The role of GSTA2 polymorphisms and haplotypes in breast cancer susceptibility: A case-control study in the Portuguese population

We wish to thank Luisa Manso Oliveira, Lylliane Luz, Silvia Morgado Amaro and Maria Catarina Soveral for technical support. Center for Research in Human Molecular Genetics (CIGMH), Projects POCTI/QUI/57110/2004 from Fundacao da Ciencia e Tecnologia (FCT) and Fundacao Calouste Gulbenkian (Grant 69405) support our current research. The PhD grant SFRH/BD/17828/2004 from FCT is also acknowledged.Glutathione-S-transferases (GSTs) are a superfamily of phase II metabolizing enzymes that catalyse the detoxification of a large range of endogenous and exogenous toxic compounds, playing an important role in protecting cells against damage, through glutathione conjugation with electrophilic substances. Polymorphic variation in these enzymes that affect its activity seems to be related to individual susceptibility to various human diseases, including cancer. Of the GST super-family, the alpha class GSTs have commonly been described as one of the most versatile class, since it is responsible for detoxification of compounds such as bilirubin, bile acids and penicillin, thyroid and steroid hormones, allowing its solubilization and storage in the liver. Among the alpha class, GSTA1 and GSTA2 isoforms are the most widely expressed in human tissues. Additionally, these enzymes can catalyse conjugation of the nitrogen mustard group of alkylating anticancer drugs, some heterocyclic amines and alpha,beta-unsaturated aldehydes. Since some risk factors for increased breast cancer risk could be related to high production of reactive oxygen species during the metabolism of estrogens by catechol estrogens, or to the exposure to genotoxic compounds, and some of these toxic compounds are usually metabolized by GSTA2, we carried out a hospital based case-control study in a Caucasian Portuguese population (291 breast cancer patients without familiar history of breast cancer and 547 controls matched for age, sex and ethnicity) in order to evaluate the potential modifying role of three non-synonymous polymorphisms in the GSTA2 gene (P110S Ex 5+56C>T;, rs2234951; S112T Ex5+63G>C, rs2180314 and E210A Ex7+83A>C, rs6577) on the individual susceptibility to breast cancer. Our data show that the Studied polymorphisms are in strong linkage disequilibrium, but no association was observed between individual GSTA2 polymorphisms and haplotypes and individual susceptibility to breast cancer.publishersversionpublishe

Possible protective role of MnSOD gene polymorphism Val/Ala and Ala/Ala in women that never breast fed

Polymorphisms in genes encoding enzymes involved in estrogen metabolism are held to be candidates for associations with breast disease, since there is evidence that circulating estrogens are associated with breast cancer risk. In this study, we evaluated the frequency of different polymorphisms related with estrogen metabolism [ COMT Val158Met, CYP17 (5′UTR, T27C); HSD17β1 Gly313Ser and MnSOD Val16Ala] in a breast cancer resistant population, the Xavante Indians, and the frequencies were compared with the ones reported in other populations where breast cancer case-control studies dealing with these polymorphisms have been carried out. The data obtained showed that, apart from the MnSOD Val16Ala polymorphism where the frequency of the variant allele was much higher than that reported in other populations, all the others were within the range reported in other populations. Considering these data we carried out a case-control study in the Portuguese population (241 cases and 457 controls) in order to evaluate the potential role of this polymorphism in breast cancer susceptibility. The results obtained did not reveal a significant association between individual genotypes and breast cancer risk. However, when the population was stratified for breast feeding, it was observed that for the patients that never breast fed the presence of the variant allele (Ala) was marginally associated with a decreased risk for this pathology (adjusted OR: 0.575 (0.327-1.011). These data seem to suggest that individuals who never breast fed with MnSOD Val16Ala variant allele are at a lower risk for breast cancer, but larger studies are required to confirm these results.publishersversionpublishe

Association of common variants in mismatch repair genes and breast cancer susceptibility: a multigene study

<p>Abstract</p> <p>Background</p> <p>MMR is responsible for the repair of base-base mismatches and insertion/deletion loops. Besides this, MMR is also associated with an anti-recombination function, suppressing homologous recombination. Losses of heterozygosity and/or microsatellite instability have been detected in a large number of skin samples from breast cancer patients, suggesting a potential role of MMR in breast cancer susceptibility.</p> <p>Methods</p> <p>We carried out a hospital-based case-control study in a Caucasian Portuguese population (287 cases and 547 controls) to estimate the susceptibility to non-familial breast cancer associated with some polymorphisms in mismatch repair genes (<it>MSH3</it>, <it>MSH4</it>, <it>MSH6</it>, <it>MLH1</it>, <it>MLH3</it>, <it>PMS1 </it>and <it>MUTYH</it>).</p> <p>Results</p> <p>Using unconditional logistic regression we found that <it>MLH3 </it>(L844P, G>A) polymorphism GA (Leu/Pro) and AA (Pro/Pro) genotypes were associated with a decreased risk: OR = 0.65 (0.45-0.95) (p = 0.03) and OR = 0.62 (0.41-0.94) (p = 0.03), respectively.</p> <p>Analysis of two-way SNP interaction effects on breast cancer revealed two potential associations to breast cancer susceptibility: <it>MSH3 </it>Ala1045Thr/<it>MSH6 </it>Gly39Glu - AA/TC [OR = 0.43 (0.21-0.83), p = 0.01] associated with a decreased risk; and <it>MSH4 </it>Ala97Thr/<it>MLH3 </it>Leu844Pro - AG/AA [OR = 2.35 (1.23-4.49), p = 0.01], GG/AA [OR = 2.11 (1.12-3,98), p = 0.02], and GG/AG [adjusted OR = 1.88 (1.12-3.15), p = 0.02] all associated with an increased risk for breast cancer.</p> <p>Conclusion</p> <p>It is possible that some of these common variants in MMR genes contribute significantly to breast cancer susceptibility. However, further studies with a large sample size will be needed to support our results.</p

Leucocitose? Valores de Referência para os Leucócitos na Primeira Infância

Contexto: Os valores do leucograma são frequentemente tidos em conta na decisão diagnóstica e terapêutica da infecção na primeira infância mas, estamos a identificar correctamente os casos de leucocitose? Objectivo: Determinar os valores de referência, obtidos num contador automatizado, do leucograma na primeira infância.Metodologia: Amostragem oportunista das crianças entre os 6 e 24 meses, utentes dos cuidados de Saúde Infantil dos Centros de Saúde do Concelho de Cascais. Foram excluídas as crianças com história de infecção nas 4 semanas prévias. Após consentimento paternal, foi realizado hemograma completo automatizado num contador Coulter e doseamento da proteína C reactiva (PCR) por método imunoturbidimétrico. Excluídas as crianças com PCR positiva, analizou-se a distribuição dos valores do leucograma.Resultados: Foram inquiridas 183 crianças, tendo sido colhido sangue a 125, das quais 120 apresentaram PCR negativa. Valores obtidos na contagem de leucócitos (10° por litro): distribuição Normal, não havendo diferenças nos três semestres abrangidos; valor mínimo 6,2; máximo 23,4; média 12,323; desvio padrão 3,399; percentil 2,5%: 6,738; percentil 97,5%: 19,5; neutrófilos: 11,7 - 53,1% (p2,5-p97,5).Discussão: Estes valores, obtidos numa amostra saudável da comunidade, são ligeiramente superiores aos esperados pela Literatura. Encontraram-se poucas variações ao longo dos três semestres analizados. O predomínio de células mononucleares é característica deste grupo etário, devendo uma clara inversão desta fórmula leucocitária ser considerada anormal.Conclusão: Torna-se necessário relembrar aos clínicos a definição de leucocitose para esta idade

A importâneia da idade e dos níveis de homocisteinemia

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