Genetic mechanisms underlying sexual dimorphism in cancer and response to therapy

项目摘要/摘要 癌症由多种疾病组成，发病率和死亡率都很高。几乎所有常见的 癌症表现出某种形式的性二态，例如在发病率、预后或对治疗的反应方面。 这种二形性被认为源于男性和女性在荷尔蒙上的差异， 性染色体和环境暴露；然而，这些差异的分子基础仍然 很大程度上是未知的。对这种二形性的理解是癌症精确医学的基础，并且 可能导致发现新的生物标记物、治疗靶点和改善结果。我们建议 通过以下目标发现癌症中性二型性的分子基础：目标1将 性二型性基因表达的特征及其在肿瘤类型内部和之间的调节 NCI的癌症基因组图谱(TCGA)。利用TCGA，我们将在 转录组水平及其潜在的基因组和表观遗传学原因在癌症内部和跨癌症。目标2将 描述癌症易感性的可遗传遗传成分中的性别二型性 常见的癌症。利用来自最大的全基因组癌症关联研究的数据，我们将搜索 男性和女性在遗传结构上的差异。我们决定了 每种癌症的可遗传成分是在性别之间共享的，并估计有多少性别特定的共享 跨越癌症。利用多种基因模型，我们将进行性别感知的关联研究，以确定 对男性和女性有不同影响的基因变异。我们将测试一个遗传风险模型，在这个模型中 相同的等位基因影响两性，但风险较低的性行为需要更多或更强的遗传风险因素来 会发展成疾病。我们将测试性染色体上编码的特定风险或保护因素，这些因素会影响 性别差异很大。我们将测试基因与性别的相互作用，即常染色体基因座在性别相关的 方式，有或没有荷尔蒙介导的或其他性别二型性作用于基因表达 水平。目标3将描述性二型性对治疗的反应，并定义分子 导致这种二形性的特征和机制。利用分子和表型药物 来自癌症基因组计划(CGP)的1000多个癌细胞株的响应数据，我们将建立性别- 药物反应的特定预测模型，然后我们将应用于从全套基因表达数据 TCGA肿瘤样本为每个TCGA样本归因于性别特异性的药物反应。我们将相互关联 TCGA肿瘤分子特征的药物反应，重点是AIMS 1和2以及 根据我们的初步数据和文献推荐的候选人。我们将从功能上验证预测的性行为 使用细胞模型治疗的二型性反应，包括淋巴母细胞系的面板，人类 肝细胞和癌细胞株。这项研究的结果将定义遗传和基因组特征 性二型性在癌症生物学、敏感性和治疗反应中起着基础性作用。

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.