期刊
OPEN BIOLOGY
卷 4, 期 5, 页码 -出版社
ROYAL SOC
DOI: 10.1098/rsob.140029
关键词
cancer; mutations; 2R-ohnologue families; signal multiplexing; vertebrates
资金
- University of Dundee Wellcome Trust Institutional Strategic Support Fund
- UK Medical Research Council Developmental Pathway Funding Scheme [G0801767]
- Human Frontier Science Foundation [RGP-0038]
- Scottish University Life Science Alliance
- AstraZeneca
- Boehringer-Ingelheim
- GlaxoSmithKline
- Merck KgaA
- Janssen Pharmaceutica
- Pfizer
- MRC [MC_EX_G0801767] Funding Source: UKRI
- Diabetes UK [12/0004557] Funding Source: researchfish
- Medical Research Council [MC_EX_G0801767] Funding Source: researchfish
The complexity of signalling pathways was boosted at the origin of the vertebrates, when two rounds of whole genome duplication (2R-WGD) occurred. Those genes and proteins that have survived from the 2R-WGD-termed 2R-ohnologues-belong to families of two to four members, and are enriched in signalling components relevant to cancer. Here, we find that while only approximately 30% of human transcript-coding genes are 2R-ohnologues, they carry 42-60% of the gene mutations in 30 different cancer types. Across a subset of cancer datasets, including melanoma, breast, lung adenocarcinoma, liver and medulloblastoma, we identified 673 2R-ohnologue families in which one gene carries mutations at multiple positions, while sister genes in the same family are relatively mutation free. Strikingly, in 315 of the 322 2R-ohnologue families displaying such a skew in multiple cancers, the same gene carries the heaviest mutation load in each cancer, and usually the second-ranked gene is also the same in each cancer. Our findings inspire the hypothesis that in certain cancers, heterogeneous combinations of genetic changes impair parts of the 2R-WGD signalling networks and force information flow through a limited set of oncogenic pathways in which specific non-mutated 2R-ohnologues serve as effectors. The non-mutated 2R-ohnologues are therefore potential therapeutic targets. These include proteins linked to growth factor signalling, neurotransmission and ion channels.
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