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

Affiliations
  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
  • 2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 3Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02215, USA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 4Department of Biomedical Informatics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 5Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
  • 6Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biomedical Informatics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA.
  • 7Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 8Department of Informatics & Analytics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • 9Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
  • 10Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.
  • 11Division of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
  • 12Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02215, USA.
  • 13Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Harvard Medical School, Boston, MA 02215, USA; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02215, USA. Electronic address: srinivas.viswanathan@dfci.harvard.edu.

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August 21, 2024

Abstract

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.

Keywords:

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