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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Najeeb Halabi

PROVIDER: E-GEOD-75935 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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

Project description: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.

2015-12-12 | GSE75935 | GEO

RNA expression at chromosome 8q24 in human colon

Project description:An inherited variant on chromosome 8q24, rs6983267, is significantly associated with cancer pathogenesis. We present evidence that this region is a transcriptional enhancer, that the risk region physically interacts with the MYC proto-oncogene, and that the alleles of rs6983267 differentially bind transcription factor 7-like 2 (TCF7L2). These data provide strong support for a biological mechanism underlying this non-protein coding risk variant. Total RNA and genomic DNA were isolated from colon tissue in 5 individuals. cDNA and DNA were analyzed on separate tracks, with the genomic DNA used to identify sprurious cross-hybridization

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Natural WNT signaling variant potently synergizes with Cdkn2ab loss in skin carcinogenesis.

Project description:Cancer predisposing allelic variants have shown to be notoriously difficult to identify by conventional GWA studies. Searching for preferential co-occurrence with defined somatically acquired oncogenic lesions can significantly contribute to the identification of such alleles1. We here show that a natural Wnt-7b allelic variant in the mouse, which is not associated with increased tumour susceptibility, strongly synergizes with loss of the Cdkn2ab tumour suppressor locus in cancer development. Previously, we reported that Cdkn2ab-/- mice, generated from 129P2 ES cells develop skin carcinomas 2. The incidence of these carcinomas dropped gradually in the course of backcrossing to the FVB/N background suggesting that one or more 129P2 alleles cooperate with Cdkn2ab deficiency in skin carcinogenesis. Here we show that this skin cancer phenotype is linked to a 20Mb region of 129P2 chromosome 15 harboring the Wnt7b and Pdgfb genes. Both Wnt7b and Pdgfb are preferentially expressed from the 129P2 allele in skin carcinomas and derived cell lines. ChIPseq analysis showed enrichment of H3K27-Ac, a mark for active enhancers, in the 5’ region of the Wnt7b 129P2 gene. Moreover, the Wnt7b 129P2 allele appeared sufficient to cause in vitro transformation and anchorage-independent growth of Cdkn2ab deficient cell lines. Further we show that Wnt7b contributes to transformation through Cdk6 activation. Our observations imply that normally occurring variations in Wnt expression can elicit transformation of cells upon Cdkn2ab locus loss and point to a critical role of the Cdkn2ab locus in keeping the oncogenic potential of physiological levels of Wnt signaling in check. Consequently, it will be worthwhile to explore whether human tumours that show loss of CDKN2ab are associated with distinct allelic variants causing enhanced WNT signaling.

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4T1 RNA-Seq

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2022-01-07 | MSV000088660 | MassIVE

Transcription profiling by array of Apc-deficient mouse small intestinal epithelium upon Msx1 depletion.

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