title: Identification of 2R-ohnologue gene families displaying the same mutation-load skew in multiple cancers.
abstract: 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.
authors.affiliation: Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Michele
authors.initials: M
authors.lastname: Tinti
authors.forename: Kumara
authors.initials: K
authors.lastname: Dissanayake
authors.forename: Silvia
authors.initials: S
authors.lastname: Synowsky
authors.forename: Luca
authors.initials: L
authors.lastname: Albergante
authors.forename: Carol
authors.initials: C
authors.lastname: MacKintosh
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D030541:Databases, Genetic; D019143:Evolution, Molecular; D020440:Gene Duplication; D015894:Genome, Human; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C498432:ZFPM1 protein, human; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins
keywords: 2R-ohnologue families; cancer; mutations; signal multiplexing; vertebrates