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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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Simplified model that depicts cancer as a disorder of signal multiplexing in the cellular 2R-WGD networks of vertebrate animals. (a) The ancestor of all the vertebrates was an invertebrate chordate whose cells are depicted as being under the control of simple linear regulatory pathways. The image is of amphioxus (Branchiostoma), regarded as the best modern-day proxy for the ancestor. (b) 2R-WGD at the evolutionary origins of the vertebrate animals boosted communication networks inside our cells. Variations in these networks may underpin variety of vertebrate cell types, species and behaviours. (c) We hypothesize that certain cancers arise when different heterogeneous combinations of mutations (crosses) disconnect certain parts of the 2R-WGD regulatory networks and force too much communication flow via a restricted number of oncogenic pathways. These ‘open’ oncogenic pathways are activated by specific driver mutations (stars) and also require effector proteins that must remain mutation-free. If these effectors acquire too many deleterious mutations, the cancer cell will be lost. Though the model only depicts 2R families with high ML skews, it could be extended to include other patterns. For example, 2R families whose members carry an even ML may be in parts of the network where any member can perform the family function for the cancer, or represent functions whose total elimination gives a selective advantage to the cancer. In its simple form, the model assumes that when genes are hit by a number of different mutations (crosses) these will include loss-of-function mutations. However, it is appreciated that this may not always be so, in which case the rules of the model would change. The model highlights that the contribution of both mutated and non-mutated 2R-ohnologues to the overall function of each family in the cancer should be considered.
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RSOB140029F6: Simplified model that depicts cancer as a disorder of signal multiplexing in the cellular 2R-WGD networks of vertebrate animals. (a) The ancestor of all the vertebrates was an invertebrate chordate whose cells are depicted as being under the control of simple linear regulatory pathways. The image is of amphioxus (Branchiostoma), regarded as the best modern-day proxy for the ancestor. (b) 2R-WGD at the evolutionary origins of the vertebrate animals boosted communication networks inside our cells. Variations in these networks may underpin variety of vertebrate cell types, species and behaviours. (c) We hypothesize that certain cancers arise when different heterogeneous combinations of mutations (crosses) disconnect certain parts of the 2R-WGD regulatory networks and force too much communication flow via a restricted number of oncogenic pathways. These ‘open’ oncogenic pathways are activated by specific driver mutations (stars) and also require effector proteins that must remain mutation-free. If these effectors acquire too many deleterious mutations, the cancer cell will be lost. Though the model only depicts 2R families with high ML skews, it could be extended to include other patterns. For example, 2R families whose members carry an even ML may be in parts of the network where any member can perform the family function for the cancer, or represent functions whose total elimination gives a selective advantage to the cancer. In its simple form, the model assumes that when genes are hit by a number of different mutations (crosses) these will include loss-of-function mutations. However, it is appreciated that this may not always be so, in which case the rules of the model would change. The model highlights that the contribution of both mutated and non-mutated 2R-ohnologues to the overall function of each family in the cancer should be considered.

Mentions: Rather, we favour a conceptually simple working model (figure 6). The invertebrate ancestor of the vertebrates is depicted as having cells controlled by linear regulatory pathways. Via the 2R-WGD leap, these pathways were quadruplicated, generating the complex networks that transmit multiple regulatory signals in vertebrate cells. In certain cancers such as melanoma and breast cancer, heterogeneous patterns of multiple mutations (black crosses in figure 6) result in the shutdown of certain routes through these communication networks. Information flow is therefore forced through a limited number of ‘open’ network pathways, which are driven by activating oncogenic driver mutations (star symbols in figure 6) and also depend on specific non-mutated 2R-ohnologues as effectors.Figure 6.


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)

Simplified model that depicts cancer as a disorder of signal multiplexing in the cellular 2R-WGD networks of vertebrate animals. (a) The ancestor of all the vertebrates was an invertebrate chordate whose cells are depicted as being under the control of simple linear regulatory pathways. The image is of amphioxus (Branchiostoma), regarded as the best modern-day proxy for the ancestor. (b) 2R-WGD at the evolutionary origins of the vertebrate animals boosted communication networks inside our cells. Variations in these networks may underpin variety of vertebrate cell types, species and behaviours. (c) We hypothesize that certain cancers arise when different heterogeneous combinations of mutations (crosses) disconnect certain parts of the 2R-WGD regulatory networks and force too much communication flow via a restricted number of oncogenic pathways. These ‘open’ oncogenic pathways are activated by specific driver mutations (stars) and also require effector proteins that must remain mutation-free. If these effectors acquire too many deleterious mutations, the cancer cell will be lost. Though the model only depicts 2R families with high ML skews, it could be extended to include other patterns. For example, 2R families whose members carry an even ML may be in parts of the network where any member can perform the family function for the cancer, or represent functions whose total elimination gives a selective advantage to the cancer. In its simple form, the model assumes that when genes are hit by a number of different mutations (crosses) these will include loss-of-function mutations. However, it is appreciated that this may not always be so, in which case the rules of the model would change. The model highlights that the contribution of both mutated and non-mutated 2R-ohnologues to the overall function of each family in the cancer should be considered.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

RSOB140029F6: Simplified model that depicts cancer as a disorder of signal multiplexing in the cellular 2R-WGD networks of vertebrate animals. (a) The ancestor of all the vertebrates was an invertebrate chordate whose cells are depicted as being under the control of simple linear regulatory pathways. The image is of amphioxus (Branchiostoma), regarded as the best modern-day proxy for the ancestor. (b) 2R-WGD at the evolutionary origins of the vertebrate animals boosted communication networks inside our cells. Variations in these networks may underpin variety of vertebrate cell types, species and behaviours. (c) We hypothesize that certain cancers arise when different heterogeneous combinations of mutations (crosses) disconnect certain parts of the 2R-WGD regulatory networks and force too much communication flow via a restricted number of oncogenic pathways. These ‘open’ oncogenic pathways are activated by specific driver mutations (stars) and also require effector proteins that must remain mutation-free. If these effectors acquire too many deleterious mutations, the cancer cell will be lost. Though the model only depicts 2R families with high ML skews, it could be extended to include other patterns. For example, 2R families whose members carry an even ML may be in parts of the network where any member can perform the family function for the cancer, or represent functions whose total elimination gives a selective advantage to the cancer. In its simple form, the model assumes that when genes are hit by a number of different mutations (crosses) these will include loss-of-function mutations. However, it is appreciated that this may not always be so, in which case the rules of the model would change. The model highlights that the contribution of both mutated and non-mutated 2R-ohnologues to the overall function of each family in the cancer should be considered.
Mentions: Rather, we favour a conceptually simple working model (figure 6). The invertebrate ancestor of the vertebrates is depicted as having cells controlled by linear regulatory pathways. Via the 2R-WGD leap, these pathways were quadruplicated, generating the complex networks that transmit multiple regulatory signals in vertebrate cells. In certain cancers such as melanoma and breast cancer, heterogeneous patterns of multiple mutations (black crosses in figure 6) result in the shutdown of certain routes through these communication networks. Information flow is therefore forced through a limited number of ‘open’ network pathways, which are driven by activating oncogenic driver mutations (star symbols in figure 6) and also depend on specific non-mutated 2R-ohnologues as effectors.Figure 6.

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