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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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Distributions of cancer mutations between 2R-ohnologue and non-ohnologue transcript-coding genes in 30 different cancers. (a) The bar shows the percentage of 2R-ohnologue and non-ohnologue transcript-coding genes in the Ensembl 72 dataset, based on the provisional 2R-ohnologue list compiled by Makino & McLysaght [10]. Note that assignment of which human genes are 2R-ohnologues is still undergoing revision. (b) For each cancer type analysed [15], the graph on the left side reports the percentage of mutations that map on 2R-ohnologue and non-ohnologue genes. The right side reports the log10 value of the total number of mutations identified in each cancer type in this dataset.
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RSOB140029F1: Distributions of cancer mutations between 2R-ohnologue and non-ohnologue transcript-coding genes in 30 different cancers. (a) The bar shows the percentage of 2R-ohnologue and non-ohnologue transcript-coding genes in the Ensembl 72 dataset, based on the provisional 2R-ohnologue list compiled by Makino & McLysaght [10]. Note that assignment of which human genes are 2R-ohnologues is still undergoing revision. (b) For each cancer type analysed [15], the graph on the left side reports the percentage of mutations that map on 2R-ohnologue and non-ohnologue genes. The right side reports the log10 value of the total number of mutations identified in each cancer type in this dataset.

Mentions: Alexandrov et al. [15] validated almost 5 million somatic mutations identified in the genome sequences of 7042 samples from 30 different cancer types, but not in matched DNA from normal cells. We used the Alexandrov data to examine the distribution of mutations in 2R-ohnologue versus non-ohnologue genes (electronic supplementary material, table S1). A striking imbalance was revealed (figure 1). Although 2R-ohnologues comprise only approximately 30% of protein-coding genes in the human genome (figure 1a), they carry a higher proportion of the somatic mutations in transcript-coding genes in every cancer examined (figure 1b; statistics in the electronic supplementary material, figure S1). The proportions range from 42% of gene mutations located in 2R-ohnologues in kidney clear cell carcinoma to 60% in liver cancer and in B-cell lymphoma. The greater prevalence of mutations among 2R-ohnologues is not due to differences in gene sizes: 2R-ohnologue genes average 2400 nucleotides in length and non-ohnologues 2200 nucleotides (electronic supplementary material, figure S2).Figure 1.


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)

Distributions of cancer mutations between 2R-ohnologue and non-ohnologue transcript-coding genes in 30 different cancers. (a) The bar shows the percentage of 2R-ohnologue and non-ohnologue transcript-coding genes in the Ensembl 72 dataset, based on the provisional 2R-ohnologue list compiled by Makino & McLysaght [10]. Note that assignment of which human genes are 2R-ohnologues is still undergoing revision. (b) For each cancer type analysed [15], the graph on the left side reports the percentage of mutations that map on 2R-ohnologue and non-ohnologue genes. The right side reports the log10 value of the total number of mutations identified in each cancer type in this dataset.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

RSOB140029F1: Distributions of cancer mutations between 2R-ohnologue and non-ohnologue transcript-coding genes in 30 different cancers. (a) The bar shows the percentage of 2R-ohnologue and non-ohnologue transcript-coding genes in the Ensembl 72 dataset, based on the provisional 2R-ohnologue list compiled by Makino & McLysaght [10]. Note that assignment of which human genes are 2R-ohnologues is still undergoing revision. (b) For each cancer type analysed [15], the graph on the left side reports the percentage of mutations that map on 2R-ohnologue and non-ohnologue genes. The right side reports the log10 value of the total number of mutations identified in each cancer type in this dataset.
Mentions: Alexandrov et al. [15] validated almost 5 million somatic mutations identified in the genome sequences of 7042 samples from 30 different cancer types, but not in matched DNA from normal cells. We used the Alexandrov data to examine the distribution of mutations in 2R-ohnologue versus non-ohnologue genes (electronic supplementary material, table S1). A striking imbalance was revealed (figure 1). Although 2R-ohnologues comprise only approximately 30% of protein-coding genes in the human genome (figure 1a), they carry a higher proportion of the somatic mutations in transcript-coding genes in every cancer examined (figure 1b; statistics in the electronic supplementary material, figure S1). The proportions range from 42% of gene mutations located in 2R-ohnologues in kidney clear cell carcinoma to 60% in liver cancer and in B-cell lymphoma. The greater prevalence of mutations among 2R-ohnologues is not due to differences in gene sizes: 2R-ohnologue genes average 2400 nucleotides in length and non-ohnologues 2200 nucleotides (electronic supplementary material, figure S2).Figure 1.

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