Association between functional polymorphism in EGF 61 G/A gene and malignant melanoma
ABSTRACT Malignant melanoma, the most serious cutaneous malignancy, has attracted substantial attention because of its rapidly increasing incidence and the poor prognosis of some tumours. Little is known of the genetic factors that mediate susceptibility to, and outcome of, sporadic malignant melanoma. Because of its role in mitogenesis, which is especially relevant to wound healing, tumorigenesis, and proliferation of epidermal tissues, epidermal growth factor (EGF) is an attractive candidate in which to look for genetic polymorphisms.
We enrolled 135 white European patients with malignant melanoma and 99 healthy white European controls, and screened a selection of DNA samples for polymorphisms in the promoter and 5' untranslated region of the EGF gene by analysis. We then screened DNA samples from all participants for the identified polymorphism by restriction-fragment-length polymorphism (RFLP) analysis. In-vitro EGF production was measured in peripheral-blood mononuclear cells from 34 controls, and the results were compared with the individuals' EGF genotypes.
We identified a single nucleotide substitution (G to A) at position 61 of the EGF gene. Allele frequencies in the controls were 56% EGF 61*A and 44% EGF 61*G. Cells from individuals homozygous for the 61*A allele produced significantly less EGF than cells from 61*G homozygotes (p=0.0004) or heterozygous A/G individuals (p=0.001). Compared with the A/A genotype, G/G was significantly associated with Breslow thickness (p=0.045) and with risk of malignant melanoma (odds ratio 4.9 [95% CI 2.3-10.2], p<0.0001).
This study suggests that high EGF production might be important in the development of malignant melanoma.
- SourceAvailable from: Steven Errington
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- "A previous analysis from northern England has shown that a marked rise in incidence was confined to females (Magnanti et al., 2008). It is well known that both genetic susceptibility and exposure to UVR are key factors in etiology (Cockburn et al., 2001; Wachsmuth et al., 2001; Shahbazi et al., 2002; El Ghissassi et al., 2009). The finding of a seasonal association between time of birth and risk of subsequently developing melanoma suggests that early life exposures may be implicated (Basta et al., 2011). "
ABSTRACT: Previous studies have found marked increases in melanoma incidence. The increase amongst young people in northern England was especially apparent amongst females. However, overall five-year survival has greatly improved. The present study aimed to determine if socio-economic factors may be involved in both etiology and survival. All 224 cases of malignant melanoma diagnosed in patients aged 10-24 years during 1968-2003 were extracted from a specialist population-based regional registry. Negative binomial regression was used to examine the relationship between incidence and area-based measures of socio-economic deprivation and small-area population density. Cox regression was used to analyse the relationship between survival and deprivation and population density. There was significantly decreased risk associated with living in areas of higher unemployment (relative risk per 1% increase in unemployment=0.93; 95% confidence interval [CI] 0.90-0.96, P<0.001). Survival was better in less deprived areas (hazard ratio [HR] per tertile of household overcrowding=1.52; 95% CI 1.05 to 2.20; P=0.026) but this effect was reduced in the period 1986-2003 (HR=0.61; 95% CI 0.40 to 0.92; P=0.018). This study found that increased risk of melanoma was linked with some aspect of greater affluence. In contrast, worse survival was associated with living in a more deprived area.Journal of Investigative Dermatology accepted article preview online, 13 June 2014; doi:10.1038/jid.2014.246.Journal of Investigative Dermatology 06/2014; 134(11). DOI:10.1038/jid.2014.246 · 6.37 Impact Factor
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- "Genomic DNA was extracted from 10 ml peripheral whole blood by a standard protocol, with some modifications . Briefly, red blood cells were lysed three times with a buffer containing ammonium chloride, potassium dihydrogen phosphate, and disodium hydrogen phosphates. "
ABSTRACT: Multiple sclerosis is a multifactorial disorder with complex genetic basis. It is believed that genes encoding HLA molecule and cytokines are involved in the pathogenesis of MS. In this study, we have evaluated the impact of HLA-DRB1*1501 allele and TNF-alpha -308 G/A single nucleotide polymorphism, and their interaction, in the susceptibility to MS in Iranian population. Genomic DNA samples were prepared from whole blood of 366 MS Patients and 414 control subjects. The genotypes were determined by SSP-PCR method. Frequency of alleles and genotypes were compared between the two groups by using Fisher's exact test. HLA-DRB1*1501 allele was more frequent among patients (OR=1.57, P=0.0026). TNF-α -308 G allele and G/G genotype had higher frequency among MS patients than control subjects (G vs. A: OR=1.26, P<0.05); G/G vs. A/A: OR=4.59, P=0.0003). The odds ratio was higher among HLA-DRB1*1501 positive individuals. Co-existence of TNF G and HLA-DRB1*1501 alleles showed higher prevalence among MS patients (OR=7.07, P=0.0007). Our results have shown that HLA-DRB1*1501 allele and TNF-α -308 G/A polymorphism are associated with the risk of multiple sclerosis in Iranian population. We also observed an interaction between these two loci that support the role of HLA alleles and cytokine genes and gene-gene interaction in the development and pathogenesis of MS.Clinical Immunology 02/2011; 139(3):277-81. DOI:10.1016/j.clim.2011.02.012 · 3.99 Impact Factor
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- "Genomic DNA was extracted from 10 ml of peripheral whole blood by a standard protocol with some modifications . Briefly, red blood cells were lysed three times with a buffer containing ammonium chloride, potassium dihydrogen phosphate and disodium hydrogen phosphates. "
ABSTRACT: We have evaluated the role of the HLA-DRB1*1501 allele and the IL-2 -330 T/G polymorphism and their interaction in susceptibility to multiple sclerosis on 360 patients and 426 matched healthy individuals. We used the SSP-PCR method to determine the alleles. Fisher's exact test was used to analyses. We observed a significant increase in the T allele at IL-2 -330 position in patients (OR=1.34, P<0.05), and the T/T and T/G genotypes were more frequent among patients than controls. The HLA-DRB1*1501 allele was overrepresented in patients as compared to the control group (OR=1.7, P=0.0006). The two-locus analysis of the interaction between the IL-2 promoter polymorphism and the HLA-DRB1 allele showed that the HLA-DRB1*1501/T haplotype was more frequent in patients than controls (OR=16, P<0.0001). Our findings support previous findings about the role of the HLA-DRB1*1501 allele in susceptibility to MS. This work also provides new findings about the importance of gene-gene interactions in the development of MS.Clinical Immunology 10/2010; 137(1):134-8. DOI:10.1016/j.clim.2010.05.010 · 3.99 Impact Factor