A microsatellite polymorphism in the heme oxygenase‐1 gene promoter is associated with risk for melanoma

Abstract

Heme oxygenase-1 (HO-1) has been demonstrated to play an important role in the regulation of signaling systems, which are involved in the control of cell cycle progression and apoptosis. Recently, a (GT)n dinucleotide repeat polymorphism in the HO-1 promoter was shown to modulate HO-1 gene expression. Short (<25 GT) repeats are associated with an increased HO-1 upregulation after stimulation than are longer repeats. Malignant melanoma (MM) is the most serious cutaneous malignancy with high tendency to aggressive growth and resistance to apoptosis. Therefore, we sought to study the influence of this polymorphism on the progression of MM. We determined the HO-1 promoter genotype in 152 patients with MM and 398 healthy controls and studied their association in regard to susceptibility to MM, Breslow thickness and disease-free survival. In our study, the homozygous short allele with <25 (GT)n repeats (S/S) was found more frequently in the melanoma group compared to the healthy control population (21 and 12%, respectively). The calculated risk for acquiring primary MM in S/S carriers was 2-fold higher compared to those with L-allele types (95% confidence interval: 1.2-2.4, p 5 0.03). Additionally, the S/S genotype was significantly associated with primary tumors with deeper Breslow thickness compared to L-allele (>25 repeats) carriers (mean Breslow thickness: 4.0 6 2.9 mm versus 3.1 6 1.7 mm, p 5 0.03). These data suggest that HO-1 might render a higher risk for MM in S/S genotype individuals and could represent an important candidate gene in the pathogenesis and growth of malignant melanoma. ' 2006 Wiley-Liss, Inc.

Genetic Variability in Iron-Related Oxidative Stress Pathways (Nrf2, NQ01, NOS3, andHO-1), Iron Intake, and Risk of Postmenopausal Breast Cancer

“…This may, in part, explain why individuals in the highest tertile of iron consumption carrying two short HO-1 alleles were found to be at nonsignificantly elevated risk of breast cancer compared with LL individuals. In support of this, homozygous carriers of short repeats have been found to be at greater risk of malignant melanoma compared with L and M allele carriers (102).…”

Overexpression of Heme Oxygenase-1 in Murine Melanoma

“…Analysis of HO-1 promoter polymorphism in healthy people and cancer patients indicates that the risk of acquiring and more serious progression of malignant melanoma is significantly higher in people harboring a shorter (GT)n repeats sequence, associated with a higher HO-1 activity. 65 It must be stressed, however, that effects of HO-1 activation may be different in the case of tumor induction compared with tumor progression. Two clinical trials analyzing the frequency of tumor development (oral squamous cell carcinoma in betel chewers and lung adenocarcinoma in cigarette smokers) have suggested that high expression of HO-1 may be beneficial for patients and may decrease the incidence of carcinogenesis.…”

Role of the CDKN1A/p21, CDKN1C/p57, and CDKN2A/p16 Genes in the Risk of Atherosclerosis and Myocardial Infarction

“…GT-dinucleotide repeats in the promoters of several genes have been associated with the risk of suffering breast cancer, schizophrenia, melanoma, and atherosclerosis, among other diseases. [27][28][29][30][31] Microsatellite polymorphisms in the promoter of the heme oxygenase-1 and matrix metalloproteinase-9 genes have been associated with angiographic restenosis after coronary stenting and the progression of intima-media thickening and constrictive remodeling of carotid atherosclerotic plaques, respectively. 30,31 (GT)n repeat is one of the most frequent variation in the human genome and, when located in a promoter region, may affect transcriptional activity.…”