DescriptionE-Posters - Session PO.MCB09.06 - Genomic Profiling of Tumors 4 - abstract no. 4734 / 9
Persistent Identifierhttp://hdl.handle.net/10722/286463
ISSN
2020 Impact Factor: 12.701
2015 SCImago Journal Rankings: 5.372
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorDai, W-
dc.contributor.authorChung, LSD-
dc.contributor.authorChow, KYL-
dc.contributor.authorLeong, ML-
dc.contributor.authorChan, KC-
dc.contributor.authorKo, JMY-
dc.contributor.authorLung, ML-
dc.date.accessioned2020-08-31T07:04:14Z-
dc.date.available2020-08-31T07:04:14Z-
dc.date.issued2020-
dc.identifier.citationProceedings of the 111th Annual Meeting of the American Association for Cancer Research (AACR), Virtual Meeting II, 22-24 June 2020. In Cancer Research, 2020, v. 80 n. 16, Suppl., abstract no. 4734-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10722/286463-
dc.descriptionE-Posters - Session PO.MCB09.06 - Genomic Profiling of Tumors 4 - abstract no. 4734 / 9-
dc.description.abstractBackground: Investigation of biological mechanisms underlying genetic alterations in cancer can assist the understanding of the inter-patient heterogeneity and identify new therapeutic targets. Although multiple genomic studies have been carried out in nasopharyngeal carcinoma (NPC), the detailed mechanisms underlying these genetic alterations and NPC pathogenesis remain unclear. Aims: We aim to identify the additional genetic events driving tumorigenesis by increasing the statistical power to distinguish the infrequent driver events from passengers, gain insights in the mechanisms underlying genetic alterations and evaluate their prognostic value for overall survival. Our ultimate goal is to identify potential new therapeutic targets for NPC treatment. Methods: We performed an integrative genomic and transcriptomic analysis for a total of 216 NPC cases from three genomics studies to catalogue the somatic mutational signatures, somatic copy number alterations (SCNAs) and gene expression changes in NPC. Results: Three clusters with distinct SCNA patterns were uncovered. Cluster 1 (SCNA-L-gain), accounting for 66.7% of total cases, has consistent CN loss in chromosomes 3, 14 and 16, which are typical SCNAs in NPC; Cluster 2 (SCNA-M-gain, 8.2%) is characterized as a moderate level of CN gain involved in selected chromosomes 17, 19 and 22. Strikingly, Cluster 3 (SCNA-H-gain, 25.1%) has extensive CN gains across the genome with regional loss near telomeres in several chromosomes. Noticeably, a new mutational signature relevant to the deficiency of the homologous recombination (HR) repair pathway (BRCAness) was discovered in a subset of NPC cases (29.6%). The survival analysis indicates that this mutational signature is significantly associated with shorter overall survival after adjustment for stage, gender and age and stratification by studies (P=0.018, HR=2.2, 95% CI 1.1-4.4). All the cases harboring the pathogenic BRCA2 germline and somatic mutations carry this mutational signature, but only account for 7.8% of such cases. A strong BRCAness signature is more frequently found in the SCNA-H-gain cluster (P=0.012), indicating HR deficiency may play a role for genomic instability in this subset of NPC patients. Conclusions: In NPC, there is a molecular subtype with extensively high copy number gain and a strong BRCAness signature. Discovery of this molecular subtype supports prospective clinical trials investigating agents, such as PARP inhibitor, to target this subset of patients. Acknowledgements: This study was funded by the Hong Kong Research Grants Council grant (AoE/M-06/08) to MLL-
dc.languageeng-
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/-
dc.relation.ispartofCancer Research-
dc.relation.ispartofAmerican Association for Cancer Research (AACR) Virtual Meeting II-
dc.titleNasopharyngeal carcinoma molecular subgroups for somatic copy number alterations (SCNAs)-
dc.typeConference_Paper-
dc.identifier.emailDai, W: weidai2@hku.hk-
dc.identifier.emailChung, LSD: dittman@HKUCC-COM.hku.hk-
dc.identifier.emailChan, KC: biocandy@hku.hk-
dc.identifier.emailKo, JMY: joko@hku.hk-
dc.identifier.emailLung, ML: mlilung@hku.hk-
dc.identifier.authorityDai, W=rp02146-
dc.identifier.authorityKo, JMY=rp02011-
dc.identifier.authorityLung, ML=rp00300-
dc.identifier.doi10.1158/1538-7445.AM2020-4734-
dc.identifier.hkuros313289-
dc.identifier.volume80-
dc.identifier.issue16, Suppl.-
dc.identifier.spageabstract no. 4734-
dc.identifier.epageabstract no. 4734-
dc.identifier.isiWOS:000590059306124-
dc.publisher.placeUnited States-
dc.identifier.issnl0008-5472-

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