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NSD1 mutations by HPV status in head and neck cancer: differences in survival and response to DNA-damaging agents.
Cancers Head Neck 2019; 4:3CH

Abstract

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.

Authors+Show Affiliations

1Department of Surgery, Division of Otolaryngology, Yale University, New Haven, CT USA.1Department of Surgery, Division of Otolaryngology, Yale University, New Haven, CT USA.2Department of Otolaryngology/Head and Neck Surgery, The University of North Carolina at Chapel Hill, 170 Manning Drive, Campus Box 7070, Chapel Hill, NC 27599-7070 USA. 3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.2Department of Otolaryngology/Head and Neck Surgery, The University of North Carolina at Chapel Hill, 170 Manning Drive, Campus Box 7070, Chapel Hill, NC 27599-7070 USA. 3Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31321084

Citation

Pan, Cassie, et al. "NSD1 Mutations By HPV Status in Head and Neck Cancer: Differences in Survival and Response to DNA-damaging Agents." Cancers of the Head & Neck, vol. 4, 2019, p. 3.
Pan C, Izreig S, Yarbrough WG, et al. NSD1 mutations by HPV status in head and neck cancer: differences in survival and response to DNA-damaging agents. Cancers Head Neck. 2019;4:3.
Pan, C., Izreig, S., Yarbrough, W. G., & Issaeva, N. (2019). NSD1 mutations by HPV status in head and neck cancer: differences in survival and response to DNA-damaging agents. Cancers of the Head & Neck, 4, p. 3. doi:10.1186/s41199-019-0042-3.
Pan C, et al. NSD1 Mutations By HPV Status in Head and Neck Cancer: Differences in Survival and Response to DNA-damaging Agents. Cancers Head Neck. 2019;4:3. PubMed PMID: 31321084.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - NSD1 mutations by HPV status in head and neck cancer: differences in survival and response to DNA-damaging agents. AU - Pan,Cassie, AU - Izreig,Said, AU - Yarbrough,Wendell G, AU - Issaeva,Natalia, Y1 - 2019/07/08/ PY - 2019/01/16/received PY - 2019/05/31/accepted PY - 2019/7/20/entrez PY - 2019/7/20/pubmed PY - 2019/7/20/medline KW - HPV KW - Head and neck cancer KW - NSD1 KW - Survival KW - Treatment SP - 3 EP - 3 JF - Cancers of the head & neck JO - Cancers Head Neck VL - 4 N2 - 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. SN - 2059-7347 UR - https://www.unboundmedicine.com/medline/citation/31321084/NSD1_mutations_by_HPV_status_in_head_and_neck_cancer:_differences_in_survival_and_response_to_DNA-damaging_agents L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31321084/ DB - PRIME DP - Unbound Medicine ER -