In this study, we sought to understand the basis for the unusual female bias in a subtype of renal cell carcinoma (Xp11 translocation renal cell carcinoma, tRCC). In contrast to the male predominance of common renal cell carcinomas, tRCC shows an approximately 2:1 female sex bias.
A unique feature of tRCC is that it is driven by oncogenic fusions involving the TFE3 oncogene located on chromosome X (chrX). Females have two X chromosomes while males have one X chromosome and one Y chromosome. But in female cells, only one X chromosome is actively transcribed: most genes on the second copy of chrX in females are inactivated by a process known as X-chromosome inactivation. Our study sought to determine whether tRCC can be initiated by oncogenic fusions originating from the previously silenced X chromosome (chrXi) and to examine what events occur afterward during tRCC progression.
We employed whole genome sequencing on a tRCC cohort and performed haplotype-specific analyses of chrX alterations, enabling us to distinguish between changes on chrXa and chrXi. Our study demonstrates that in males, TFE3 rearrangements arise from the one active chrX homolog (chrXa). In females, TFE3 rearrangements can arise from either chrXa or chrXi, accounting for the female predominance of this disease. Furthermore, when oncogenic TFE3 fusions arise between chrXi and an autosome in females, they can lead to partial activation of previously silenced genes on chrX or partial silencing of previously active genes on the autosome.
Overall, this study establishes a genetic basis for the female sex bias in tRCC and highlights the plasticity of X-inactivation in cancer.
Written by:
- Srinivas R. Viswanathan, MD, PhD, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston MA; Department of Medicine, Harvard Medical School, Boston, MA; Cancer Program, Broad Institute of MIT and Harvard; Cambridge, MA; Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
- Cheng-Zhong Zhang, PhD, Department of Data Science, Dana-Farber Cancer Institute; Department of Pathology, Brigham and Women's Hospital, Boston, MA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA.