Low expression of NSD1, NSD2, and NSD3 define a subset of human papillomavirus-positive oral squamous carcinomas with unfavorable prognosis

doi:10.1186/s13027-021-00347-6

. 2021 Feb 15;16(1):13.

doi: 10.1186/s13027-021-00347-6.

Low expression of NSD1, NSD2, and NSD3 define a subset of human papillomavirus-positive oral squamous carcinomas with unfavorable prognosis

Steven F Gameiro^#¹, Farhad Ghasemi^#², Peter Y F Zeng³, Neil Mundi³, Christopher J Howlett⁴, Paul Plantinga⁴, John W Barrett³, Anthony C Nichols^{5

6

7

8

9}, Joe S Mymryk^{10

11

12

13

14}

Affiliations

¹ Department of Microbiology and Immunology, The University of Western Ontario, London, ON, N6A 3K7, Canada.
² Department of Surgery, The University of Western Ontario, London, ON, N6A 3K7, Canada.
³ Department of Otolaryngology, Head & Neck Surgery, The University of Western Ontario, London, ON, N6A 3K7, Canada.
⁴ Department of Pathology, The University of Western Ontario, London, ON, N6A 3K7, Canada.
⁵ Department of Otolaryngology, Head & Neck Surgery, The University of Western Ontario, London, ON, N6A 3K7, Canada. Anthony.Nichols@lhsc.on.ca.
⁶ Department of Pathology, The University of Western Ontario, London, ON, N6A 3K7, Canada. Anthony.Nichols@lhsc.on.ca.
⁷ Department of Oncology, The University of Western Ontario, London, ON, N6A 3K7, Canada. Anthony.Nichols@lhsc.on.ca.
⁸ London Regional Cancer Program, Lawson Health Research Institute, London, ON, N6C 2R5, Canada. Anthony.Nichols@lhsc.on.ca.
⁹ Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, Room B3-431A, 800 Commissioners Road East, London, ON, N6A 5W9, Canada. Anthony.Nichols@lhsc.on.ca.
¹⁰ Department of Microbiology and Immunology, The University of Western Ontario, London, ON, N6A 3K7, Canada. jmymryk@uwo.ca.
¹¹ Department of Otolaryngology, Head & Neck Surgery, The University of Western Ontario, London, ON, N6A 3K7, Canada. jmymryk@uwo.ca.
¹² Department of Oncology, The University of Western Ontario, London, ON, N6A 3K7, Canada. jmymryk@uwo.ca.
¹³ London Regional Cancer Program, Lawson Health Research Institute, London, ON, N6C 2R5, Canada. jmymryk@uwo.ca.
¹⁴ London Regional Cancer Program, 790 Commissioners Rd. East, London, Ontario, N6A 4L6, Canada. jmymryk@uwo.ca.

^# Contributed equally.

PMID: 33588906
PMCID: PMC7885607
DOI: 10.1186/s13027-021-00347-6

Low expression of NSD1, NSD2, and NSD3 define a subset of human papillomavirus-positive oral squamous carcinomas with unfavorable prognosis

Steven F Gameiro et al. Infect Agent Cancer. 2021.

. 2021 Feb 15;16(1):13.

doi: 10.1186/s13027-021-00347-6.

Authors

Affiliations

¹ Department of Microbiology and Immunology, The University of Western Ontario, London, ON, N6A 3K7, Canada.
² Department of Surgery, The University of Western Ontario, London, ON, N6A 3K7, Canada.
³ Department of Otolaryngology, Head & Neck Surgery, The University of Western Ontario, London, ON, N6A 3K7, Canada.
⁴ Department of Pathology, The University of Western Ontario, London, ON, N6A 3K7, Canada.
⁵ Department of Otolaryngology, Head & Neck Surgery, The University of Western Ontario, London, ON, N6A 3K7, Canada. Anthony.Nichols@lhsc.on.ca.
⁶ Department of Pathology, The University of Western Ontario, London, ON, N6A 3K7, Canada. Anthony.Nichols@lhsc.on.ca.
⁷ Department of Oncology, The University of Western Ontario, London, ON, N6A 3K7, Canada. Anthony.Nichols@lhsc.on.ca.
⁸ London Regional Cancer Program, Lawson Health Research Institute, London, ON, N6C 2R5, Canada. Anthony.Nichols@lhsc.on.ca.
⁹ Department of Otolaryngology - Head and Neck Surgery, Schulich School of Medicine & Dentistry, Western University, Room B3-431A, 800 Commissioners Road East, London, ON, N6A 5W9, Canada. Anthony.Nichols@lhsc.on.ca.
¹⁰ Department of Microbiology and Immunology, The University of Western Ontario, London, ON, N6A 3K7, Canada. jmymryk@uwo.ca.
¹¹ Department of Otolaryngology, Head & Neck Surgery, The University of Western Ontario, London, ON, N6A 3K7, Canada. jmymryk@uwo.ca.
¹² Department of Oncology, The University of Western Ontario, London, ON, N6A 3K7, Canada. jmymryk@uwo.ca.
¹³ London Regional Cancer Program, Lawson Health Research Institute, London, ON, N6C 2R5, Canada. jmymryk@uwo.ca.
¹⁴ London Regional Cancer Program, 790 Commissioners Rd. East, London, Ontario, N6A 4L6, Canada. jmymryk@uwo.ca.

^# Contributed equally.

PMID: 33588906
PMCID: PMC7885607
DOI: 10.1186/s13027-021-00347-6

Abstract

Background: Frequent mutations in the nuclear receptor binding SET domain protein 1 (NSD1) gene have been observed in head and neck squamous cell carcinomas (HNSCC). NSD1 encodes a histone 3 lysine-36 methyltransferase. NSD1 mutations are correlated with improved clinical outcomes and increased sensitivity to platinum-based chemotherapy agents in human papillomavirus-negative (HPV-) tumors, despite weak T-cell infiltration. However, the role of NSD1 and related family members NSD2 and NSD3 in human papillomavirus-positive (HPV+) HNSCC is unclear.

Methods: Using data from over 500 HNSCC patients from The Cancer Genome Atlas (TCGA), we compared the relative level of mRNA expression of NSD1, NSD2, and NSD3 in HPV+ and HPV- HNSCC. Correlation analyses were performed between T-cell infiltration and the relative level of expression of NSD1, NSD2, and NSD3 mRNA in HPV+ and HPV- HNSCC. In addition, overall survival outcomes were compared for both the HPV+ and HPV- subsets of patients based on stratification by NSD1, NSD2, and NSD3 expression levels.

Results: Expression levels of NSD1, NSD2 or NSD3 were not correlated with altered lymphocyte infiltration in HPV+ HNSCC. More importantly, low expression of NSD1, NSD2, or NSD3 correlated with significantly reduced overall patient survival in HPV+, but not HPV- HNSCC.

Conclusion: These results starkly illustrate the contrast in molecular features between HPV+ and HPV- HNSCC tumors and suggest that NSD1, NSD2, and NSD3 expression levels should be further investigated as novel clinical metrics for improved prognostication and patient stratification in HPV+ HNSCC.

Keywords: Epigenetics; HPV; Head and neck cancer; Head and neck squamous cell carcinoma; Histone methyltransferase; The Cancer Genome Atlas; WHSC1; WHSC1L1.

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Conflict of interest statement

The author reports no conflicts of interest in this work.

Figures

**Fig. 1**
Expression of *NSD1*, *NSD2*, and *NSD3* genes in HNSCC stratified by HPV status. Normalized RNA-seq data was extracted from TCGA database for the HNSCC cohort for HPV+, HPV-, and matched normal-adjacent control tissues. Numbers in brackets refer to the number of samples included in each analysis. Statistical p value significance levels are indicated as follows: * p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001; **** p ≤ 0.0001; ns – not significant

**Fig. 2**
Correlation matrix of *NSD* paralogs and viral oncogene expression. Normalized RNA-seq data for *NSD1*, *NSD2*, *NSD3*, HPV E6, and HPV E7 was compared in a pairwise fashion for both the HPV+ (left) and HPV- (right) TCGA HNSCC cohorts. Numbers indicated in the boxes are the calculated Spearman’s rank correlation coefficient of the indicated gene pairs. Statistical p value significance levels are indicated as follows: * p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001; **** p ≤ 0.0001; ns – not significant

**Fig. 3**
T-cell infiltration is higher in HPV+ HNSCC compared to HPV- and normal control counterparts. A previously reported 13 gene T-cell transcript signature was calculated for HPV+, HPV-, and matched normal-adjacent control tissues. Numbers in brackets refer to the number of samples included in each analysis. Statistical p value significance levels are indicated as follows: * p ≤ 0.05; ** p ≤ 0.01; *** p ≤ 0.001; **** p ≤ 0.0001; ns—not significant

**Fig. 4**
T-cell infiltration is not correlated with *NSD1* expression in HPV+ HNSCC, but is weakly correlated in HPV- HNSCC. A previously reported 13 gene T-cell transcript signature was calculated for each sample in the TCGA HNSCC cohort and compared pairwise with normalized RNA-seq data for *NSD1*, *NSD2*, and *NSD3* for HPV+ (a) and HPV- (b) HNSCC samples. For each *NSD* paralog, the correlation with the T-cell transcript signature was calculated by Spearman’s Rho analysis

**Fig. 5**
Low *NSD1*, *NSD2*, or *NSD3* expression is strongly associated with reduced survival in patients with HPV+ but not HPV- HNSCC. Overall survival of patients grouped by high, mid, or low expression of *NSD1*, *NSD2*, or *NSD3* in the HPV+ (a) and HPV- (b) HNSCC cohorts. Comparison between groups were calculated with the 2-sided log-rank test (p value) and multiple comparisons corrected with the Benjamini–Hochberg method utilizing an FDR threshold of 10% (q value). Numbers in brackets indicate the number of samples included in each expression group

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References

1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424. - PubMed
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[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424. - PubMed

[2] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424. - PubMed

[3] Baxi S, Fury M, Ganly I, Rao S, Pfister DG. Ten years of progress in head and neck cancers. J Natl Compr Cancer Netw. 2012;10:806–810. doi: 10.6004/jnccn.2012.0084. - DOI - PMC - PubMed

[4] Baxi S, Fury M, Ganly I, Rao S, Pfister DG. Ten years of progress in head and neck cancers. J Natl Compr Cancer Netw. 2012;10:806–810. doi: 10.6004/jnccn.2012.0084. - DOI - PMC - PubMed

[5] Hashibe M, Brennan P, Chuang S-C, et al. Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the international head and neck Cancer epidemiology consortium. Cancer Epidemiol Biomark Prev. 2009;18:541–550. doi: 10.1158/1055-9965.EPI-08-0347. - DOI - PMC - PubMed

[6] Hashibe M, Brennan P, Chuang S-C, et al. Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the international head and neck Cancer epidemiology consortium. Cancer Epidemiol Biomark Prev. 2009;18:541–550. doi: 10.1158/1055-9965.EPI-08-0347. - DOI - PMC - PubMed

[7] Marur S, D’Souza G, Westra WH, Forastiere AA. HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol. 2010;11:781–789. doi: 10.1016/S1470-2045(10)70017-6. - DOI - PMC - PubMed

[8] Marur S, D’Souza G, Westra WH, Forastiere AA. HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol. 2010;11:781–789. doi: 10.1016/S1470-2045(10)70017-6. - DOI - PMC - PubMed

[9] Nichols AC, Palma DA, Dhaliwal SS, et al. The epidemic of human papillomavirus and oropharyngeal cancer in a Canadian population. Curr Oncol. 2013;20:212–219. doi: 10.3747/co.20.1375. - DOI - PMC - PubMed

[10] Nichols AC, Palma DA, Dhaliwal SS, et al. The epidemic of human papillomavirus and oropharyngeal cancer in a Canadian population. Curr Oncol. 2013;20:212–219. doi: 10.3747/co.20.1375. - DOI - PMC - PubMed

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Low expression of NSD1, NSD2, and NSD3 define a subset of human papillomavirus-positive oral squamous carcinomas with unfavorable prognosis

Affiliations

Low expression of NSD1, NSD2, and NSD3 define a subset of human papillomavirus-positive oral squamous carcinomas with unfavorable prognosis

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

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References

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