RESUMO
The gene ST7 has recently been implicated as the broad-range tumor suppressor on human chromosome 7q31.1. We did not detect somatic mutations in ST7 in any of 149 primary ovarian, breast or colon carcinomas. These data suggest that epigenetic downregulation or haploinsufficiency, rather than somatic genetic alterations, may be the primary mechanism of abrogation of ST7 function in these tumor types.
Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 7 , Genes Supressores de Tumor , Proteínas de Membrana/genética , Mutação , Neoplasias Ovarianas/genética , Neoplasias Colorretais , Feminino , HumanosRESUMO
Polymorphic variants of microsomal epoxide hydrolase (mEPHX) with altered enzyme activity have been associated with an increased risk for ovarian cancer. We assessed the frequency of exon 3 and exon 4 variants of mEPHX among 291 ovarian cancers and 257 controls from a UK-based population. The distribution of the exon 3 alleles among both the cancer and control groups was significantly different from that expected under Hardy-Weinberg equilibrium suggesting that the PCR restriction fragment length polymorphism (PCR-RFLP) genotyping assay might be flawed. The codon 113 polymorphism was reassessed using a two-color allele-specific PCR-based assay. We found that a codon 119 G>A polymorphism, present in 20% of the British population and linked to the wild-type exon 3 allele, resulted in some Tyr113/His113 heterozygotes being falsely classified as His113/His113 homozygotes when using the PCR-RFLP assay. Consequently, we reassessed all our codon 113 data using the new allele-specific assay. We found no evidence of an association of ovarian cancer risk with the exon 3 Tyr113>His113 variant. Similarly the frequencies of the exon 4 His139>Arg139 genotypes were not significantly different between cases and controls. Stratifying the genotyping data according to the predicted mEPHX activity revealed a highly significant decrease in high mEPHX activity among the serous ovarian cancers (P=0.01) suggesting that high mEPHX activity may be protective for this histological sub-type. Furthermore previous disease association studies of exon 3 alleles which utilized the PCR-RFLP assay may be compromised by the existence of a codon 119 G>A polymorphism which may be common in Caucasian populations.
Assuntos
Epóxido Hidrolases/genética , Microssomos/enzimologia , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/genética , Adenocarcinoma Mucinoso/enzimologia , Adenocarcinoma Mucinoso/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Endometrioide/enzimologia , Carcinoma Endometrioide/genética , Estudos de Casos e Controles , Cistadenocarcinoma Seroso/enzimologia , Cistadenocarcinoma Seroso/genética , Primers do DNA , Suscetibilidade a Doenças , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/enzimologia , Neoplasias Ovarianas/enzimologia , Reação em Cadeia da Polimerase , Polimorfismo Genético , Estudos RetrospectivosRESUMO
The production of estrogen from androgen via the estrogen biosynthesis pathway is catalyzed by aromatase P450 (cyp19). We have assessed the frequency of allelic variants of the CYP19 intron 4 [TTTA]n repeat in 327 breast cancer cases and 253 controls from southern England. Previous studies have suggested that the [TTTA](10) repeat and [TTTA](12) repeat variants represent low penetrance breast cancer susceptibility alleles. Compared with controls our breast cancer cases had a statistically significant positive association with the [TTTA](10) allele (1.5 versus 0.2%, P = 0.028) and the [TTTA](8) allele (13.5 versus 8.7%, P = 0.012). The frequency of the [TTTA](12) allele was not significantly elevated in our study group compared with controls (2.3 versus 2.2%, P = 1.00). The CYP19 intron 4 [TTTA]n repeat is unlikely to have a functional effect on aromatase activity and it is more likely that the [TTTA](8) and [TTTA](10) variants are in linkage disequilibrium with other functional CYP19 variants.