Polimorfismos GSTM1, GSTT1 e GSTP1, fatores de risco para câncer de mama e densidade mamográfica em mulheres submetidas a rastreamento mamográfico
Ernestina Silva de AguiarI, II; Juliana GiacomazziI, II, III; Aishameriane Venes SchmidtIV; Hugo BockV, XII; Maria Luiza Saraiva-PereiraV-VIII, X, XII; Lavínia Schuler-FacciniVIII, X; Dakir Duarte FilhoIII; Pollyanna Almeida Costa dos SantosX; Roberto GiuglianiI, V, VIII, IX, X, XII; Maira CaleffiIII; Suzi Alves CameyXI; Patrícia Ashton-ProllaI-III, VIII-X
IPost-Graduate Program in Medicine: Medical Sciences; Universidade Federal do Rio Grande do Sul. Porto Alegre, Brazil
IIGenomic Medicine Laboratory, Hospital de Clínicas de Porto Alegre, Brazil
IIINúcleo Mama Porto Alegre, Associação Hospitalar Moinhos de Vento, Porto Alegre, Brazil
IVUniversidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
VGenetic Identification Laboratory, Hospital de Clínicas de Porto Alegre, Brazil
VIPost-Graduate Program in Cellular and Molecular Biology, Universidade Federal do Rio Grande do Sul
VIIDepartment of Biochemistry, Universidade Federal do Rio Grande do Sul, Brazil
VIIIMedical Genetics Service, Hospital de Clínicas de Porto Alegre, Brazil.
IXDepartment of Genetics, Universidade Federal do Rio Grande do Sul. Porto Alegre, Brazil
XPost-Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul. Porto Alegre, Brazil
XIDepartment of Statistics, Institute of Mathematics, Universidade Federal do Rio Grande do Sul. Porto Alegre, Brazil
XIIPost-Graduate Program in Biological Science: Biochemistry; Universidade Federal do Rio Grande do Sul. Porto Alegre, Brazil
Genetic polymorphisms in genes related to the metabolism of xenobiotics, such as genes of the glutathione S-transferases (GSTM1, GSTT1, and GSTP1) superfamily have been associated with an increased risk for breast cancer (BC). Considering the high incidence of BC in the city of Porto Alegre in southern Brazil, the purpose of this study was to characterize genotypic and allelic frequencies of polymorphisms in GSTM1, GSTT1, and GSTP1, and correlate these molecular findings with established risk factors for breast cancer including mammographic density, in a sample of 750 asymptomatic women undergoing mammographic screening. Molecular tests were performed using the multiplex polymerase chain reaction (PCR) for GSTM1 and GSTT1, and quantitative PCR for GSTP1 polymorphisms. Overall, the frequencies of GSTM1 and GSTT1 null genotypes were 45% and 21%, respectively. For GSTP1 polymorphism, genotypic frequencies were 44% for the Ile/Ile genotype, 44% for the Ile/Val genotype, and 12% for Val/Val genotype, with an allelic frequency of 66% for the wild type allele in this population, similar to results of previous international publications. There was a statistically significant association between the combined GSTM1 and GSTT1 null genotypes (M-/T-) and mammographic density in post menopausal women (p = 0.031). When the GSTT1 null (T-) genotype was analyzed isolated, the association with mammographic density in post menopausal women and in the overall sample was also statistically significant (p = 0.023 and p = 0.027, respectively). These findings suggest an association of GSTM1 and GSTT1 null genotypes with mammographic density.
Keywords: Breast cancer. Risk factors. Genetic polymorphisms. GSTT1. GSTM1. GSTP1.
Polimorfismos genéticos em genes relacionados com o metabolismo de xenobióticos, como os genes da superfamília das glutationa S-transferases (GSTM1, GSTT1 e GSTP1) têm sido associados com o aumento do risco para câncer de mama (CM). Considerando a alta incidência de CM na cidade de Porto Alegre, região Sul do Brasil, a proposta deste estudo foi caracterizar genótipos e frequências alélicas dos polimorfismos GSTM1, GSTT1 e GSTP1, e correlacionar esses achados moleculares com fatores de risco já estabelecidos para câncer de mama, incluindo densidade mamográfica, em uma amostra de 750 mulheres assintomáticas durante o rastreamento mamográfico. Para os testes moleculares foi utilizado multiplex da reação em cadeia de polimerase (PCR) para GSTM1 e GSTT1, e PCR quantitativo para o polimorfismo GSTP1. As frequências dos genótipos GSTM1 e GSTT1 nulos foram 45% e 21%, respectivamente. Para o polimorfismo GSTP1, as frequências genotipicas foram: 44% para o genótipo Ile/Ile, 44% para o genótipo Ile/Val e 12% para o genótipo Val/Val. A frequência do alelo lle nesta população foi 66%, semelhante a outros estudos. Houve uma associação significativa entre a combinação dos genótipos (T-/M-) nulos e densidade mamográfica nas mulheres pós-menopáusicas (p = 0,031). Quando analisamos isoladamente o genótipo GSTT1 nulo (T-) também encontramos uma associação significativa com a densidade mamográfica nas mulheres pós-menopáusicas (p = 0,027) e na amostra total. Estes achados sugerem uma associação dos genótipos (T-/M-) nulos com densidade mamográfica.
Palavras-chave: Câncer de mama. Fatores de risco. Polimorfismos genéticos. GSTT1. GSTM1. GSTP1.
Breast cancer (BC) is the second most common type of malignancy worldwide and the first among women1. In Brazil, BC is a significant public health problem due to its morbidity and high incidence and mortality rates, representing the leading cause of cancer-related deaths in women of all ages. The state of Rio Grande do Sul (RS), for reasons still unknown, has one of the highest BC incidence and mortality rates in the country. In this state, BC is currently the leading cause of cancer deaths in young women (30-49 years of age)2.
In Brazil, approximately 75% of the population has access to health care only through the Brazilian Public Health System (SUS, Sistema Único de Saúde), which is responsible for the provision of breast health care to the majority of the population. Regarding mammographic screening, a national survey conducted in 2003 confirms the lack of a structured screening program in the country, showing that 49.7% of women above the age of 50 have never been submitted to a mammography3.
Several epidemiologic studies have suggested that environmental carcinogens contribute to the risk for BC and that genetic differences in the metabolism of those carcinogens may be associated with individual variations in susceptibility to this tumor4,5. Genes involved in the metabolism of carcinogens have been used as markers of individual susceptibility to cancer. Their products, detoxicating enzymes, may exacerbate or suppress the activity of xenobiotics6,7. Thus, changes in the balance between activation and detoxification of carcinogens may explain part of the individual variations in response to exposure to these agents8.
Glutathione S-transferases (GST), which are involved in phase II of biotransformation, acting on carcinogens, environmental pollutants, drugs, and other xenobiotics, has been implicated as key detoxification enzymes. A significant effect on tolerance to carcinogens has been demonstrated when there is deficiency of specific isozymes of this family9. The three major genes of the GST family are GSTM1, GSTT1, and GSTP110. GSTM1 is located on chromosome 1p13.3, and 20% to 50% of the population has a homozygous deletion of the gene, not expressing its product, the gstm1 enzyme11. GSTM1 is involved in the detoxification of polycyclic aromatic hydrocarbons and other carcinogens, and the cells of individuals with GSTM1 null genotypes are more susceptible to damage to DNA caused by these agents12. GSTT1 is located on chromosome 22q11.2, similarly polymorphic, and its null allele has been observed at a frequency of 20 to 60%, in different human populations12. GSTP1 is located on chromosome 11q13, and the presence of a polymorphism at codon 105 (substitution of isoleucine for valine, rs1695) results in reduced activity of the gstp1 enzyme13. The GSTP1 Ile105Val polymorphism has been associated with increased susceptibility to various forms of cancer, particularly those related to tobacco use and BC12,13. There are few previous studies on the prevalence of these polymorphisms in a region with high incidence and mortality rates for BC, and therefore, the purpose of this study was to determine the frequency of GSTM1, GSTT1, and GSTP1 polymorphisms in a sample of BC unaffected-women undergoing routine mammographic screening.
A convenient subsample of 890 breast cancer-unaffected women (ages 40-69 years) enrolled in a mammography screening program (Núcleo Mama Porto Alegre - NMPOA cohort) in the city of Porto Alegre was recruited for this study during routine mammographic visits between November 2005 and March 200614. Invitation to participate in the study was consecutive among women that scheduled their screening mammographies during this period. The refusal rate was 15.7%. A total of 750 women were included in the analysis. Sample size was calculated to estimate the frequencies of polymorphisms in GSTM1, GSTT1, and GSTP1 with a 95% confidence level taking into consideration the allelic frequencies described in previously published papers. In accordance to this, we used the minimum allele frequency (MAF) of each polymorphism to obtain the sample size. Of note, since this sample included only women from the NMPOA cohort, we can not say that it is representative of the general population. For this reason we preferred to use the term "frequency" instead of "prevalence".
Collection of demographic and clinical data
Clinical data and information on BC risk factors were gathered from anamnesis sheets and medical history recorded in patient charts. Estimates on the lifetime risk of developing BC were obtained for all women using the Gail model15 and results of the mammographic examination and mammographic density used the BIRADS and breast density categories of the American College of Radiology16. As for ethnicity, the self-designation of participants in the cohort was considered at enrollment, with categorization between whites and non-whites.
Genomic DNA was obtained from peripheral blood samples using the standard method17. GSTP1 Ile105Val polymorphism was studied by allelic discrimination using a commercially available TaqMan assay method; fluorescence was measured on an ABI 7500 Sequence Detector (Applied Biosystems, Foster City, CA). GSTM1 and GSTT1 polymorphisms were analyzed concurrently by multiplex-PCR and the region of interest of the GSTP1 gene (amplicon of 176bp) was added to this reaction to provide an internal control for double null allele genotypes, as described previously18. The amplified products were resolved by electrophoresis on 2% agarose gels and viewed in ultraviolet light. The presence or absence of the GSTM1 and GSTT1 genes was assessed by the detection of amplification products of 215bp and 480bp, respectively; distinction between homozygotes and heterozygotes was not possible with this method. Throughout the manuscript, genotyping results are presented as follows: genotypic frequencies in percentage of individuals and allelic frequencies as percentage of alleles.
For descriptive analyses, categorical variables were described by their absolute and/or relative frequencies and quantitative variables were expressed as mean and standard deviation (SD). For statistical data inference, the t test for independent variables and ANOVA were used to compare mean values of the quantitative variables. The existence of an association between categorical variables, the comparison of genotype frequencies and the deviation of genotype frequencies from those expected were examined by the chi-square test. In all analyses, a significance level of 0.05 was adopted. Comparative analysis of genotypic frequencies between the present study and other studies was done using the WINPEPI (PEPI-for-Windows)19. SPSS version 14.0 was used for data handling and further statistical analyses.
Study approval was obtained from the ethics committees of participating institutions (Hospital de Clínicas de Porto Alegre and Hospital Moinhos de Vento) and all women recruited for the study signed the informed consent.
The average age at inclusion was 51 years (SD = 7.6 years) and 421 women (56.1%) reported being postmenopausal. For the sample as a whole, the average lifetime risk of developing BC, estimated by the Gail model, was 7.8% (SD = 3.3%). Overall, 36.4% and 41.1% of the women had a body mass index (BMI) of 25-29.99 or > 30, respectively. Seven hundred and thirty two women (97.6%) had mammography results in the BIRADS 1 or 2 categories, 9 (1.2%) had BIRADS 3 mammographic results and 5 (1.1%) had a mammographic result corresponding to the BIRADS 4 category. Four hundred and thirteen (55.1%) women had fatty breast tissue or moderately fatty breast tissue, < 25% and 26-50% of glandular area, respectively; 304 (40.5%) had moderately dense, dense or heterogeneity dense tissue, 57-75%, > 75% and 50-75% of glandular area, respectively; and 33 (4.4%) women did not have mammographic density available. A detailed description of BC risk factors is presented in Table 1.
The frequencies of GSTM1 and GSTT1 null genotypes were 45% and 21%, respectively, and 10% of the women had combined GSTM1 and GSTT1 null genotypes. The genotypic frequencies of the GSTP1 polymorphism were: 44% for the Ile/Ile genotype, 44% for the Ile/Val genotype, and 12% for the Val/Val genotype. The frequency of the Ile allele in this sample was 66%. When we categorized the group under study in white and non-white women, we observed that the GSTP1 homozygous Val/Val genotype was more frequent in non-white women. Furthermore, the GSTP1 genotype frequencies were not in Hardy-Weinberg equilibrium (p = 0.005). These results are presented in Table 2.
When assessing the association of GSTM1, GSTT1 and GSTP1 genotypes with established risk factors for BC, there was no association with age, age at menarche, age at menopause or body mass index (data not shown). However, there was a difference between the combined GSTM1 and GSTT1 null genotypes and mammographic density in post-menopausal women (p=0.031). In individual analyses, the GSTT1 null genotype was also associated with mammographic density in post menopausal women (p = 0.023), and in the overall sample (p = 0.027). As for ethnicity, considering the classification based on self-designation, there was an association between T- and breast density between white and non-white women (p = 0.028). There was no association between GSTP1 alleles and genotypes with mammographic density. These results are presented in Table 3.
The frequencies of GSTM1 and GSTT1 null genotypes found in this study were not different from those described in previous publications involving subjects from southern Brazil18,20 (Supplemental Materials, Tables S1 and S2). The GSTM1 null genotype frequency was comparable to those reported in other studies with Brazilian and non-Brazilian populations9,21-25. Similarly, the GSTP1 polymorphism genotype frequencies was similar to those found in other Brazilian studies20,23, and in studies in non-Brazilian populations predominantly with European ancestry26,27, but considerably different from those described in studies of China and Australia28,29. Finally, the frequency of the GSTT1 null gene in this sample was much lower than previously found in other Western countries4,28.
Established reproductive risk factors for BC were not frequent in the sample studied: mean age at menarche was relatively late, and mean age at birth of the first child and at menopause were early. A small number of women were nulliparous and were users of hormone replacement therapy for more than 5 years. However, there were frequent reports of first-degree family history of BC, and a very significant proportion of women were overweight and/or obese. In a study of 3,665 women not affected by BC, from the same mammographic screening cohort (Núcleo Mama Porto Alegre - NMPOA cohort), Reyes et al.30 described a high prevalence of increased BMI (69% of women with BMI > 25) and a low frequency of BC risk factors traditionally included in the Gail model. As expected for a population-based sample, both in the study of Reyes et al. and in this study, estimates of the lifetime risk for developing BC using the Gail model were not higher than expected for the general population. However, Reyes et al. observed that there was a statistically significant difference between categories of mammographic density and estimation of risk by the Gail model: increase of mammographic density and increase of estimated lifetime risk of developing cancer. Considering that BMI and mammographic density are risk factors for BC, Reyes et al. suggested, as others publications, that the inclusion of these variables could improve risk estimation models in certain populations31,32,33. Gail et al. (2008, 2009)34,35 also attempted to include to the model, data on seven single-nucleotide polymorphisms (SNPs) previously associated with risk of BC, but found only small differences from the estimates obtained with the original variables, possibly due to the choice of SNPs used in the study. The polymorphisms studied by Gail in 7 genes or regions of risk did not include the genes studied here, but the initiative shows that the inclusion of genotyping in risk models may contribute to improving the accuracy and results of such models.
Several pieces of evidence indicate an association between GSTM1 and GSTT1 null genotypes and greater susceptibility to a number of tumors (colon, breast, bladder, head, and neck). Specifically in relation to risk for BC, the results are somewhat controversial. In a previous study from Brazil (Amorim et al. 2002)36, and in some studies of white and African-American women in other countries37-39, there are reports that show no association between GSTT1 and GSTM1 null alleles and risk for BC. On the other hand, an increased risk for BC has been observed in women with combined GSTM1 and GSTT1 null genotypes in a few studies3,40. There are also prior reports of an association between GSTT1 and GSTM1 null genotypes and increased mammographic density, a recognized risk factor for BC. In a Brazilian study, Morais et al. (2008)21 found that women with GSTM1 deletions had dense breast patterns more often.
In the present study, we identified a statistically significant association between GSTM1 and GSTT1 null genotypes and mammographic density (< 50% or > 50% dense) in post-menopausal women (p = 0.031). The GSTT1 null genotype alone, was also statistically associated with mammographic density in post-menopausal women (p = 0.023) and the overall sample (p = 0.027). These findings confirm results from previous studies from our group14 and other authors, and suggest that the inclusion of specific genotypic analyses and mammographic density may improve the estimation of BC risk in specific populations.
Competing interests: The authors declare that they have no competing interests.
Acknowledgements and funding: This study was supported in part by grants from CNPq (grant number 400949/2005-9 to R. Giugliani), Susan G. Komen for the Cure (POP#0403033), Fundo de Incentivo a Pesquisa e Eventos (FIPE) Hospital de Clínicas de Porto Alegre (05-182) and also by a "Programa de Apoio a Núcleos de Excelência (PRONEX)" grant from FAPERGS, Brazil. PA-P and RG are researchers from CNPq.
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▲ Corresponding author:
Department of Genetics - UFRGS and Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre
Rua Ramiro Barcelos 2350
CEP 90035-903, Porto Alegre RS. Brazil
Recebido em: 03/03/2011
Versão final apresentada em: 22/02/2012
Aprovado em: 27/05/2012
Financing: CNPq - processo nº 400949/2005-9.
Susan G. Komen for the Cure nº (POP#0403033).
Fundo de Incentivo a Pesquisa e Eventos (FIPE) Hospital de Clínicas de Porto Alegre nº (05-182).