Association between loss of Y chromosome and poor prognosis in male head and neck squamous cell carcinoma

Abstract

Background: Head and neck squamous cell carcinoma (HNSCC) is more prevalent in men than women and this disparity cannot be fully explained by known risk factors. Recent studies have shown that loss of Y chromosome (LoY) confers an increased risk of solid cancer and reduces life expectancy in men.

Methods: Using publicly available data from The Cancer Genome Atlas, we investigated the prevalence of LoY and its association with clinicopathological features in male HNSCC.

Results: LoY was detectable in around 25% of male HNSCC. Men with human papillomavirus-negative tumors exhibiting LoY experienced significantly worse overall survival than those with no LoY. Moreover, LoY tumors exhibited overexpression of genes involved in redox processes, including genes previously implicated in resistance to both radiotherapy and cisplatin-based chemotherapeutics.

Conclusion: LoY may be an indicator of poor prognosis in male HNSCC that is linked to the overexpression of genes associated with resistance to standard care therapies.

Keywords: Y chromosome; aneuploidy; head and neck cancer; immune system; therapeutic resistance.

Figure 1

Loss of Y chromosome (LoY) in male head and neck squamous cell carcinoma (HNSCC). A, Density plot of Y chromosome copy number index values for 369 male HNSCC. B,C, Density plots of Y chromosome copy number index values for 283 human papillomavirus (HPV)‐negative and 85 HPV‐positive male HNSCC, respectively. D, Density plot of first principal component values for male oral cavity tumor cases from Chen et al. E, Representative images of fluorescence in situ hybridization (FISH) analysis—X and Y chromosome probes shown in green and red, respectively: top left, female sample; top right, male sample which has retained the Y chromosome; bottom panels, two male samples which have lost the Y chromosome [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Loss of Y chromosome (LoY) may be associated with smoking history but not age for human papillomavirus (HPV)‐negative male head and neck squamous cell carcinoma (HNSCC). A, Violin plots of Y chromosome copy number index values by smoking history for HPV‐negative male HNSCC—horizontal lines denote median values. B,C, Plots of Y chromosome copy number index values against age at diagnosis for HPV‐negative and HPV‐positive male HNSCC, respectively

Figure 3

Loss of Y chromosome (LoY) is associated with shorter overall survival in male head and neck squamous cell carcinoma (HNSCC). Kaplan‐Meier plots of overall survival for male HNSCC in A, human papillomavirus (HPV)‐negative cases split by LoY status; B, HPV‐positive cases split by LoY status; and C, HPV‐negative cases split by LoY status and compared to HPV‐negative females with HNSCC

Figure 4

Loss of Y chromosome (LoY) reflects an aneuploid phenotype in human papillomavirus (HPV)‐negative male head and neck squamous cell carcinoma (HNSCC). A,B, Density plots of total autosomal aneuploidy index values for HPV‐negative and HPV‐positive male HNSCC, respectively. C,D, Plots of Y chromosome copy number index values against total autosomal aneuploidy index values for HPV‐negative and HPV‐positive male HNSCC, respectively. E,F, Boxplots of total autosomal aneuploidy index values split by sex for HPV‐negative and HPV‐positive HNSCC, respectively. G, Boxplots of total autosomal aneuploidy index values split by sex for HPV‐negative HNSCC with males split by LoY status

Figure 5

Aneuploidy, but not Loss of Y chromosome (LoY), is associated with TP53 mutation in human papillomavirus (HPV)‐negative male head and neck squamous cell carcinoma (HNSCC). A,B, Violin plots of Y chromosome copy number index values by TP53 mutational status for HPV‐negative and HPV‐positive male HNSCC, respectively—horizontal lines denote median values. C,D, Boxplots of total autosomal aneuploidy index values by TP53 mutational status for HPV‐negative and HPV‐positive male HNSCC, respectively. E,F, Boxplots of total autosomal aneuploidy index values for HPV‐negative HNSCC split by sex, with males further split by LoY status, for cases with or without evidence of a mutation in TP53, respectively

Figure 6

Aneuploidy is not associated with poor survival in male human papillomavirus (HPV)‐negative head and neck squamous cell carcinoma (HNSCC). Kaplan‐Meier plots of overall survival in A, HPV‐negative male HNSCC and B, HPV‐positive male HNSCC, with patients split in each case by low/high total autosomal aneuploidy index