Probing the role of somatic X-chromosome alterations in shaping cancer sex differences

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PROJECT SUMMARY Cancer is a major global public health problem and the second leading cause of death in the United States. Many cancer types display differences in incidence between the sexes, and these differences are only partially explainable by non-genetic factors, such as hormonal differences, carcinogen exposure, lifestyle, and access to health care. To date, our understanding of how genetic factors – particularly those encoded on the sex chromosomes – contribute to sex-specific differences in cancer pathogenesis has remained incomplete. A fundamental genetic difference between males and females is in the composition and regulation of the X- chromosome (chrX); relative to male somatic cells, female somatic cells have an extra chrX. Most of the genes on one copy of chrX in females are epigenetically silenced via the process of X-chromosome inactivation (XCI), resulting in one active (chrXa) and one inactive (chrXi) chromosome X. Additionally, we have recently discovered that XIST – the long non-coding RNA that initiates XCI – can be somatically expressed in a subset of male cancers. We therefore hypothesize that somatic alterations of the X chromosome may perturb XCI in both females and males, leading to either oncogenic or deleterious gene expression changes. In this project, we will study the role of somatic chrX alterations in cancer in both male and female contexts via two aims. In Aim 1, we will anchor our studies in translocation renal cell carcinoma (tRCC), a subtype of kidney cancer usually driven by oncogenic rearrangements involving the TFE3 gene on chrX. While all other kidney cancers are male- predominant, tRCC displays a ~2:1 female bias in incidence, prompting the hypothesis that the presence of an extra copy of chrX in females doubles the risk for developing oncogenic TFE3 fusions. This implies that TFE3 rearrangements can arise from chrXi in females, which would necessitate a disruption of XCI and the reactivation of ordinarily silenced genes. We will develop haplotype-specific bioinformatic methods to distinguish between chrXa and chrXi and deploy these methods across a range of genomic datasets to understand the transcriptional consequences of rearrangements on each of the chrX homologs in tRCC. We will also model TFE3 fusions using CRISPR/Cas9 to explore the differential transcriptional and functional implications of TFE3 rearrangements involving chrXa vs chrXi. In Aim 2, we will expand upon our surprising observation that some male cancers can somatically activate XIST expression. We will determine to what extent somatic activation of XIST in males is associated with the features of stable chrX silencing seen in female XCI. We will also determine whether somatic XIST activation in males confers selective genetic vulnerabilities that may represent sex-specific cancer dependencies. This project will leverage innovative genomic and functional genetic approaches to explore fundamental questions about how somatic alterations on chrX contribute to cancer pathogenesis. More broadly, this work seeks to establish a new paradigm for our understanding of the genetic factors that drive sex bias in cancer initiation and progression and to identify novel strategies to target tumors in a sex-specific fashion.