Association between functional polymorphism in EGF 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[Show abstract] [Hide abstract]
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
- [Show abstract] [Hide abstract]
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
- [Show abstract] [Hide abstract]
ABSTRACT: The monoclonal antibodies cetuximab and panitumumab, directed against the epidermal growth factor receptor (EGFR), are licensed for the treatment of KRAS wild-type metastatic colorectal cancer (mCRC). Such 'molecular restriction' derived from post-hoc analyses of randomized trials and from other retrospective series all indicate how tumors bearing KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutations are resistant to EGFR inhibition. Even if highly sensitive for nonresponse, KRAS testing is not very specific. In fact, a limited but still considerable proportion of KRAS wild-type patients rapidly progress on treatment with an EGFR inhibitor. New potential molecular determinants of benefit from such treatment are under investigation and may further refine the selection of patients. Pharmacogenomic analyses and translational studies are also ongoing for exploring the field of acquired resistance to anti-EGFRs, since all patients eventually progress. New biological data are awaited for optimizing the use of molecular agents in colorectal cancer and for identifying promising targets that could allow to better understand and, potentially, overcome mechanisms of primary or secondary resistance to EGFR inhibitors.rapeutic Advances in Medical Oncology, The 11/2009; 1(3):167-81. DOI:10.1177/1758834009348984