Sex Discrepancy Characterization Revealed by Somatic DNA Alterations in MIBC

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Sex Discrepancy Characterization Revealed by Somatic DNA Alterations in Muscle-Invasive Bladder Carcinoma

Muscle-invasive bladder carcinoma (MIBC) demonstrates striking sex disparities in incidence, prognosis, and therapeutic outcomes. Males exhibit a three-fold higher incidence of bladder cancer compared to females, yet females face poorer survival rates once diagnosed. Despite these clinical differences, the molecular mechanisms underlying sex-specific disparities remain poorly elucidated. This study leverages genomic data from The Cancer Genome Atlas (TCGA) to systematically characterize sex-specific somatic DNA alterations in MIBC, uncovering critical differences in mutation rates, recurrently mutated genes, and copy number variations (CNVs) between male and female patients.

Sex Differences in Global Mutation Rates

Analysis of 304 Caucasian MIBC samples (224 males, 80 females) revealed a significantly higher somatic mutation burden in males compared to females. The total mean mutation rate per megabase was 4.10 in males versus 3.59 in females (Fisher exact P < 2.20 × 10−16). This discrepancy persisted across four major mutation type categories:

  1. *TpC→[T/G] mutations*: Relative mutation rates of 4.68 (males) vs. 3.99 (females) (P* < 2.20 × 10−16).
  2. *TpC→A mutations*: Higher in males (P* < 4.65 × 10−9).
  3. *[A/C/G]pC→mutations*: Elevated in males (P* < 4.65 × 10−9).
  4. A→mutations: Increased frequency in males (P < 4.65 × 10−9).

No significant difference was observed for “null + indel” mutations. Individual somatic mutation rates also differed, with males exhibiting a mean of 281.4 mutations and females 229.2 mutations per sample (Wilcoxon rank-sum P = 0.01). The median mutation counts further highlighted this disparity: 205.5 for males vs. 157.5 for females.

Cumulative and Sex-Specific Gene Mutation Profiles

Cumulative mutation analysis identified 17,286 genes with somatic alterations in the cohort. Males displayed higher cumulative mutation rates, with 264 genes mutated in >5% of samples (1.40% of total genes). Among the top ten most frequently mutated genes in each sex, seven overlapped (TTN, TP53, KDM6A, ARID1A, MUC16, KMT2E, and PIK3CA), while three were sex-specific:

  • Male-specific: SYNE1, KMT2C, GRG1B.
  • Female-specific: FAT1, MUC17, HMCN1.

Genes like TP53, KDM6A, ARID1A, and PIK3CA are well-established drivers of bladder carcinogenesis. Rigorous statistical testing (Fisher exact test with Bonferroni correction and propensity score adjustment for age, stage, and smoking status) identified nine genes with significant sex differences (SYNE1, MUC5B, FRY, HERC2, PARD3, ATR, DMXL1, SUPT16H, and CDH23), all showing higher mutation rates in males except F8. Notably, SYNE1 ranked among the top ten mutated genes in males.

Recurrent Somatic Mutations and Functional Implications

MutSigCV analysis detected 23 genes with recurrent somatic mutations in males and 11 in females (false discovery rate [FDR] q ≤ 0.05). Eight genes were recurrently mutated in both sexes: CDKN2A, KDM6A, TBC1D12, TP53, PIK3CA, RB1, ELF3, and ZFP36L1. Sex-specific recurrent mutations included:

  • Male-specific: ARID1A, CDKN1A, STAG2, TSC1, RHOB, TXNIP, RBM10, PARD3, HLA-A, EP300, C3orf70, NUDT11, ASXL2, ZFP36L2, PTEN.
  • Female-specific: HRAS, NFE2L2, FBXW7.

Four novel female-specific genes (HRAS, NFE2L2, FBXW7, and YAP1) were implicated in female MIBC progression. These genes regulate critical pathways, including the RAS-MAPK signaling (HRAS), oxidative stress response (NFE2L2), and cell cycle control (FBXW7).

Sex-Specific Copy Number Alterations

Genomic Identification of Significant Targets in Cancer (GISTIC) analysis revealed 39 amplifications and 22 deletions in males versus 26 amplifications and 19 deletions in females (Figure 1). Key findings included:

  • Female-specific deletion: Chromosome 11q22-23, a region containing ATM and CASP1, showed significant deletion in females.
  • Male-specific amplification: Chromosome 16q12-13, harboring CDH1 and CYLD, exhibited male-specific amplification.

Sex differences in CNV signal intensity and recurrence were notable. For instance, RB1, CCNE1, YAP1, and BCL2L1 regions showed stronger alterations in females, whereas NCOR1, EGFR, ERBB2, MYC, and PTEN were prominent in males. These variations may contribute to differential tumor evolution and therapeutic responses between sexes.

Validation of Sex-Specific Genomic Features

Three validation approaches confirmed the robustness of these findings:

  1. Non-Caucasian TCGA cohorts: Higher male mutation rates persisted across diverse populations.
  2. COSMIC database analysis: The nine sex-specific genes identified in this study displayed mutation frequencies intermediate between male and female rates in unstratified COSMIC data, underscoring the importance of sex-specific analysis.
  3. TCGA reanalysis: Previous TCGA studies on 131 and 412 MIBC samples corroborated the recurrence of sex-specific mutations and CNVs. Updated bioinformatics tools used in this study enhanced detection accuracy for novel mutations, such as TBC1D12, HLA-A, ASXL2, RBM10, PTEN, C3orf70, PSIP1, MARK2, PARD3, FOXE1, and KRTAP4-7.

Mechanistic and Clinical Implications

The higher somatic mutation burden in males may partly explain their increased susceptibility to bladder cancer. Sex hormones, lifestyle factors (e.g., smoking), and genomic instability likely interplay to drive these differences. For instance, androgen receptor signaling has been linked to bladder cancer initiation and progression, potentially exacerbating mutagenic processes in males.

Conversely, female-specific mutations in HRAS, NFE2L2, FBXW7, and YAP1 suggest unique molecular pathways driving aggressive disease in women. YAP1, a Hippo pathway effector, promotes cell proliferation and chemoresistance, while NFE2L2 activation confers oxidative stress resistance. These findings highlight the need for sex-tailored therapeutic strategies targeting distinct genomic vulnerabilities.

Conclusion

This study provides the first comprehensive characterization of sex-specific somatic DNA alterations in MIBC. Males exhibit higher mutation rates and distinct recurrent mutations, potentially linked to their elevated disease incidence. Females, despite lower mutation burden, harbor unique driver mutations associated with adverse outcomes. These findings underscore the importance of integrating sex as a biological variable in bladder cancer genomics and precision oncology.

doi.org/10.1097/CM9.0000000000000487

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