TY - JOUR
T1 - A meta-analysis of somatic mutations from next generation sequencing of 241 melanomas
T2 - A road map for the study of genes with potential clinical relevance
AU - Xia, Junfeng
AU - Jia, Peilin
AU - Hutchinson, Katherine E.
AU - Dahlman, Kimberly B.
AU - Johnson, Douglas
AU - Sosman, Jeffrey
AU - Pao, William
AU - Zhao, Zhongming
PY - 2014/7
Y1 - 2014/7
N2 - Next generation sequencing (NGS) has been used to characterize the overall genomic landscape of melanomas. Here, we systematically examined mutations from recently published melanoma NGS data involving 241 paired tumor-normal samples to identify potentially clinically relevant mutations. Melanomas were characterized according to an in-house clinical assay that identifies well-known specific recurrent mutations in five driver genes: BRAF (affecting V600), NRAS (G12, G13, and Q61), KIT (W557, V559, L576, K642, and D816), GNAQ (Q209), and GNA11 (Q209). Tumors with none of these mutations are termed "pan negative." We then mined the driver mutation-positive and pan-negative melanoma NGS data for mutations in 632 cancer genes that could influence existing or emerging targeted therapies. First, we uncovered several genes whose mutations were more likely associated with BRAF- or NRAS -driven melanomas, including TP53 and COL1A1 with BRAF, and PPP6C, KALRN, PIK3R4, TRPM6, GUCY2C, and PRKAA2 with NRAS. Second, we found that the 69 "pan-negative" melanoma genomes harbored alternate infrequent mutations in the five known driver genes along with many mutations in genes encoding guanine nucleotide binding protein a-subunits. Third, we identified 12 significantly mutated genes in "pan-negative" samples (ALK , STK31, DGKI, RAC1, EPHA4 , ADAMTS18, EPHA7, ERBB4, TAF1L, NF1, SYK, and KDR), including five genes (RAC1, ADAMTS18, EPHA7, TAF1L, and NF1) with a recurrent mutation in at least two "pan-negative" tumor samples. This meta-analysis provides a road map for the study of additional potentially actionable genes in both driver mutation-positive and pan-negative melanomas.
AB - Next generation sequencing (NGS) has been used to characterize the overall genomic landscape of melanomas. Here, we systematically examined mutations from recently published melanoma NGS data involving 241 paired tumor-normal samples to identify potentially clinically relevant mutations. Melanomas were characterized according to an in-house clinical assay that identifies well-known specific recurrent mutations in five driver genes: BRAF (affecting V600), NRAS (G12, G13, and Q61), KIT (W557, V559, L576, K642, and D816), GNAQ (Q209), and GNA11 (Q209). Tumors with none of these mutations are termed "pan negative." We then mined the driver mutation-positive and pan-negative melanoma NGS data for mutations in 632 cancer genes that could influence existing or emerging targeted therapies. First, we uncovered several genes whose mutations were more likely associated with BRAF- or NRAS -driven melanomas, including TP53 and COL1A1 with BRAF, and PPP6C, KALRN, PIK3R4, TRPM6, GUCY2C, and PRKAA2 with NRAS. Second, we found that the 69 "pan-negative" melanoma genomes harbored alternate infrequent mutations in the five known driver genes along with many mutations in genes encoding guanine nucleotide binding protein a-subunits. Third, we identified 12 significantly mutated genes in "pan-negative" samples (ALK , STK31, DGKI, RAC1, EPHA4 , ADAMTS18, EPHA7, ERBB4, TAF1L, NF1, SYK, and KDR), including five genes (RAC1, ADAMTS18, EPHA7, TAF1L, and NF1) with a recurrent mutation in at least two "pan-negative" tumor samples. This meta-analysis provides a road map for the study of additional potentially actionable genes in both driver mutation-positive and pan-negative melanomas.
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U2 - 10.1158/1535-7163.MCT-13-0804
DO - 10.1158/1535-7163.MCT-13-0804
M3 - Article
C2 - 24755198
AN - SCOPUS:84904152952
SN - 1535-7163
VL - 13
SP - 1918
EP - 1928
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 7
ER -