Project Details
Description
PROJECT SUMMARY/ABSTRACT
Cancer comprises a diverse group of diseases with significant morbidity and mortality. Nearly all common
cancers exhibit some form of sexual dimorphism, for example in incidence, prognosis, or response to therapy.
This dimorphism has been hypothesized to derive from differences between males and females in hormones,
sex chromosomes, and environmental exposures; however the molecular basis of these disparities remains
largely unknown. An understanding of this dimorphism is fundamental to precision medicine in cancer, and
may lead to discovery of novel biomarkers, therapeutic targets, and improved outcomes. We propose to
discover the molecular basis of sexual dimorphism in cancer though the following Aims: Aim 1 will
characterize sexual dimorphism in gene expression and its regulation within and between tumor types
of NCI's The Cancer Genome Atlas (TCGA). Leveraging TCGA, we will characterize sexual dimorphism at
the transcriptome level and its potential genomic and epigenetic causes within and across cancers. Aim 2 will
characterize sexual dimorphism in the heritable genetic component of cancer susceptibility across
common cancers. Utilizing data from the largest genome-wide association studies of cancer we will search for
differences in the genetic architecture between males and females. We determine what proportion of the
heritable component of each cancer is shared across sexes, and also estimate how much sex-specific sharing
across cancers. Using multiple genetic models, we will perform sex-aware association studies to identify
genetic variants that affect males and females differently. We will test a model for genetic risk, whereby the
same alleles affect both sexes, but the lower-risk sex would require more or stronger genetic risk factors to
develop disease. We will test for specific risk or protective factors encoded on the sex chromosomes that affect
the sexes differentially. We will test for gene-sex interactions whereby autosomal loci act in a sex-dependent
manner, with or without hormonally-mediated or other sexual dimorphism acting at the gene expression
level. Aim 3 will characterize sexual dimorphism in response to therapeutics and define the molecular
features and mechanisms contributing to that dimorphism. Utilizing molecular and phenotypic drug
response data from over 1000 cancer cell lines from the Cancer Genome Project (CGP), we will build sex-
specific predictive models of drug response that we will then apply to gene expression data from the full set of
TCGA tumor samples to impute a sex-specific drug response for each TCGA sample. We will correlate
imputed drug responses to TCGA tumor molecular features, with focus on those identified in Aims 1 and 2 and
candidates suggested by our preliminary data and the literature. We will functionally validate predicted sexually
dimorphic response to therapy using cell models, including panels of lymphoblastoid cell lines, human
hepatocytes, and cancer cell lines. The results of this study will define genetic and genomic features that
underlie sexual dimorphism in cancer biology, susceptibility, and response to therapeutics.
Status | Finished |
---|---|
Effective start/end date | 6/1/19 → 5/31/23 |
Funding
- National Cancer Institute: $1.00
- National Cancer Institute: $31,595.00
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