Systematic analysis of somatic mutations impacting gene expression in 12 tumour types

被引:72
作者
Ding, Jiarui [1 ,2 ]
McConechy, Melissa K. [3 ,4 ]
Horlings, Hugo M. [3 ,4 ]
Ha, Gavin [1 ]
Chan, Fong Chun [1 ]
Funnell, Tyler [1 ]
Mullaly, Sarah C. [1 ]
Reimand, Jueri [5 ]
Bashashati, Ali [1 ]
Bader, Gary D. [5 ]
Huntsman, David [1 ,3 ,4 ]
Aparicio, Samuel [1 ,4 ]
Condon, Anne [2 ]
Shah, Sohrab P. [1 ,2 ,4 ,6 ]
机构
[1] BC Canc Agcy, Dept Mol Oncol, Vancouver, BC V5Z 1L3, Canada
[2] Univ British Columbia, Dept Comp Sci, Vancouver, BC V6T 1Z4, Canada
[3] BC Canc Agcy, Ctr Translat & Appl Genom, Vancouver, BC V5Z 4E6, Canada
[4] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V6T 2B5, Canada
[5] Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada
[6] Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada
关键词
COPY-NUMBER ALTERATIONS; CELL LUNG-CANCER; DISCOVERY; RNA; HETEROGENEITY; ARCHITECTURE; LANDSCAPE; PATHWAYS; PATTERNS; REVEALS;
D O I
10.1038/ncomms9554
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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-offunction 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.
引用
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页数:13
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