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Mutational landscape and significance across 12 major cancer types.

Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, Leiserson MD, Miller CA, Welch JS, Walter MJ, Wendl MC, Ley TJ, Wilson RK, Raphael BJ, Ding L - Nature (2013)

Bottom Line: The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the number of driver mutations required during oncogenesis is relatively small.Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis.Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.

View Article: PubMed Central - PubMed

Affiliation: The Genome Institute, Washington University in St Louis, Missouri 63108, USA.

ABSTRACT
The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort. We illustrate the distributions of mutation frequencies, types and contexts across tumour types, and establish their links to tissues of origin, environmental/carcinogen influences, and DNA repair defects. Using the integrated data sets, we identified 127 significantly mutated genes from well-known (for example, mitogen-activated protein kinase, phosphatidylinositol-3-OH kinase, Wnt/β-catenin and receptor tyrosine kinase signalling pathways, and cell cycle control) and emerging (for example, histone, histone modification, splicing, metabolism and proteolysis) cellular processes in cancer. The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the number of driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types. Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis. Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.

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The 127 SMGs from 20 cellular processes in cancer identified in 12 cancer typesPercentages of samples mutated in individual tumour types and Pan-Cancer are shown, with the highest percentage in each gene among 12 cancer types in bold.
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Figure 2: The 127 SMGs from 20 cellular processes in cancer identified in 12 cancer typesPercentages of samples mutated in individual tumour types and Pan-Cancer are shown, with the highest percentage in each gene among 12 cancer types in bold.

Mentions: Genes under positive selection, either in individual or multiple tumour types, tend to display higher mutation frequencies above background. Our statistical analysis3, guided by expression data and curation (Methods), identified 127 such genes (SMGs; Supplementary Table 4). These SMGs are involved in a wide range of cellular processes, broadly classified into 20 categories (Fig. 2), including transcription factors/regulators, histone modifiers, genome integrity, receptor tyrosine kinase signalling, cell cycle, mitogen-activated protein kinases (MAPK) signalling, phosphatidylinositol-3-OH kinase (PI(3)K) signalling, Wnt/β-catenin signalling,histones, ubiquitin-mediated proteolysis, and splicing (Fig. 2). The identification of MAPK, PI(3)K and Wnt/β-catenin signalling pathways is consistent with classical cancer studies. Notably, newer categories (for example, splicing, transcription regulators, metabolism, proteolysis and histones) emerge as exciting guides for the development of new therapeutic targets. Genes categorized as histone modifiers (Z = 0.57), PI(3)K signalling (Z = 1.03), and genome integrity (Z = 0.66) all relate to more than one cancer type, whereas transcription factor/regulator (Z = 0.40), TGF-β signalling (Z = 0.66), and Wnt/β-catenin signalling (Z = 0.55) genes tend to associate with single types (Methods).


Mutational landscape and significance across 12 major cancer types.

Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, Leiserson MD, Miller CA, Welch JS, Walter MJ, Wendl MC, Ley TJ, Wilson RK, Raphael BJ, Ding L - Nature (2013)

The 127 SMGs from 20 cellular processes in cancer identified in 12 cancer typesPercentages of samples mutated in individual tumour types and Pan-Cancer are shown, with the highest percentage in each gene among 12 cancer types in bold.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927368&req=5

Figure 2: The 127 SMGs from 20 cellular processes in cancer identified in 12 cancer typesPercentages of samples mutated in individual tumour types and Pan-Cancer are shown, with the highest percentage in each gene among 12 cancer types in bold.
Mentions: Genes under positive selection, either in individual or multiple tumour types, tend to display higher mutation frequencies above background. Our statistical analysis3, guided by expression data and curation (Methods), identified 127 such genes (SMGs; Supplementary Table 4). These SMGs are involved in a wide range of cellular processes, broadly classified into 20 categories (Fig. 2), including transcription factors/regulators, histone modifiers, genome integrity, receptor tyrosine kinase signalling, cell cycle, mitogen-activated protein kinases (MAPK) signalling, phosphatidylinositol-3-OH kinase (PI(3)K) signalling, Wnt/β-catenin signalling,histones, ubiquitin-mediated proteolysis, and splicing (Fig. 2). The identification of MAPK, PI(3)K and Wnt/β-catenin signalling pathways is consistent with classical cancer studies. Notably, newer categories (for example, splicing, transcription regulators, metabolism, proteolysis and histones) emerge as exciting guides for the development of new therapeutic targets. Genes categorized as histone modifiers (Z = 0.57), PI(3)K signalling (Z = 1.03), and genome integrity (Z = 0.66) all relate to more than one cancer type, whereas transcription factor/regulator (Z = 0.40), TGF-β signalling (Z = 0.66), and Wnt/β-catenin signalling (Z = 0.55) genes tend to associate with single types (Methods).

Bottom Line: The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the number of driver mutations required during oncogenesis is relatively small.Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis.Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.

View Article: PubMed Central - PubMed

Affiliation: The Genome Institute, Washington University in St Louis, Missouri 63108, USA.

ABSTRACT
The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort. We illustrate the distributions of mutation frequencies, types and contexts across tumour types, and establish their links to tissues of origin, environmental/carcinogen influences, and DNA repair defects. Using the integrated data sets, we identified 127 significantly mutated genes from well-known (for example, mitogen-activated protein kinase, phosphatidylinositol-3-OH kinase, Wnt/β-catenin and receptor tyrosine kinase signalling pathways, and cell cycle control) and emerging (for example, histone, histone modification, splicing, metabolism and proteolysis) cellular processes in cancer. The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the number of driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types. Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis. Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.

Show MeSH
Related in: MedlinePlus