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Identification of 2R-ohnologue gene families displaying the same mutation-load skew in multiple cancers.

Tinti M, Dissanayake K, Synowsky S, Albergante L, MacKintosh C - Open Biol (2014)

Bottom Line: The complexity of signalling pathways was boosted at the origin of the vertebrates, when two rounds of whole genome duplication (2R-WGD) occurred.The non-mutated 2R-ohnologues are therefore potential therapeutic targets.These include proteins linked to growth factor signalling, neurotransmission and ion channels.

View Article: PubMed Central - PubMed

Affiliation: Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.

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.

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Associations between specific cancers and specific mutation-load-skewed 2R-ohnologue families. (a) Data extracted from figure 3, showing the cancers for which there are ML skews in the p53/p63/p73 and FOG1/FOG2 protein families. (b) A graph showing those 2R-ohnologue families that display a skewed ML in the cumulative data from those melanoma and colorectal cancer samples that have either a B-RafV600E or N-RasQ61K/R mutation (data in the electronic supplementary material, table S5). ‘Common’ indicates 2R-ohnologue families that have a skewed ML in the data from both the B-RafV600E-mutated and the N-RasQ61K/R-mutated samples.
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RSOB140029F4: Associations between specific cancers and specific mutation-load-skewed 2R-ohnologue families. (a) Data extracted from figure 3, showing the cancers for which there are ML skews in the p53/p63/p73 and FOG1/FOG2 protein families. (b) A graph showing those 2R-ohnologue families that display a skewed ML in the cumulative data from those melanoma and colorectal cancer samples that have either a B-RafV600E or N-RasQ61K/R mutation (data in the electronic supplementary material, table S5). ‘Common’ indicates 2R-ohnologue families that have a skewed ML in the data from both the B-RafV600E-mutated and the N-RasQ61K/R-mutated samples.

Mentions: The p53/63/73 family has an ML skew in 14 cancer types (red nodes in figures 3 and 4a). Also linked to many cancers is the FOG1/2 (Friend of GATA 1/2) family in which FOG2 is more commonly mutated than FOG1 (orange node on figures 3 and 4a; electronic supplementary material, table S3). Between them, the p53/63/73 and FOG1/2 ML-skewed families link to 22 of the 30 cancers examined, with an overlap of only three cancer types (figure 4a). Other 2R-ohnologue families displaying high ML skews in 10 or more cancers are those with the following proteins most mutated: potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1), tectorin alpha (TECTA), receptor-type tyrosine-protein phosphatase delta (PTPRD), low-density lipoprotein receptor-related protein 1B (LRP1B), MAM domain-containing glycosylphosphatidylinositol anchor protein 2 (MDGA2) and protein phosphatase 1 regulatory subunit 9A (neurabin-1) (electronic supplementary material, table S3).Figure 4.


Identification of 2R-ohnologue gene families displaying the same mutation-load skew in multiple cancers.

Tinti M, Dissanayake K, Synowsky S, Albergante L, MacKintosh C - Open Biol (2014)

Associations between specific cancers and specific mutation-load-skewed 2R-ohnologue families. (a) Data extracted from figure 3, showing the cancers for which there are ML skews in the p53/p63/p73 and FOG1/FOG2 protein families. (b) A graph showing those 2R-ohnologue families that display a skewed ML in the cumulative data from those melanoma and colorectal cancer samples that have either a B-RafV600E or N-RasQ61K/R mutation (data in the electronic supplementary material, table S5). ‘Common’ indicates 2R-ohnologue families that have a skewed ML in the data from both the B-RafV600E-mutated and the N-RasQ61K/R-mutated samples.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4042849&req=5

RSOB140029F4: Associations between specific cancers and specific mutation-load-skewed 2R-ohnologue families. (a) Data extracted from figure 3, showing the cancers for which there are ML skews in the p53/p63/p73 and FOG1/FOG2 protein families. (b) A graph showing those 2R-ohnologue families that display a skewed ML in the cumulative data from those melanoma and colorectal cancer samples that have either a B-RafV600E or N-RasQ61K/R mutation (data in the electronic supplementary material, table S5). ‘Common’ indicates 2R-ohnologue families that have a skewed ML in the data from both the B-RafV600E-mutated and the N-RasQ61K/R-mutated samples.
Mentions: The p53/63/73 family has an ML skew in 14 cancer types (red nodes in figures 3 and 4a). Also linked to many cancers is the FOG1/2 (Friend of GATA 1/2) family in which FOG2 is more commonly mutated than FOG1 (orange node on figures 3 and 4a; electronic supplementary material, table S3). Between them, the p53/63/73 and FOG1/2 ML-skewed families link to 22 of the 30 cancers examined, with an overlap of only three cancer types (figure 4a). Other 2R-ohnologue families displaying high ML skews in 10 or more cancers are those with the following proteins most mutated: potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1), tectorin alpha (TECTA), receptor-type tyrosine-protein phosphatase delta (PTPRD), low-density lipoprotein receptor-related protein 1B (LRP1B), MAM domain-containing glycosylphosphatidylinositol anchor protein 2 (MDGA2) and protein phosphatase 1 regulatory subunit 9A (neurabin-1) (electronic supplementary material, table S3).Figure 4.

Bottom Line: The complexity of signalling pathways was boosted at the origin of the vertebrates, when two rounds of whole genome duplication (2R-WGD) occurred.The non-mutated 2R-ohnologues are therefore potential therapeutic targets.These include proteins linked to growth factor signalling, neurotransmission and ion channels.

View Article: PubMed Central - PubMed

Affiliation: Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.

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.

Show MeSH
Related in: MedlinePlus