Pre-prints from two transcriptome-wide association studies of high-grade serous ovarian cancer (collaboration with Lawrenson/Gayther/Pasaniuc labs) and prostate cancer (lead by Pasaniuc lab) are now on-line. The studies use integration of gene expression and GWAS data to identify novel cancer risk-associated loci and potential susceptibility genes.
In both cancers, we found that genetic components of expression in tumors were frequently associated with cancer risk, implicating genes that may potentially act on risk and progression. This finding motivates using large-scale studies of gene expression in tumors as a resource to understand risk mechanisms (in fact, the majority of gene expression data for these analyses was already collected in public datasets from The Cancer Genome Atlas).
Both studies additionally performed a splice-TWAS and identified genetic predictors of splice variation as a mechanism that is frequently associated with cancer risk independently of overall gene expression. In particular, the ovarian study reported significantly stronger ovarian cell line essentiality for genes implicated through splicing and highlighted a novel splice-specific TWAS asspcoatopm that exhibits essentiality comparable to classic drivers like MYC. A challenge for following up this analysis is that the majority of alternatively spliced genes did not have lead associations in a canonical splice site, motivating further work into the functional characteristics of disease-associated splice variants.
The prostate study additionally presents results from a new TWAS/gene fine-mapping approach which calculates credible sets of genes (see more details on the method in the FOCUS pre-print), and finds that most loci can be narrowed down to a single credible gene with current expression reference panels. See also a tweet summary of the prostate paper by first author Nick Mancuso, and a recent TWAS of breast cancer risk with experimental follow-up by Wu et al. 2018 Nat Genet.
Multi-Tissue Transcriptome-Wide Association Studies Identify 21 Novel Candidate Susceptibility Genes for High Grade Serous Epithelial Ovarian Cancer. A Gusev[+], K Lawrenson[+], F Segato, M Fonseca, S Kar, J Lee, T Pejovic, Ovarian Cancer Association Consortium, B Karlan, M Freedman, H Noushmehr, P Pharoah, B Pasaniuc[*], S Gayther[*]. 2018
Large-scale transcriptome-wide association study identifies new prostate cancer risk regions. N Mancuso, S Gayther, A Gusev, W Zheng, KL Penney, the PRACTICAL consortium, CRUK, BPC3, CAPS, PEGASUS, Z Kote-Jarai, R Eeles, ML Freedman, C Haiman, B Pasaniuc. 2018