RESUMO
Xeroderma pigmentosum is a rare autosomal recessive disease that is associated with a severe deficiency in nucleotide excision repair. The presence of a distinct the nucleotide excision repair (NER) mutation signature in melanoma suggests that perturbations in this critical repair process are likely to be involved with disease risk. We hypothesized that persons with polymorphic NER gene(s) are likely to have reduced NER activity and are consequently at an increased risk of melanoma development. We assessed the association between 94 SNPs within seven XP genes (XPA-XPG) and the melanoma risk in the Polish population. We genotyped 714 unselected melanoma patients and 1,841 healthy adults to determine if there were any polymorphisms differentially represented in the disease group. We found that a significantly decreased risk of melanoma was associated with the Xeroderma pigmentosum complementation (XPC) rs2228000_CT genotype (odds ratio [OR] = 0.15; p < 0.001) and the rs2228000_TT genotype (OR = 0.11; p < 0.001) compared to the reference genotype. Haplotype analysis within XPC revealed the rs2228001_A + G1475A_G + G2061A_A + rs2228000_T + rs3731062_C haplotype (OR = 0.26; p < 0.05) was associated with a significantly decreased disease risk. The haplotype analysis within the Xeroderma pigmentosum group D (XPD) showed a modest association between two haplotypes and a decrease in melanoma risk. There were no major differences between the prevalence of the XP polymorphisms among young or older patients with melanoma. Linkage disequilibrium of XPC: rs2228001, G1475A, G2061A, rs2228000 and rs3731062 was found. The data from our study support the notion that only XPC and XPD genes are associated with melanoma susceptibility.
Assuntos
Proteínas de Ligação a DNA/genética , Melanoma/genética , Proteína Grupo D do Xeroderma Pigmentoso/genética , Xeroderma Pigmentoso/genética , Idoso , Reparo do DNA , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , RiscoRESUMO
BACKGROUND: There is continuing interest in identifying low-penetrance genes which are associated with an increased susceptibility to common types of cancer, including malignant melanoma. METHODS: We sought to examine the association between four VDR common variants (rs1544410, rs731236, rs10735810, rs4516035) and the risk of melanoma in the Polish population. We also determined the prevalence of compound carriers of VDR and known MM genetic risk factors MC1R and CDKN2A (A148T) variants. We examined 763 unselected melanoma cases, 763 healthy adults matched for sex and age with the melanoma cases and 777 newborns. RESULTS: None of the VDR variants alone or as compound carriers of two or more of the VDR genotypes were associated with MM risk. There were no major differences between the prevalences of the examined variants among patients with MM on UV-exposed and UV-non exposed skin areas, as well as among early-onset and late-onset cases. We found no association between VDR and MC1R or between VDR and CDKN2A common variants. A statistically significant over-representation of one VDR haplotype: rs731236_A+rs1544410_T (OR=3.2, p=0.02) was detected. Linkage disequilibrium of rs1544410 and rs731236 was confirmed. CONCLUSION: To answer the question, whether VDR can be regarded as melanoma susceptibility gene, additional, large multi-center association studies have to be performed.
Assuntos
Melanoma/epidemiologia , Melanoma/genética , Receptores de Calcitriol/genética , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/genética , Adulto , Estudos de Casos e Controles , Inibidor p16 de Quinase Dependente de Ciclina/genética , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos/genética , Humanos , Recém-Nascido , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polônia/epidemiologia , Prognóstico , Receptor Tipo 1 de Melanocortina/genética , Fatores de RiscoRESUMO
In the current study, we evaluated the possible associations of seven common variants of the DNA repair and cell cycle control genes BRCA2 and CHEK2 with malignant melanoma (MM). We genotyped 630 unselected MM patients and over 3700 controls (newborns, age- and sex-matched healthy adults with negative cancer family histories, and the adults selected at random by family doctors) for the prevalence of three common variants of the BRCA2 (T1915M, N991D and N372H) and four common variants of the CHEK2 (1100delC, VS2+1G --> A, I157T and del5395). Our study strongly suggests that the common variant of the BRCA2 gene -- the N991D variant is associated with malignant melanoma risk (OR=1.8, p=0.002 after Bonferroni correction). Patients homozygote for the N991D variant were present in 0.32% of cases and only 0.13% of controls. The other variants studied were not over-represented among MM patients when compared to the general population. In conclusion, we report an increased melanoma risk among carriers of the N991D change of the BRCA2 and no association of the CHEK2 changes with malignant melanoma.
Assuntos
Reparo do DNA/genética , Genes BRCA2 , Predisposição Genética para Doença/genética , Melanoma/genética , Proteínas Serina-Treonina Quinases/genética , Neoplasias Cutâneas/genética , Estudos de Casos e Controles , Quinase do Ponto de Checagem 2 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Reação em Cadeia da Polimerase/métodosRESUMO
There are suggestions in the literature that common variants in the XPD gene may be associated with an altered risk of melanoma and breast cancer. To establish if the XPD common variants Asp312Asn and Lys751Gln are associated with an increased melanoma or breast cancer risk we performed an association study based on genotyping 426 unselected patients with malignant melanoma (MM) and 1830 consecutive breast cancer cases and compared the results to 1262 geographically matched newborns, 621 adults from the region of Szczecin (unselected for age and cancer family history), 421 healthy adults age- and sex-matched with the melanoma cases and 511 healthy controls matched with the breast cancer patients from the region of Szczecin. Additionally we examined the prevalence of three additional XPD variants, Gly156Gly, Leu485Pro and Arg112His amongst the 421 unselected melanoma patients. All of the variants when evaluated singularly were found not to be associated either with melanoma or breast cancer risk in younger or older patients. A modest association was observed with breast cancer risk when the Lys751Gln_CC/Asp312Asn_AA genotype (OR=1.5, p<0.05) segregated together. Individuals harboring the Lys751Gln_CC/Gly156Gly_CC genotype were significantly over-represented among late-onset melanoma cases (OR=1.7, p<0.05). The results of analyses of linkage disequilibrium and haplotype frequency support the thesis that a combination of at least two SNPs (Lys751Gln_CC/Gly156Gly_CC or Lys751Gln_CC/Asp312Asn_AA) inherited as a haplotype was associated with disease. These two pairs of SNPs could therefore be regarded as a single hereditary unit that would have a very small probability of being disrupted by recombination. Additional studies are required to determine whether these particular changes can be associated with an increased risk of other malignancies at different sites of origin.
Assuntos
Neoplasias da Mama/genética , Melanoma/genética , Proteína Grupo D do Xeroderma Pigmentoso/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/etiologia , Feminino , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Melanoma/etiologia , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RiscoRESUMO
An intra-neural haemangioma of the digital nerve of the left index finger is described, the first report of such a lesion in a digit. Treatment consisted of excision of the tumour and the affected portion of the nerve, followed by direct coaptation of the nerve ends.
