Extreme Downregulation of Chromosome Y and Cancer Risk in Men

Abstract

Background: Understanding the biological differences between sexes in cancer is essential for personalized treatment and prevention. We hypothesized that the extreme downregulation of chromosome Y gene expression (EDY) is a signature of cancer risk in men and the functional mediator of the reported association between the mosaic loss of chromosome Y (LOY) and cancer.

Methods: We advanced a method to measure EDY from transcriptomic data. We studied EDY across 47 nondiseased tissues from the Genotype Tissue-Expression Project (n = 371) and its association with cancer status across 12 cancer studies from The Cancer Genome Atlas (n = 1774) and seven other studies (n = 7562). Associations of EDY with cancer status and presence of loss-off function mutations in chromosome X were tested with logistic regression models, and a Fisher's test was used to assess genome-wide association of EDY with the proportion of copy number gains. All statistical tests were two-sided.

Results: EDY was likely to occur in multiple nondiseased tissues (P < .001) and was statistically significantly associated with the EGFR tyrosine kinase inhibitor resistance pathway (false discovery rate = 0.028). EDY strongly associated with cancer risk in men (odds ratio [OR] = 3.66, 95% confidence interval [CI] = 1.58 to 8.46, P = .002), adjusted by LOY and age, and its variability was largely explained by several genes of the nonrecombinant region whose chromosome X homologs showed loss-of-function mutations that co-occurred with EDY during cancer (OR = 2.82, 95% CI = 1.32 to 6.01, P = .007). EDY associated with a high proportion of EGFR amplifications (OR = 5.64, 95% CI = 3.70 to 8.59, false discovery rate < 0.001) and EGFR overexpression along with SRY hypomethylation and nonrecombinant region hypermethylation, indicating alternative causes of EDY in cancer other than LOY. EDY associations were independently validated for different cancers and exposure to smoking, and its status was accurately predicted from individual methylation patterns.

Conclusions: EDY is a male-specific signature of cancer susceptibility that supports the escape from X-inactivation tumor suppressor hypothesis for genes that protect women compared with men from cancer risk.

Figure 1.

Relative chromosome Y expression (Ry) shown as a function of age for 12 cancer studies from The Cancer Genome Atlas. The figure shows tumor (black) and normal samples (blue). Samples with loss of chromosome Y (LOY), obtained from genotype intensity data, are shown in red triangles. Samples with extreme downregulation of chromosome Y gene expression (EDY) (green triangles) are those with low values of Ry relative to samples with no chromosome Y losses or gains. Although EDY and LOY status overlap, numerous individuals are observed with LOY but no EDY, particularly those with high values of Ry. Normal samples consistently have high Ry values across studies.

Figure 2.

Additive Bayesian network models for age, cancer, loss of chromosome Y (LOY), and extreme downregulation of chromosome Y gene expression (EDY) shown for 12 cancer studies from The Cancer Genome Atlas (TCGA). The left figure shows the driver model, where cancer depends on EDY, EDY on LOY, and LOY on age. Maximum likelihood estimate and Bayes information criterion (BIC) are shown on top. The right figure shows the passenger model, where EDY depends on LOY, LOY on cancer, and cancer on age. In the TCGA studies, the higher likelihood and lower BIC favor the driver model over the passenger model.

Figure 3.

Extreme downregulation of chromosome Y gene expression (EDY) shown as a marker of cancer status of biological samples and individuals. The figure shows the association between EDY and cancer status across different independent studies with publicly available data. A) In The Cancer Genome Atlas (TCGA) study (n = 1774), the odds ratio (OR) of EDY for tumor status of the biological samples of cancer patients was obtained from logistic-regression models adjusting by age for 12 different cancers. The overall estimate of the effect of EDY was computed by a random effects meta-analysis and its heterogeneity with a χ² test. P values are two-sided. B) The association between EDY and cancer status of individuals was independently tested in colorectal (n = 142) and kidney (n = 29) cancer case-control studies (GSE66836, GSE36895) and in a population sample of 550 individuals from the Estonian Genome Center of the University of Tartu study. C) A large transcriptomic dataset (n = 6898) was used to assess EDY’s association with multiple cancer diagnoses (E-MTAB-3732). D) Two studies on lung squamous cell carcinoma (GSE5123, LUSC from TCGA, total n = 243) were used to test the association between EDY and cigarettes smoked per day. CI = confidence interval; LUSC = lung squamous cell carcinoma.

Figure 4.

Association of extreme downregulation of chromosome Y gene expression (EDY) with chromosome Y methylation and genome-wide copy number variant proportion for individuals with and without loss of chromosome Y (LOY). A) Number of cancer samples in all four LOY and EDY statuses across 12 cancer studies in The Cancer Genome Atlas (BLCA, COAD, ESCA, KICH, KIRC, KIRP, LIHC, LUAD, LUSC, PRAD, READ, and THCA). B) Odds ratios (OR) of EDY for methylation sites across Y, stratified by LOY (LOY: vertical axis, no LOY: horizontal axis). A total of 52 statistically significant associations for both LOY statuses are in red. Associations for the SRY (sex determining region Y) gene are shown. C) Genome-wide differences in copy number variant (CNV) proportion, positive (+) and negative (−), between no EDY and EDY, and stratified by LOY (no LOY: top, LOY: bottom). BLCA = bladder urothelial carcinoma; COAD = colon adenocarcinoma; ESCA = esophageal carcinoma; KICH = kidney chromophobe; KIRC = kidney renal clear cell carcinoma; KIRP = kidney renal papillary cell carcinoma; LIHC = liver hepatocellular carcinoma; LUAD = lung adenocarcinoma; LUSC = lung squamous cell carcinoma; PRAD = prostate adenocarcinoma; READ = rectum adenocarcinoma; THCA = thyroid carcinoma.