Combined Genome and Transcriptome Sequencing to Identify Allelic Selection in Epithelial Ovarian Cancer

Identifying genes where a variant allele is preferentially expressed in tumors could lead to a better understanding of cancer biology and optimization of targeted therapy. However, tumor sample heterogeneity complicates standard approaches for detecting preferential allele expression. We therefore developed a novel approach combining genome and transcriptome sequencing data from the same sample that corrects for sample heterogeneity and identifies significant preferentially expressed alleles. We applied this analysis to epithelial ovarian cancer samples consisting of matched primary ovary and peritoneum and lymph node metastasis. We find that preferentially expressed variant alleles include germline and somatic variants, are shared at a relatively high frequency between patients and are in gene networks known to be involved in cancer processes. Analysis at a patient level identifies patient-specific preferentially expressed alleles in genes that are targets for known drugs. Analysis at a site level identifies patterns of site specific preferential allele expression with similar pathways being impacted in the primary and metastasis sites. We conclude that genes with preferentially expressed variant alleles can act as cancer drivers and that targeting those alleles could lead to new therapeutic strategies. Three cancer patients, three tumor samples per patient from different sites, two normal tissue samples from two different patients, four cell lines.

鉴定在肿瘤中呈现变异等位基因（variant allele）偏好性表达的基因，有助于深化对癌症生物学的理解，并优化靶向治疗方案。然而，肿瘤样本异质性使得检测等位基因偏好性表达的常规方法变得复杂。为此，我们开发了一种全新的分析方法，整合同一样本的基因组测序（genome sequencing）与转录组测序（transcriptome sequencing）数据，可校正样本异质性并识别具有显著偏好性表达的变异等位基因。
我们将该分析方法应用于上皮性卵巢癌（epithelial ovarian cancer）样本，该样本包含匹配的原发卵巢灶、腹膜灶及淋巴结转移灶样本。
研究发现，呈现偏好性表达的变异等位基因涵盖生殖系变异（germline variant）与体细胞变异（somatic variant），在患者群体中以较高频率共现，且位于已知参与癌症进程的基因调控网络中。
基于患者个体层面的分析，可识别出已知药物靶点基因中具有患者特异性的偏好性表达变异等位基因。基于样本位点层面的分析，则可识别位点特异性的等位基因偏好性表达模式，且原发灶与转移灶均受相似的信号通路影响。
综上，携带偏好性表达变异等位基因的基因可作为癌症驱动基因（cancer driver），靶向此类等位基因有望催生全新的治疗策略。
本研究纳入的样本包括：3名癌症患者各3份取自不同位点的肿瘤样本、2名不同患者的正常组织样本各2份，以及4种细胞系。