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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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Related in: MedlinePlus

VisANT map of 2R-ohnologue families that display skewed MLs in different cancer types; graph created using VisANT (visant.bu.edu [27]) from the data in the electronic supplementary material, table S3. Each cancer was assigned a node in blue and lines connect these cancers to the 2R-ohnologue families (in green, red or orange) that display a skewed ML in that cancer. For a line to join a cancer and a 2R-ohnologue family, at least one gene in the family had to carry at least 10 different mutations in that cancer. Also, we plotted only those families with ML skew above the thresholds of at least 0.9 for families containing two genes (that is one gene carried more than or equal to 90% of the mutated positions for its family), at least 0.8 for families with three genes and at least 0.7 for families of four genes. The red node labelled ‘P53-F’ is the p53/p63/p73 family, and the orange node marked ‘FOG-F’ represents FOG1/FOG2.
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RSOB140029F3: VisANT map of 2R-ohnologue families that display skewed MLs in different cancer types; graph created using VisANT (visant.bu.edu [27]) from the data in the electronic supplementary material, table S3. Each cancer was assigned a node in blue and lines connect these cancers to the 2R-ohnologue families (in green, red or orange) that display a skewed ML in that cancer. For a line to join a cancer and a 2R-ohnologue family, at least one gene in the family had to carry at least 10 different mutations in that cancer. Also, we plotted only those families with ML skew above the thresholds of at least 0.9 for families containing two genes (that is one gene carried more than or equal to 90% of the mutated positions for its family), at least 0.8 for families with three genes and at least 0.7 for families of four genes. The red node labelled ‘P53-F’ is the p53/p63/p73 family, and the orange node marked ‘FOG-F’ represents FOG1/FOG2.

Mentions: A total of 673 2R-ohnologue families displayed highly skewed MLs in one or more cancers (electronic supplementary material, table S3). This dataset was visualized in a VisANT network graph in which each cancer type is assigned a hexagonal blue node, connected to circular nodes (green, red or orange) that each represent a 2R-ohnologue family with a skewed ML in that cancer (figure 3). The ‘elegant relaxing’ VisANT rule was applied [27], which means that 2R-ohnologue families with a skewed ML in only one cancer fan to the outside of the graph, while those with a skewed ML in multiple cancers are pulled towards the centre (figure 3). The layout of the graph therefore reflects patterns in the data.Figure 3.


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)

VisANT map of 2R-ohnologue families that display skewed MLs in different cancer types; graph created using VisANT (visant.bu.edu [27]) from the data in the electronic supplementary material, table S3. Each cancer was assigned a node in blue and lines connect these cancers to the 2R-ohnologue families (in green, red or orange) that display a skewed ML in that cancer. For a line to join a cancer and a 2R-ohnologue family, at least one gene in the family had to carry at least 10 different mutations in that cancer. Also, we plotted only those families with ML skew above the thresholds of at least 0.9 for families containing two genes (that is one gene carried more than or equal to 90% of the mutated positions for its family), at least 0.8 for families with three genes and at least 0.7 for families of four genes. The red node labelled ‘P53-F’ is the p53/p63/p73 family, and the orange node marked ‘FOG-F’ represents FOG1/FOG2.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

RSOB140029F3: VisANT map of 2R-ohnologue families that display skewed MLs in different cancer types; graph created using VisANT (visant.bu.edu [27]) from the data in the electronic supplementary material, table S3. Each cancer was assigned a node in blue and lines connect these cancers to the 2R-ohnologue families (in green, red or orange) that display a skewed ML in that cancer. For a line to join a cancer and a 2R-ohnologue family, at least one gene in the family had to carry at least 10 different mutations in that cancer. Also, we plotted only those families with ML skew above the thresholds of at least 0.9 for families containing two genes (that is one gene carried more than or equal to 90% of the mutated positions for its family), at least 0.8 for families with three genes and at least 0.7 for families of four genes. The red node labelled ‘P53-F’ is the p53/p63/p73 family, and the orange node marked ‘FOG-F’ represents FOG1/FOG2.
Mentions: A total of 673 2R-ohnologue families displayed highly skewed MLs in one or more cancers (electronic supplementary material, table S3). This dataset was visualized in a VisANT network graph in which each cancer type is assigned a hexagonal blue node, connected to circular nodes (green, red or orange) that each represent a 2R-ohnologue family with a skewed ML in that cancer (figure 3). The ‘elegant relaxing’ VisANT rule was applied [27], which means that 2R-ohnologue families with a skewed ML in only one cancer fan to the outside of the graph, while those with a skewed ML in multiple cancers are pulled towards the centre (figure 3). The layout of the graph therefore reflects patterns in the data.Figure 3.

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