Editors' ChoiceCancer

An EXITS strategy for decreasing cancer risk in women

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Science Translational Medicine  07 Dec 2016:
Vol. 8, Issue 368, pp. 368ec197
DOI: 10.1126/scitranslmed.aal2806

It has long been known that men have about 20% increased age-adjusted risk of developing cancer relative to women. For some individual (non–sex restricted) cancer types, males are affected at ratios in excess of 2:1. This effect is observed worldwide even after adjusting for socioeconomic and environmental factors, and its mechanistic basis is largely unexplained.

One potential explanation for male cancer predominance, suggested in previous studies, is that a subset of X-chromosome tumor suppressor genes (TSGs) may escape from X-inactivation. Men can therefore lose these TSGs through a single mutational event, whereas women are protected by the presence of a second functional copy. To systematically search for the existence of putative “escape from X-inactivation tumor suppressor” (EXITS) genes, a team of researchers performed an unbiased analysis of genome sequencing data from over 4100 tumors representing 21 tumor types. This analysis revealed that six of 783 nonpseudoautosomal region (PAR) X-chromosome genes—ATRX, CNKSR2, DDX3X, KDM5C, KDM6A, and MAGEC3—contained loss-of-function mutations more frequently in males than in females, whereas similar bias was never detected in 18,055 autosomal and PAR genes. EXITS genes were identified through pan-cancer analyses and those restricted to individual tumor types and included genes previously implicated as tumor suppressors. Together, these results imply that biallelic expression of EXITS genes in women is likely to explain a portion of the male predominance in cancer incidence.

This work is likely to inspire additional studies in several areas. First, it is likely that more EXITS genes exist because sample size estimates suggest that much larger numbers of tumors must be analyzed to achieve saturating detection of the coding, noncoding, and epigenetic alterations that may influence EXITS gene expression. Second, it will be important to understand how EXITS genes may interface with other factors likely to influence male cancer predominance, such as alcohol and tobacco exposure and endocrine biology. Last, this study implies that tumors of the same type in males and females may have distinct genetic underpinnings and, as such, distinct biology and therapeutic responses that should be considered in basic and clinical study design.

A. Dunford et al., Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias. Nat. Genet. 10.1038/ng.3726 (2016). [Abstract]

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