Identification of cancer sex-disparity in the functional integrity of p53 and its X chromosome network

Abstract

The disproportionately high prevalence of male cancer is poorly understood. We tested for sex-disparity in the functional integrity of the major tumor suppressor p53 in sporadic cancers. Our bioinformatics analyses expose three novel levels of p53 impact on sex-disparity in 12 non-reproductive cancer types. First, TP53 mutation is more frequent in these cancers among US males than females, with poorest survival correlating with its mutation. Second, numerous X-linked genes are associated with p53, including vital genomic regulators. Males are at unique risk from alterations of their single copies of these genes. High expression of X-linked negative regulators of p53 in wild-type TP53 cancers corresponds with reduced survival. Third, females exhibit an exceptional incidence of non-expressed mutations among p53-associated X-linked genes. Our data indicate that poor survival in males is contributed by high frequencies of TP53 mutations and an inability to shield against deregulated X-linked genes that engage in p53 networks.

TP53 Status, Patient Sex, and the Immune Response as Determinants of Lung Cancer Patient Survival

“…Unexpectedly, patients with wt TP53 LUSC had significantly reduced survival compared with their mutant TP53 counterparts ( Figure 5 D, p < 0.0001). This was the opposite outcome from LUAD, as we show here ( Figure 1 ), and also to the overall survival in most nonreproductive cancers [ 17 ], where TP53 mutation corresponds with poorest survival. Reduced survival among LUSC patients with wt TP5 3 is a trend for both females and males ( Figure 5 E, p = 0.07 and Figure 5 F, p = 0.17, respectively, with comparably fewer patients with wt TP53 apparently limiting the measurable significance).…”

“…Our recent findings demonstrate that for the vast majority of patients with nonreproductive cancers worse survival corresponds with TP53 mutation [17]. In this current study, we sought to test whether this was evident across the major subtypes of NSCLC.…”

“…We recently reported significant correlation between poor overall survival and mutation of the major tumor suppressor gene TP53 for the vast majority of US patients with spontaneous cancers of nonreproductive organs [17]. Of particular relevance to lung cancer, we calculated that TP53 mutation risk is higher in NSCLC for males than females, in the US population [17].…”

“…We recently reported significant correlation between poor overall survival and mutation of the major tumor suppressor gene TP53 for the vast majority of US patients with spontaneous cancers of nonreproductive organs [17]. Of particular relevance to lung cancer, we calculated that TP53 mutation risk is higher in NSCLC for males than females, in the US population [17]. Whether high incidence of TP53 mutation in men correlates with poor survival for LUAD and LUSC individually is particularly relevant due to the established link between smoking and TP53 mutation [18].…”

Sex differences in cancer mechanisms

“…The T/G allele drives an estrogen-dependent increase in cancer risk in females [249]. A recent study by Haupt et al identified a network of X-linked genes associated with p53 function [250]. They found that mutations in p53 regulatory genes on the X-chromosome were expressed at the mRNA level less frequently in females than in males with the same mutation.…”