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The identification of patient‐specific mutations reveals dual pathway activation in most patients with melanoma and activated receptor tyrosine kinases in BRAF/NRAS wild‐type melanomas
Author(s) -
Appenzeller Silke,
Gesierich Anja,
Thiem Alexander,
Hufnagel Anita,
Jessen Christina,
Kneitz Hermann,
Regensburger Martina,
Schmidt Cornelia,
Zirkenbach Vanessa,
Bischler Thorsten,
Schilling Bastian,
Siedel Claudia,
Goebeler MariaElisabeth,
Houben Roland,
Schrama David,
Gehrig Andrea,
Rost Simone,
Maurus Katja,
Bargou Ralf,
Rosenwald Andreas,
Schartl Manfred,
Goebeler Matthias,
Meierjohann Svenja
Publication year - 2019
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.31843
Subject(s) - neuroblastoma ras viral oncogene homolog , druggability , cancer research , receptor tyrosine kinase , melanoma , cancer , medicine , gene , germline mutation , copy number variation , mutation , targeted therapy , germline , kinase , genetics , biology , genome , kras
Background Increasing knowledge of cancer genomes has triggered the development of specific targeted inhibitors, thus providing a valuable therapeutic pool. Methods In this report, the authors analyze the presence of targetable alterations in 136 tumor samples from 92 patients with melanoma using a comprehensive approach based on targeted DNA sequencing and supported by RNA and protein analysis. Three topics of high clinical relevance are addressed: the identification of rare, activating alterations; the detection of patient‐specific, co‐occurring single nucleotide variants (SNVs) and copy number variations (CNVs) in parallel pathways; and the presence of cancer‐relevant germline mutations. Results The analysis of patient‐matched blood and tumor samples was done with a custom‐designed gene panel that was enriched for genes from clinically targetable pathways. To detect alterations with high therapeutic relevance for patients with unknown driver mutations, genes that are untypical for melanoma also were included. Among all patients, CNVs were identified in one‐third of samples and contained amplifications of druggable kinases, such as CDK4, ERBB2, and KIT. Considering SNVs and CNVs, 60% of patients with metastases exhibited co‐occurring activations of at least 2 pathways, thus providing a rationale for individualized combination therapies. Unexpectedly, 9% of patients carry potentially protumorigenic germline mutations frequently affecting receptor tyrosine kinases. Remarkably two‐thirds of BRAF/NRAS wild‐type melanomas harbor activating mutations or CNVs in receptor tyrosine kinases. Conclusions The results indicate that the integrated analysis of SNVs, CNVs, and germline mutations reveals new druggable targets for combination tumor therapy.