%0 Journal Article %1 appenzeller_identification_2019 %A Appenzeller, Silke %A Gesierich, Anja %A Thiem, Alexander %A Hufnagel, Anita %A Jessen, Christina %A Kneitz, Hermann %A Regensburger, Martina %A Schmidt, Cornelia %A Zirkenbach, Vanessa %A Bischler, Thorsten %A Schilling, Bastian %A Siedel, Claudia %A Goebeler, Maria-Elisabeth %A Houben, Roland %A Schrama, David %A Gehrig, Andrea %A Rost, Simone %A Maurus, Katja %A Bargou, Ralf %A Rosenwald, Andreas %A Schartl, Manfred %A Goebeler, Matthias %A Meierjohann, Svenja %D 2019 %J Cancer %K melanoma oncogene precision_oncology therapy tumor_suppressor %N 4 %P 586--600 %R 10.1002/cncr.31843 %T 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 %U https://onlinelibrary.wiley.com/doi/abs/10.1002/cncr.31843 %V 125 %X 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.

@article{appenzeller_identification_2019, abstract = {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.}, added-at = {2019-10-23T15:12:39.000+0200}, author = {Appenzeller, Silke and Gesierich, Anja and Thiem, Alexander and Hufnagel, Anita and Jessen, Christina and Kneitz, Hermann and Regensburger, Martina and Schmidt, Cornelia and Zirkenbach, Vanessa and Bischler, Thorsten and Schilling, Bastian and Siedel, Claudia and Goebeler, Maria-Elisabeth and Houben, Roland and Schrama, David and Gehrig, Andrea and Rost, Simone and Maurus, Katja and Bargou, Ralf and Rosenwald, Andreas and Schartl, Manfred and Goebeler, Matthias and Meierjohann, Svenja}, biburl = {https://www.bibsonomy.org/bibtex/2fa12db95e1f375732aa140bd8ed1e5f2/cusysmed}, copyright = {© 2018 American Cancer Society}, day = 15, doi = {10.1002/cncr.31843}, file = {Full Text PDF:/home/thorsten/Zotero/storage/HPBUBFIZ/Appenzeller et al. - 2019 - The identification of patient-specific mutations r.pdf:application/pdf}, interhash = {434b565a13eb024b76198811112325cb}, intrahash = {fa12db95e1f375732aa140bd8ed1e5f2}, issn = {1097-0142}, journal = {Cancer}, keywords = {melanoma oncogene precision_oncology therapy tumor_suppressor}, language = {en}, month = {February}, number = 4, pages = {586--600}, timestamp = {2019-10-24T14:51:54.000+0200}, title = {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}, url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/cncr.31843}, urldate = {2019-05-15}, volume = 125, year = 2019 }