Biology subjects

Gayther, S.

Publications and source records attributed to Gayther, S..

6 recordsLinked to original sources

bioRxiv2023

Cis- and trans-eQTL TWAS of breast and ovarian cancer identify more than 100 risk associated genes in the BCAC and OCAC consortia

Transcriptome-wide association studies (TWAS) have investigated the role of genetically regulated transcriptional activity in the etiologies of breast and ovarian cancer. However, methods performed to date have only considered regulatory effects of risk associated SNPs thought to act in cis on a nearby target gene. With growing evidence for distal (trans) regulatory effects of variants on gene expression, we performed TWAS of breast and ovarian cancer using a Bayesian genome-wide TWAS method (BGW-TWAS) that considers effects of both cis- and trans-expression quantitative trait loci (eQTLs). We applied BGW-TWAS to whole genome and RNA sequencing data in breast and ovarian tissues from the Genotype-Tissue Expression project to train expression imputation models. We applied these models to large-scale GWAS summary statistic data from the Breast Cancer and Ovarian Cancer Association Consortia to identify genes associated with risk of overall breast cancer, non-mucinous epithelial ovarian cancer, and 10 cancer subtypes. We identified 101 genes significantly associated with risk with breast cancer phenotypes and 8 with ovarian phenotypes. These loci include established risk genes and several novel candidate risk loci, such as ACAP3, whose associations are predominantly driven by trans-eQTLs. We replicated several associations using summary statistics from an independent GWAS of these cancer phenotypes. We further used genotype and expression data in normal and tumor breast tissue from the Cancer Genome Atlas to examine the performance of our trained expression imputation models. This work represents a first look into the role of trans-eQTLs in the complex molecular mechanisms underlying these diseases.

genetics↗

bioRxiv2020

DNA methylation landscapes of matched primary and recurrent high grade serous ovarian cancers are preserved throughout disease progression and chemoresistance.

Little is known about the role of global DNA methylation in recurrence and chemoresistance of high grade serous ovarian cancer (HGSOC). We performed whole genome bisulfite sequencing (WGBS) and whole transcriptome sequencing (RNA-seq) to establish methylation and gene expression signatures in 62 primary and recurrent tumors from 28 patients diagnosed with stage III/IV HGSOC. Eleven of these patients carried pathogenic germline BRCA1/BRCA2 mutations. Genome-wide methylation and transcriptomic features identified in primary tumors were largely preserved in matched recurrent tumors from the same patient (P-value = 7.16 x 10-7 and 1.41 x 10-3 in BRCA1/2 and non-BRCA1/2 cases respectively). Tumors from BRCA1/2 carriers displayed high levels of heterogeneity, with significantly more shared methylation changes identified between primary and recurrent tumors from non-BRCA1/2 patients, which may be related to the poorer survival we observe in HGSOCs from non-BRCA1/2 carriers (P-value = 0.0056). Partially methylated domains (PMDs) dominated the epigenetic variation across all tumors, and were more hypomethylated in BRCA1/2 than non-BRCA1/2 cases. Differential gene expression analysis identified upregulation of genes from immune pathways including antigen processing and presentation in tumors from BRCA1/2 carriers, implicating increased immune response in the improved survival observed in these patients. In summary, this study shows a previously unreported conservation of methylation and gene expression in recurrent HGSOCs. These data have implications for the possible effectiveness of epigenetic based therapies to treat both primary and recurrent ovarian cancers.

genomics↗

bioRxiv2020

Single-cell Transcriptomics Identifies Gene Expression Networks Driving Differentiation and Tumorigenesis in the Human Fallopian Tube

The human fallopian tube harbors the cell-of-origin for the majority of high-grade serous ovarian cancers (HGSCs), but its cellular composition, particularly the epithelial component, is poorly characterized. We performed single-cell transcriptomic profiling in 12 primary fallopian specimens from 8 patients, analyzing around 53,000 individual cells to map the major immune, fibroblastic and epithelial cell types present in this organ. We identified 10 epithelial sub-populations, characterized by diverse transcriptional programs including SOX17 (enriched in secretory epithelial cells), TTF3 and RFX3 (enriched in ciliated cells) and NR2F2 (enriched in early, partially differentiated secretory cells). Based on transcriptional signatures, we reconstructed a trajectory whereby secretory cells differentiate into ciliated cells via a RUNX3high intermediate. Computational deconvolution of the cellular composition of advanced HGSCs based on epithelial subset signatures identified the early secretory population as a likely precursor state for the majority of HGSCs. The signature of this rare population of cells comprised both epithelial (EPCAM, KRT) and mesenchymal (THY1, ACTA2) features, and was enriched in mesenchymal-type HGSCs (P = 6.7 x 10-27), a group known to have particularly poor prognoses. This cellular and molecular compendium of the human fallopian tube in cancer-free women is expected to advance our understanding of the earliest stages of fallopian epithelial neoplasia.

genomics↗

bioRxiv2018

Large-scale transcriptome-wide association study identifies new prostate cancer risk regions

Although genome-wide association studies (GWAS) for prostate cancer (PrCa) have identified more than 100 risk regions, most of the risk genes at these regions remain largely unknown. Here, we integrate the largest PrCa GWAS (N=142,392) with gene expression measured in 45 tissues (N=4,458), including normal and tumor prostate, to perform a multi-tissue transcriptomewide association study (TWAS) for PrCa. We identify 235 genes at 87 independent 1Mb regions associated with PrCa risk, 9 of which are regions with no genome-wide significant SNP within 2Mb. 24 genes are significant in TWAS only for alternative splicing models in prostate tumor thus supporting the hypothesis of splicing driving risk for continued oncogenesis. Finally, we use a Bayesian probabilistic approach to estimate credible sets of genes containing the causal gene at pre-defined level; this reduced the list of 235 associations to 120 genes in the 90% credible set. Overall, our findings highlight the power of integrating expression with PrCa GWAS to identify novel risk loci and prioritize putative causal genes at known risk loci.

genetics↗

bioRxiv2018

Integrated Molecular Profiling Studies to Characterize the Cellular Origins of High-Grade Serous Ovarian Cancer

Historically, high-grade serous ovarian cancers (HGSOCs) were thought to arise from ovarian surface epithelial cells (OSECs) but recent data implicate fallopian tube secretory epithelial cells (FTSECs) as the major precursor. We performed transcriptomic and epigenomic profiling to characterize molecular similarities between OSECs, FTSECs and HGSOCs. Transcriptomic signatures of FTSECs were preserved in most HGSOCs reinforcing FTSECs as the predominant cell-of-origin; though an OSEC-like signature was associated with increased chemosensitivity (Padj = 0.03) and was enriched in proliferative-type tumors, suggesting a dualistic model for HGSOC origins. More super-enhancers (SEs) were shared between FTSECs and HGSOCs than between OSECS and HGSOCs (P < 2.2 x 10-16). SOX18, ELF3 and EHF transcription factors (TFs) coincided with HGSOC SEs and represent putative novel drivers of tumor development. Our integrative analyses support a predominantly fallopian origin for HGSOCs and indicate tumorigenesis may be driven by different TFs according to cell-of-origin.

cancer biology↗

bioRxiv2018

Multi-Tissue Transcriptome-Wide Association Studies Identify 21 Novel Candidate Susceptibility Genes for High Grade Serous Epithelial Ovarian Cancer

Genome-wide association studies (GWASs) have identified about 30 different susceptibility loci associated with high grade serous ovarian cancer (HGSOC) risk. We sought to identify potential susceptibility genes by integrating the risk variants at these regions with genetic variants impacting gene expression and splicing of nearby genes. We compiled gene expression and genotyping data from 2,169 samples for 6 different HGSOC-relevant tissue types. We integrated these data with GWAS data from 13,037 HGSOC cases and 40,941 controls, and performed a transcriptome-wide association study (TWAS) across >70,000 significantly heritable gene/exon features. We identified 24 transcriptome-wide significant associations for 14 unique genes, plus 90 significant exon-level associations in 20 unique genes. We implicated multiple novel genes at risk loci, e.g. LRRC46 at 19q21.32 (TWAS P=1x10-9) and a PRC1 splicing event (TWAS P=9x10-8) which was splice-variant specific and exhibited no eQTL signal. Functional analyses in HGSOC cell lines found evidence of essentiality for GOSR2, INTS1, KANSL1 and PRC1; with the latter gene showing levels of essentiality comparable to that of MYC. Overall, gene expression and splicing events explained 41% of SNP-heritability for HGSOC (s.e. 11%, P=2.5x10-4), implicated at least one target gene for 6/13 distinct genome-wide significant regions and revealed 2 known and 26 novel candidate susceptibility genes for HGSOC.\n\nSTATEMENT OF SIGNIFICANCEFor many ovarian cancer risk regions, the target genes regulated by germline genetic variants are unknown. Using expression data from >2,100 individuals, this study identified novel associations of genes and splicing variants with ovarian cancer risk; with transcriptional variation now explaining over one-third of the SNP-heritability for this disease.

genomics↗