RESUMO
Polymorphisms in genes involved in steroidogenesis as well as sensitivity to insulin as potential cancer risk factors have received constantly-growing attention over this decade. The peculiarities of endocrine and metabolic features of cancer identified earlier in BRCA1 mutation carriers prompted an investigation of the frequency of polymorphisms in the genes of IRS-1 and enzymes of estrogen biosynthesis and metabolism, such as aromatase (CYP19), estrogen 4-hydroxylase and catechol-O-methyl transferase (COMT) in 12 BRCA1 mutation carriers and in 22 non-carriers. The results were compared with the earlier data from the patients with the same diagnosis (n = 110 and n = 295, respectively) but untested for BRCA1 mutation. BRCA1 mutation carriers tended to show increasing fractions of heterozygotes for AG (COMT Vall58Met p = 0.24) and active allele A6 featuring 11 TTTA repeats in the 4-th introne [corrected] of CYP19 gene (p 0.09). [corrected] The frequency of co-occurring CC (CYP1B1) Arg48Gly), AG (COMT Vall58Met ) and A6 (CYP19) in BRCA1 mutation carriers (5 out of 12, 41.6% ) was significantly higher than that in non-carriers (2 out of 22, 9.1% ) (p = 0.03). Immunohistochemical assay showed aromatase expression levels to be the highest among cases of BRCA1 mutation and A6 (CYP19) while CYP1B1 expression was the highest in those of combination of BRCA1 mutation and low-activity AA genotype (COMT Vall58Mer). Our results warrant further large-scale cooperative studies of the problem.
Assuntos
Neoplasias da Mama/genética , Estrogênios/metabolismo , Genes BRCA1 , Proteínas Substratos do Receptor de Insulina/genética , Mutação , Polimorfismo de Nucleotídeo Único , Adulto , Aromatase/genética , Hidrocarboneto de Aril Hidroxilases/genética , Neoplasias da Mama/metabolismo , Catecol O-Metiltransferase/genética , Citocromo P-450 CYP1B1 , Sistema Enzimático do Citocromo P-450/genética , Estrogênios/biossíntese , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Heterozigoto , Humanos , Pessoa de Meia-IdadeRESUMO
Glucose intolerance and insulin resistance belong to the group of leading risk factors for breast (BC) and endometrial cancer (EC). Differences in the intensity of association of these endocrine disturbances with BC and EC may at least partly be explained by non-identity in polygenic nature of the mentioned hormone-metabolic shifts and oncological diseases themselves as well. In this study, which included 105 healthy postmenopausal women and 301 female cancer patients (110 BC and 191 EC) without overt diabetes mellitus, we compared the frequency of the following genetic polymorphisms: insulin receptor substrate-1, IRS Gly972Arg; leptin receptor, LEPR Lys109Arg and Gln223Arg; mitochondrial uncoupling protein-2, UCP2_866G/A; and gene ND3 of mitochondrial DNA, mtDNA 10398A/G. Genotyping was performed with allele-specific real-time PCR. According to data received, certain genetic markers associated with impaired glucose tolerance and/or insulin resistance (namely, leptin receptor genotypes 223 Gln/Arg and Gln/Gln) are revealed in oncological patients more often than in females without cancer. Other markers (like genotype UCP2 866AA and polymorphism mtDNA 10398A) appeared to be relatively more frequent in EC than in BC providing one of the interpretations for the lower insulin sensitivity and higher incidence of carbohydrate metabolism disturbances in the first of these two diseases.
Assuntos
Neoplasias da Mama/genética , Metabolismo dos Carboidratos/genética , Neoplasias do Endométrio/genética , Intolerância à Glucose/genética , Resistência à Insulina/genética , Metabolismo dos Lipídeos/genética , Polimorfismo Genético , Adulto , Idoso , DNA Mitocondrial/genética , Complexo I de Transporte de Elétrons/genética , Feminino , Marcadores Genéticos/genética , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Canais Iônicos/genética , Pessoa de Meia-Idade , Proteínas Mitocondriais/genética , Receptores para Leptina/genética , Proteína Desacopladora 2RESUMO
The genetic polymorphism of metabolizers of tobacco smoke carcinogens can influence individual susceptibility to lung cancer. The study was concerned with the Mspl-polymorphism of the CYP1A1 gene responsible for encoding aryl hydrocarbon hydroxylase. It also plays a role in the activation of polycyclic aromatic hydrocarbons (PAH). The CYP1A1 alleles and genotype distribution in 146 lung cancer patients was compared with that in 230 healthy donors. Another control group consisted of 259 "cancer-resistant" subjects, i.e. tumor-free smokers and non-smokers aged 75 and more. The CYP1A1 allele incidence (19%) in patients with squamous lung cancer was significantly higher than in the control cohorts (11%) which is consistent with the leading role of PAH in the etiology of this pathology.