title: Systematic analysis of somatic mutations impacting gene expression in 12 tumour types.
abstract: We present a novel hierarchical Bayes statistical model, xseq, to systematically quantify the impact of somatic mutations on expression profiles. We establish the theoretical framework and robust inference characteristics of the method using computational benchmarking. We then use xseq to analyse thousands of tumour data sets available through The Cancer Genome Atlas, to systematically quantify somatic mutations impacting expression profiles. We identify 30 novel cis-effect tumour suppressor gene candidates, enriched in loss-of-function mutations and biallelic inactivation. Analysis of trans-effects of mutations and copy number alterations with xseq identifies mutations in 150 genes impacting expression networks, with 89 novel predictions. We reveal two important novel characteristics of mutation impact on expression: (1) patients harbouring known driver mutations exhibit different downstream gene expression consequences; (2) expression patterns for some mutations are stable across tumour types. These results have critical implications for identification and interpretation of mutations with consequent impact on transcription in cancer.
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.|Department of Computer Science, University of British Columbia, 2366 Main Mall, Vancouver, British Columbia, Canada V6T 1Z4.
authors.forename: Jiarui
authors.initials: J
authors.lastname: Ding
authors.affiliation: Centre for the Translational and Applied Genomics, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 4E6.|Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2B5.
authors.forename: Melissa K
authors.initials: MK
authors.lastname: McConechy
authors.affiliation: Centre for the Translational and Applied Genomics, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 4E6.|Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2B5.
authors.forename: Hugo M
authors.initials: HM
authors.lastname: Horlings
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.
authors.forename: Gavin
authors.initials: G
authors.lastname: Ha
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.
authors.forename: Fong
authors.initials: F
authors.lastname: Chun Chan
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.
authors.forename: Tyler
authors.initials: T
authors.lastname: Funnell
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Mullaly
authors.affiliation: The Donnelly Centre, University of Toronto, 160 College Street, Toronto, Ontario, Canada M5S 3E1.
authors.forename: Jüri
authors.initials: J
authors.lastname: Reimand
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.
authors.forename: Ali
authors.initials: A
authors.lastname: Bashashati
authors.affiliation: The Donnelly Centre, University of Toronto, 160 College Street, Toronto, Ontario, Canada M5S 3E1.
authors.forename: Gary D
authors.identifier: http://orcid.org/0000-0003-0185-8861
authors.initials: GD
authors.lastname: Bader
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.|Centre for the Translational and Applied Genomics, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 4E6.|Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2B5.
authors.forename: David
authors.initials: D
authors.lastname: Huntsman
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.|Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2B5.
authors.forename: Samuel
authors.initials: S
authors.lastname: Aparicio
authors.affiliation: Department of Computer Science, University of British Columbia, 2366 Main Mall, Vancouver, British Columbia, Canada V6T 1Z4.
authors.forename: Anne
authors.initials: A
authors.lastname: Condon
authors.affiliation: Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L3.|Department of Computer Science, University of British Columbia, 2366 Main Mall, Vancouver, British Columbia, Canada V6T 1Z4.|Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 2B5.|Canada's Michael Smith Genome Sciences Centre, 570 West 7th Avenue, Vancouver, British Columbia, Canada V5Z 4S6.
authors.forename: Sohrab P
authors.initials: SP
authors.lastname: Shah
mesh_terms: D001499:Bayes Theorem; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008957:Models, Genetic; D015233:Models, Statistical; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*