Effect of DNA repair host factors on temozolomide or dacarbazine melanoma treatment in Caucasians.
OBJECTIVE
The efficacy of temozolomide (TMZ) or dacarbazine (DTIC) in melanoma treatment depends on low O-6-methylguanine-DNA-methyltransferase (MGMT) repair and on high mismatch repair. The aim of this study was to identify individual host markers for hematologic side effects and the treatment efficacy of TMZ or DTIC in melanoma treatment.


METHODS
Fifty-one Caucasian patients with metastasized melanoma were recruited. In each patient, the mRNA expression of MGMT and two essential mismatch repair genes, MLH1 and MSH2, was measured in peripheral blood. The coding gene regions, including splice sites, were sequenced to identify genetic variants, and the promoter methylation status of the genes was determined.


RESULTS
Both constitutively low and high mRNA expression of MGMT, MLH1, and MSH2 were significantly associated with reduced hematologic side effects (P = 0.008-0.020), but did not correlate with treatment efficacy. We identified five variants in the MGMT gene, 13 variants in MLH1, and seven variants in MSH2, including five novel genetic variants in MLH1. Variations of the hosts' gene expression of MGMT, MLH1, and MSH2 did not result from promoter methylation. Of note, one variant in MSH2 (rs2303428) was associated with increased hematologic side effects and showed a tendency for better treatment response.


CONCLUSIONS
Our results indicate that either low or high host expression of MGMT, MLH1, and MSH2 may serve as a marker for reduced hematologic side effects of TMZ or DTIC, but not for treatment efficacy in melanoma. The genetic variant rs2303428 (MSH2) might serve as a predictive marker for hematologic side effects and treatment response.
Boeckmann
Lars
L
Department of Dermatology, Georg-August-University Goettingen, Germany. semmert@gwdg.de
Schirmer
Markus
M
Rosenberger
Albert
A
Struever
Diana
D
Thoms
Kai-Martin
KM
Gutzmer
Ralf
R
Has
Cristina
C
Kunz
Manfred
M
Kuschal
Christiane
C
Laspe
Petra
P
Schoen
Michael P
MP
Brockmoeller
Juergen
J
Emmert
Steffen
S
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D004260:DNA Repair / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics / Q000378:metabolism; D000077204:Temozolomide; D014407:Tumor Cells, Cultured; D044465:White People / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D018906:Antineoplastic Agents, Alkylating; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D000077204:Temozolomide