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Discovery and saturation analysis of cancer genes across 21 tumour types.

Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR, Meyerson M, Gabriel SB, Lander ES, Getz G - Nature (2014)

Bottom Line: We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumour types.Down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies.We estimate that near-saturation may be achieved with 600-5,000 samples per tumour type, depending on background mutation frequency.

View Article: PubMed Central - PubMed

Affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.

ABSTRACT
Although a few cancer genes are mutated in a high proportion of tumours of a given type (>20%), most are mutated at intermediate frequencies (2-20%). To explore the feasibility of creating a comprehensive catalogue of cancer genes, we analysed somatic point mutations in exome sequences from 4,742 human cancers and their matched normal-tissue samples across 21 cancer types. We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumour types. Our analysis also identified 33 genes that were not previously known to be significantly mutated in cancer, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies. We estimate that near-saturation may be achieved with 600-5,000 samples per tumour type, depending on background mutation frequency. The results may help to guide the next stage of cancer genomics.

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Cancer genes in selected tumor types. Genes are arranged on the horizontal line according to p-value (combined value for the three tests in MutSig). Yellow region contains genes that achieve FDR q≤0.1. Orange interval contains p-values for the next 20 genes. Gene name color indicates whether the gene is a known cancer gene (blue), a novel gene with clear connection to cancer (red; discussed in text), or an additional novel gene (black). Circle color indicates the frequency (percent of patients carrying non-silent somatic mutations) in that tumor type. See also Supplementary Figure 5.
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Figure 2: Cancer genes in selected tumor types. Genes are arranged on the horizontal line according to p-value (combined value for the three tests in MutSig). Yellow region contains genes that achieve FDR q≤0.1. Orange interval contains p-values for the next 20 genes. Gene name color indicates whether the gene is a known cancer gene (blue), a novel gene with clear connection to cancer (red; discussed in text), or an additional novel gene (black). Circle color indicates the frequency (percent of patients carrying non-silent somatic mutations) in that tumor type. See also Supplementary Figure 5.

Mentions: A total of 224 genes were found to be significant in one or more tumor types, and 334 gene × tumor-type pairs were found to be significant. The number of genes detected per tumor type varied considerably (range 1 – 58), with seven types having fewer than 10 genes and two (breast and endometrial) having more than 30 (Figure 2; Supplementary Figure 5; Table 1). The specific genes differed substantially across tumor types, although some pairs of tumor types showed clear similarity, such as lung squamous cancer and head and neck squamous cancer (Methods, Supplementary Figure 6).


Discovery and saturation analysis of cancer genes across 21 tumour types.

Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR, Meyerson M, Gabriel SB, Lander ES, Getz G - Nature (2014)

Cancer genes in selected tumor types. Genes are arranged on the horizontal line according to p-value (combined value for the three tests in MutSig). Yellow region contains genes that achieve FDR q≤0.1. Orange interval contains p-values for the next 20 genes. Gene name color indicates whether the gene is a known cancer gene (blue), a novel gene with clear connection to cancer (red; discussed in text), or an additional novel gene (black). Circle color indicates the frequency (percent of patients carrying non-silent somatic mutations) in that tumor type. See also Supplementary Figure 5.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4048962&req=5

Figure 2: Cancer genes in selected tumor types. Genes are arranged on the horizontal line according to p-value (combined value for the three tests in MutSig). Yellow region contains genes that achieve FDR q≤0.1. Orange interval contains p-values for the next 20 genes. Gene name color indicates whether the gene is a known cancer gene (blue), a novel gene with clear connection to cancer (red; discussed in text), or an additional novel gene (black). Circle color indicates the frequency (percent of patients carrying non-silent somatic mutations) in that tumor type. See also Supplementary Figure 5.
Mentions: A total of 224 genes were found to be significant in one or more tumor types, and 334 gene × tumor-type pairs were found to be significant. The number of genes detected per tumor type varied considerably (range 1 – 58), with seven types having fewer than 10 genes and two (breast and endometrial) having more than 30 (Figure 2; Supplementary Figure 5; Table 1). The specific genes differed substantially across tumor types, although some pairs of tumor types showed clear similarity, such as lung squamous cancer and head and neck squamous cancer (Methods, Supplementary Figure 6).

Bottom Line: We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumour types.Down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies.We estimate that near-saturation may be achieved with 600-5,000 samples per tumour type, depending on background mutation frequency.

View Article: PubMed Central - PubMed

Affiliation: Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.

ABSTRACT
Although a few cancer genes are mutated in a high proportion of tumours of a given type (>20%), most are mutated at intermediate frequencies (2-20%). To explore the feasibility of creating a comprehensive catalogue of cancer genes, we analysed somatic point mutations in exome sequences from 4,742 human cancers and their matched normal-tissue samples across 21 cancer types. We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumour types. Our analysis also identified 33 genes that were not previously known to be significantly mutated in cancer, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies. We estimate that near-saturation may be achieved with 600-5,000 samples per tumour type, depending on background mutation frequency. The results may help to guide the next stage of cancer genomics.

Show MeSH
Related in: MedlinePlus