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NSD1 mutations by HPV status in head and neck cancer: differences in survival and response to DNA-damaging agents

BACKGROUND: Compared to HPV-negative head and neck squamous cell carcinomas (HNSCCs), HPV-positive HNSCCs are associated with a favorable prognosis in part due to their improved treatment sensitivity. Inactivating mutations in NSD1 were shown to be a favorable prognostic biomarker in laryngeal cance...

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Autores principales: Pan, Cassie, Izreig, Said, Yarbrough, Wendell G., Issaeva, Natalia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613249/
https://www.ncbi.nlm.nih.gov/pubmed/31321084
http://dx.doi.org/10.1186/s41199-019-0042-3
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author Pan, Cassie
Izreig, Said
Yarbrough, Wendell G.
Issaeva, Natalia
author_facet Pan, Cassie
Izreig, Said
Yarbrough, Wendell G.
Issaeva, Natalia
author_sort Pan, Cassie
collection PubMed
description BACKGROUND: Compared to HPV-negative head and neck squamous cell carcinomas (HNSCCs), HPV-positive HNSCCs are associated with a favorable prognosis in part due to their improved treatment sensitivity. Inactivating mutations in NSD1 were shown to be a favorable prognostic biomarker in laryngeal cancers. Here, we characterize NSD1 mutations from the expanded The Cancer Genome Atlas (TCGA) HNSCC cohort (n = 522) and examine their prognostic implications based on HPV status of the tumor. We also begin to examine if NSD1 regulates response to platinum-based drugs and other DNA-damaging agents. METHODS: TCGA HNSCC samples were segregated by HPV and NSD1 mutations using cBioPortal and patient survival was determined. Pathogenicity of mutations was predicted using UMD-Predictor. NSD1-depleted cell lines were established by transfection with control or shRNAs against NSD1, followed by puromycin selection, and confirmed by qRT-PCR. Cell sensitivity to DNA damaging agents was assessed using short-term proliferation and long-term clonogenic survival assays. RESULTS: Among 457 HPV(−) tumors, 13% contained alterations in the NSD1 gene. The majority (61.3%) of NSD1 gene alterations in HPV(−) specimens were truncating mutations within or before the enzymatic SET domain. The remaining alterations included homozygous gene deletions (6.7%), missense point mutations (30.7%) and inframe deletions (1.3%). UMD-Predictor categorized 18 of 23 missense point mutations as pathogenic. For HPV(+) HNSCC (n = 65), 6 NSD1 mutations, comprised of two truncating (33%) and 4 missense point (66%) mutations, were identified. Three of the 4 missense point mutations were predicted to be pathogenic or probably pathogenic by UMD-Predictor. Kaplan-Meier survival analysis determined significantly improved survival of HPV(−) HNSCC patients whose tumors harbored NSD1 gene alterations, as compared to patients with wild-type NSD1 tumors. Interestingly, the survival effect of NSD1 mutations observed in HPV-negative HNSCC was reversed in HPV(+) tumors. Proliferation and clonogenic survival of two HPV(−) cell lines stably expressing control or NSD1 shRNAs showed that NSD1-depleted cells were more sensitive to cisplatin and carboplatin, but not to other DNA damaging drugs. CONCLUSIONS: Genetic alterations in NSD1 hold potential as novel prognostic biomarkers in HPV(−) head and neck cancers. NSD1 mutations in HPV(+) cancers may also play a prognostic role, although this effect must be examined in a larger cohort. NSD1 downregulation results in improved sensitivity to cisplatin and carboplatin, but not to other DNA-damaging agents, in epithelial cells. Increased sensitivity to platinum-based chemotherapy agents associated with NSD1 depletion may contribute to improved survival in HPV(−) HNSCCs. Further studies are needed to determine mechanisms through which NSD1 protects HPV(−) HNSCC cells from platinum-based therapy, as well as confirmation of NSD1 effect in HPV(+) HNSCC.
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spelling pubmed-66132492019-07-18 NSD1 mutations by HPV status in head and neck cancer: differences in survival and response to DNA-damaging agents Pan, Cassie Izreig, Said Yarbrough, Wendell G. Issaeva, Natalia Cancers Head Neck Research BACKGROUND: Compared to HPV-negative head and neck squamous cell carcinomas (HNSCCs), HPV-positive HNSCCs are associated with a favorable prognosis in part due to their improved treatment sensitivity. Inactivating mutations in NSD1 were shown to be a favorable prognostic biomarker in laryngeal cancers. Here, we characterize NSD1 mutations from the expanded The Cancer Genome Atlas (TCGA) HNSCC cohort (n = 522) and examine their prognostic implications based on HPV status of the tumor. We also begin to examine if NSD1 regulates response to platinum-based drugs and other DNA-damaging agents. METHODS: TCGA HNSCC samples were segregated by HPV and NSD1 mutations using cBioPortal and patient survival was determined. Pathogenicity of mutations was predicted using UMD-Predictor. NSD1-depleted cell lines were established by transfection with control or shRNAs against NSD1, followed by puromycin selection, and confirmed by qRT-PCR. Cell sensitivity to DNA damaging agents was assessed using short-term proliferation and long-term clonogenic survival assays. RESULTS: Among 457 HPV(−) tumors, 13% contained alterations in the NSD1 gene. The majority (61.3%) of NSD1 gene alterations in HPV(−) specimens were truncating mutations within or before the enzymatic SET domain. The remaining alterations included homozygous gene deletions (6.7%), missense point mutations (30.7%) and inframe deletions (1.3%). UMD-Predictor categorized 18 of 23 missense point mutations as pathogenic. For HPV(+) HNSCC (n = 65), 6 NSD1 mutations, comprised of two truncating (33%) and 4 missense point (66%) mutations, were identified. Three of the 4 missense point mutations were predicted to be pathogenic or probably pathogenic by UMD-Predictor. Kaplan-Meier survival analysis determined significantly improved survival of HPV(−) HNSCC patients whose tumors harbored NSD1 gene alterations, as compared to patients with wild-type NSD1 tumors. Interestingly, the survival effect of NSD1 mutations observed in HPV-negative HNSCC was reversed in HPV(+) tumors. Proliferation and clonogenic survival of two HPV(−) cell lines stably expressing control or NSD1 shRNAs showed that NSD1-depleted cells were more sensitive to cisplatin and carboplatin, but not to other DNA damaging drugs. CONCLUSIONS: Genetic alterations in NSD1 hold potential as novel prognostic biomarkers in HPV(−) head and neck cancers. NSD1 mutations in HPV(+) cancers may also play a prognostic role, although this effect must be examined in a larger cohort. NSD1 downregulation results in improved sensitivity to cisplatin and carboplatin, but not to other DNA-damaging agents, in epithelial cells. Increased sensitivity to platinum-based chemotherapy agents associated with NSD1 depletion may contribute to improved survival in HPV(−) HNSCCs. Further studies are needed to determine mechanisms through which NSD1 protects HPV(−) HNSCC cells from platinum-based therapy, as well as confirmation of NSD1 effect in HPV(+) HNSCC. BioMed Central 2019-07-08 /pmc/articles/PMC6613249/ /pubmed/31321084 http://dx.doi.org/10.1186/s41199-019-0042-3 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Pan, Cassie
Izreig, Said
Yarbrough, Wendell G.
Issaeva, Natalia
NSD1 mutations by HPV status in head and neck cancer: differences in survival and response to DNA-damaging agents
title NSD1 mutations by HPV status in head and neck cancer: differences in survival and response to DNA-damaging agents
title_full NSD1 mutations by HPV status in head and neck cancer: differences in survival and response to DNA-damaging agents
title_fullStr NSD1 mutations by HPV status in head and neck cancer: differences in survival and response to DNA-damaging agents
title_full_unstemmed NSD1 mutations by HPV status in head and neck cancer: differences in survival and response to DNA-damaging agents
title_short NSD1 mutations by HPV status in head and neck cancer: differences in survival and response to DNA-damaging agents
title_sort nsd1 mutations by hpv status in head and neck cancer: differences in survival and response to dna-damaging agents
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613249/
https://www.ncbi.nlm.nih.gov/pubmed/31321084
http://dx.doi.org/10.1186/s41199-019-0042-3
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