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Somatic alterations in the melanoma genome: A high‐resolution array‐based comparative genomic hybridization study
Author(s) -
Gast Andreas,
Scherer Dominique,
Chen Bowang,
Bloethner Sandra,
Melchert Stephanie,
Sucker Antje,
Hemminki Kari,
Schadendorf Dirk,
Kumar Rajiv
Publication year - 2010
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.20785
Subject(s) - cdkn2a , neuroblastoma ras viral oncogene homolog , biology , pten , comparative genomic hybridization , genetics , locus (genetics) , cancer research , somatic cell , gene , genome , mutation , kras , pi3k/akt/mtor pathway , apoptosis
Abstract We performed DNA microarray‐based comparative genomic hybridization to identify somatic alterations specific to melanoma genome in 60 human cell lines from metastasized melanoma and from 44 corresponding peripheral blood mononuclear cells. Our data showed gross but nonrandom somatic changes specific to the tumor genome. Although the CDKN2A (78%) and PTEN (70%) loci were the major targets of mono‐allelic and bi‐allelic deletions, amplifications affected loci with BRAF (53%) and NRAS (12%) as well as EGFR (52%), MITF (40%), NOTCH2 (35%), CCND1 (18%), MDM2 (18%), CCNE1 (10%), and CDK4 (8%). The amplified loci carried additional genes, many of which could potentially play a role in melanoma. Distinct patterns of copy number changes showed that alterations in CDKN2A tended to be more clustered in cell lines with mutations in the BRAF and NRAS genes; the PTEN locus was targeted mainly in conjunction with BRAF mutations. Amplification of CCND1 , CDK4 , and other loci was significantly increased in cell lines without BRAF‐NRAS mutations and so was the loss of chromosome arms 13q and 16q. Our data suggest involvement of distinct genetic pathways that are driven either through oncogenic BRAF and NRAS mutations complemented by aberrations in the CDKN2A and PTEN genes or involve amplification of oncogenic genomic loci and loss of 13q and 16q. It also emerges that each tumor besides being affected by major and most common somatic genetic alterations also acquires additional genetic alterations that could be crucial in determining response to small molecular inhibitors that are being currently pursued. © 2010 Wiley‐Liss, Inc.