A genetic basis for sex differences in Xp11 translocation renal cell carcinoma

Xp11 translocation renal cell carcinoma (tRCC) is a rare, female-predominant cancer driven by a fusion between the transcription factor binding to IGHM enhancer 3 (TFE3) gene on chromosome Xp11.2 and a partner gene on either chromosome X (chrX) or an autosome. It remains unknown what types of rearrangements underlie TFE3 fusions, whether fusions can arise from both the active (chrXa) and inactive X (chrXi) chromosomes, and whether TFE3 fusions from chrXi translocations account for the female predominance of tRCC. To address these questions, we performed haplotype-specific analyses of chrX rearrangements in tRCC whole genomes. We show that TFE3 fusions universally arise as reciprocal translocations and that oncogenic TFE3 fusions can arise from chrXi:autosomal translocations. Female-specific chrXi:autosomal translocations result in a 2:1 female-to-male ratio of TFE3 fusions involving autosomal partner genes and account for the female predominance of tRCC. Our results highlight how X chromosome genetics constrains somatic chrX alterations and underlies cancer sex differences. [Display omitted] •TFE3 driver fusions usually arise via reciprocal, balanced rearrangements in Xp11 tRCC•Female sex bias of tRCC explained by rearrangements of both the active and inactive X•Active vs. inactive X rearrangements impose sex-specific evolutionary constraints•Inactive X:autosome translocations linked to X-reactivation and/or autosome silencing Whole-genome analysis of a female-predominant kidney cancer reveals the mechanisms by which X chromosome genetics constrains somatic X chromosome alterations and underlies sex bias in tumorigenesis.