Importance of polymorphisms in NF-kappaB1 and NF-kappaBIalpha genes for melanoma risk, clinicopathological features and tumor progression in Swedish melanoma patients

Abstract

Purpose: Importance of polymorphisms in NF-kappaB1 and NF-kappaBIalpha genes for melanoma risk, clinicopathological features and tumor progression is analyzed in Swedish melanoma patients.

Patients and methods: Functional polymorphisms of NF-kappaB1 and NF-kappaBIalpha genes were examined in 185 melanoma patients and 438 tumor-free individuals. Associations of the polymorphisms with melanoma risk, age and pigment phenotypes of the patients and clinicopathological tumor characteristics were analyzed. DNAs were isolated from mononuclear cells of venous blood. Polymorphisms of the genes were genotyped by a PCR-RFLP technique, and transcription level of NF-kappaBIalpha was examined by a quantitative real-time reverse transcription PCR.

Results: Both ATTG insertion polymorphism of NF-kappaB1 and A to G polymorphism of NF-kappaBIalpha genes were correlated with melanoma risk, especially, in a combination of ATTG( 2 )/ATTGT(2) and GG. NF-kappaB1 ATTG(2)/ATTG(2) and NF-kappaBIalpha GG genotypes were associated with male gender and age >65 years (at diagnosis). Patients with ATTG(1)/ATTG(1 )genotype had thinner tumors and lower Clark levels at diagnosis. Frequency of ATTG(1)/ATTG(1) genotype was higher in patients with melanomas on intermittently sun-exposed pattern of the body and NF-kappaBIalpha GG was more frequent in the patients with melanomas at rarely exposed sites. There were no differences in the gene transcription level between patients with different NF-kappaBIalpha genotypes.

Conclusion: NF-kappaB1 and NF-kappaBIalpha genes might be susceptible genes for melanoma risk and functional polymorphisms of these genes might be biological predictors for melanoma progression.

Fig. 1

Age distribution of melanoma patients at diagnosis (n = 185), mean age 54 years (range 19–80)

Fig. 2

Genotypes of NF-κB1 in melanoma patients and tumor-free individuals by PCR-RFLP. Lane 1 100bp DNA ladder. Lanes 2 and 4 NF-κB1 WT ATTG₁/ATTG₁ genotype. Lane 3, 5 and 6 NF-κB1 heterozygote ATTG₁/ATTG₂ genotype. Lane 7 NF-κB1 polymorphic homozygote ATTG₂/ATTG₂ genotype, and lane 8 was negative control without DNA template added

Fig. 3

Genotypes of NF-κBIα in melanoma patients and tumor-free individuals by PCR-RFLP. Lane 1 100bp DNA ladder. Lane 2 NF-κBIα WT AA genotype. Lane 3 and 5 NF-κBIα heterozygote AG genotype. Lane 4 and 6 NF-κBIα polymorphic homozygote GG genotype, and lane 7 negative control without DNA template added