Patterns of expression of DNA repair genes and relapse from melanoma.
OBJECTIVE
To use gene expression profiling of formalin-fixed primary melanoma samples to detect expression patterns that are predictive of relapse and response to chemotherapy.


METHODS
Gene expression profiles were identified in samples from two studies (472 tumors). Gene expression data for 502 cancer-related genes from these studies were combined for analysis.


RESULTS
Increased expression of DNA repair genes most strongly predicted relapse and was associated with thicker tumors. Increased expression of RAD51 was the most predictive of relapse-free survival in unadjusted analysis (hazard ratio, 2.98; P = 8.80 × 10(-6)). RAD52 (hazard ratio, 4.73; P = 0.0004) and TOP2A (hazard ratio, 3.06; P = 0.009) were independent predictors of relapse-free survival in multivariable analysis. These associations persisted when the analysis was further adjusted for demographic and histologic features of prognostic importance (RAD52 P = 0.01; TOP2A P = 0.02). Using principal component analysis, expression of DNA repair genes was summarized into one variable. Genes whose expression correlated with this variable were predominantly associated with the cell cycle and DNA repair. In 42 patients treated with chemotherapy, DNA repair gene expression was greater in tumors from patients who progressed on treatment. Further data supportive of a role for increased expression of DNA repair genes as predictive biomarkers are reported, which were generated using multiplex PCR.


CONCLUSIONS
Overexpression of DNA repair genes (predominantly those involved in double-strand break repair) was associated with relapse. These data support the hypothesis that melanoma progression requires maintenance of genetic stability and give insight into mechanisms of melanoma drug resistance and potential therapies.
Jewell
Rosalyn
R
Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, United Kingdom. r.a.jewell@leeds.ac.uk
Conway
Caroline
C
Mitra
Angana
A
Randerson-Moor
Juliette
J
Lobo
Samira
S
Nsengimana
Jérémie
J
Harland
Mark
M
Marples
Maria
M
Edward
Sara
S
Cook
Martin
M
Powell
Barry
B
Boon
Andy
A
de Kort
Floor
F
Parker
Katharine A
KA
Cree
Ian A
IA
Barrett
Jennifer H
JH
Knowles
Margaret A
MA
Bishop
D Timothy
DT
Newton-Bishop
Julia
J
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000378:metabolism; D015331:Cohort Studies; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D012008:Recurrence; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology
D054316:Biomarkers, Pharmacological; D045643:DNA Repair Enzymes