Distinct sets of genetic alterations in melanoma.
BACKGROUND
Exposure to ultraviolet light is a major causative factor in melanoma, although the relationship between risk and exposure is complex. We hypothesized that the clinical heterogeneity is explained by genetically distinct types of melanoma with different susceptibility to ultraviolet light.


METHODS
We compared genome-wide alterations in the number of copies of DNA and mutational status of BRAF and N-RAS in 126 melanomas from four groups in which the degree of exposure to ultraviolet light differs: 30 melanomas from skin with chronic sun-induced damage and 40 melanomas from skin without such damage; 36 melanomas from palms, soles, and subungual (acral) sites; and 20 mucosal melanomas.


RESULTS
We found significant differences in the frequencies of regional changes in the number of copies of DNA and mutation frequencies in BRAF among the four groups of melanomas. Samples could be correctly classified into the four groups with 70 percent accuracy on the basis of the changes in the number of copies of genomic DNA. In two-way comparisons, melanomas arising on skin with signs of chronic sun-induced damage and skin without such signs could be correctly classified with 84 percent accuracy. Acral melanoma could be distinguished from mucosal melanoma with 89 percent accuracy. Eighty-one percent of melanomas on skin without chronic sun-induced damage had mutations in BRAF or N-RAS; the majority of melanomas in the other groups had mutations in neither gene. Melanomas with wild-type BRAF or N-RAS frequently had increases in the number of copies of the genes for cyclin-dependent kinase 4 (CDK4) and cyclin D1 (CCND1), downstream components of the RAS-BRAF pathway.


CONCLUSIONS
The genetic alterations identified in melanomas at different sites and with different levels of sun exposure indicate that there are distinct genetic pathways in the development of melanoma and implicate CDK4 and CCND1 as independent oncogenes in melanomas without mutations in BRAF or N-RAS.
Curtin
John A
JA
Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143-0808, USA.
Fridlyand
Jane
J
Kageshita
Toshiro
T
Patel
Hetal N
HN
Busam
Klaus J
KJ
Kutzner
Heinz
H
Cho
Kwang-Hyun
KH
Aiba
Setsuya
S
Bröcker
Eva-Bettina
EB
LeBoit
Philip E
PE
Pinkel
Dan
D
Bastian
Boris C
BC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019938:Cyclin D1 / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D004273:DNA, Neoplasm / Q000032:analysis*; D004781:Environmental Exposure / Q000009:adverse effects; D005260:Female; D011905:Genes, ras; D015894:Genome, Human; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009693:Nucleic Acid Hybridization; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012307:Risk Factors; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects
D004273:DNA, Neoplasm; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; D048493:Proto-Oncogene Proteins B-raf; D051358:Cyclin-Dependent Kinase 4; D020928:Mitogen-Activated Protein Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human