生物钟PER3基因多态性与乳腺癌易感性的相关性研究

[目的]探讨参与生物节律调控的生物钟PER3基因多态性与乳腺癌易感性的关系.[方法] 2005年9月至2008年2月,836例乳腺癌患者和946名健康对照者,采用PCR技术对PER3基因多态性进行检测,分析两组PER3基因型的分布及PER3基因多态性与乳腺癌发病风险的关系.[结果]对照组PER3-/-、+/+和+/-基因型分布频率分别为72.73％、1.59％和25.69％,病例组分别为72.61％、1.79％和25.60％,两组分布差异无统计学意义(P=0.9432).经相关因素调整后,PER3基因型与乳腺癌发病风险相关性分析显示,携带PER3+/+基因型发生乳腺癌的危险是携带PER3-/-基因型的3.503倍(95％CI:1.069～11.480),是携带PER3+/-或PER3-/-基因型对象的3.337倍(95％CI:1.025～10.864).[结论]PER3+/+基因型能够增加乳腺癌的发病风险,是乳腺癌发生的独立危险因素.     

CAV-1基因多态性与散发乳腺癌易感性的相关性分析

[目的]探讨CAV-1基因多态性与散发乳腺癌的相关性。[方法]采用病例对照研究,纳入经病理确诊的135例女性乳腺癌患者作为实验组,166例女性健康体检者为对照组。通过竞争性等位基因特异性PCR法对研究对象基因位点进行分型;采用χ2检验比较CAV-1各SNP基因型及等位基因频率在两组中的分布差异;非条件Logistic回归分析CAV-1基因多态性与乳腺癌易感性的关联。[结果]在共显性模型、显性模型及等位基因模型下rs3807987及rs7804372位点多态性与乳腺癌易感性密切相关。rs3807987:相对于GG基因型,AG、AA基因携带者(AG/AA基因型)均增加乳腺癌的发病风险(P<0.05),OR值分别为2.110(95%CI:1.270~3.505)、1.968(95%CI:1.205~3.216)。rs7804372位点:相对于TT基因型,AT、AA基因携带者(AT/AA基因型)均增加乳腺癌的发病风险(P<0.05),OR值分别为2.088(95%CI:1.285~3.392)、2.059(95%CI:1.293~3.280)。rs12672038位点:在共显性模型、显性模型、等位基因模型均未见rs12672038位点多态性分布与乳腺癌发病风险之间存在相关性。[结论]CAV-1基因rs3807987与rs7804372多态性与乳腺癌易感性相关。     

BCSG1与Hsa-circ-0026352在浸润性乳腺癌遗传易感性中的交互作用

目的：探讨乳腺癌特异基因1（BCSG1）与Hsa-circ-0026352 在浸润性乳腺癌（IBC）遗传易感性中的交互作用。方法：选取2019 年6月至2022 年5月间武汉市中西医结合医院收治的100 例IBC 患者作为研究对象,采用免疫组化法检测IBC 组织及其相应癌旁组织中BCSG1的表达,将研究对象按照IBC 组织中BCSG1蛋白表达的高低分为阴性、弱阳性和强阳性组,统计三组患者的临床病理特征及雌激素受体（ER）、孕激素受体（PR）、表皮生长因子受体-2（HER2）、Hsa-circ-0026352 的表达情况,采用Logistic 回归方程和最大似然法分析BCSG1表达与上述参数的趋势性和交互作用。结果：与癌旁组织比较,IBC 组织中BCSG1蛋白呈高表达（P<0.05）;BCSG1蛋白强阳性表达与淋巴结转移、分化程度、临床分期、HER2表达、 Hsa-circ-0026352 表达有关联（P<0.05）;BCSG1强阳性表达与IBC存在交互作用（P<0.05）;BCSG1表达与IBC的交互作用在Hsa-circ-0026352 阳性表达中最为显著（趋势P<0.001）;BCSG1表达与IBC 的交互作用在临床分期Ⅲ期、低分化程度中最为显著（趋势P<0.001）。结论：BCSG1与IBC患病密切相关,且与Hsa-circ-0026352、临床分期、分化程度存在交互作用,可共同增加IBC患病风险性。     

CLOCK基因单核苷酸多态性与乳腺癌易感性的病例对照研究

目的：探讨生物钟CLOCK基因的单核苷酸多态性与乳腺癌易感性的关系。方法：采用应用聚合酶链式反应-限制性片断长度多态性（PCR-RFLP）技术检测1 499例中国汉族女性乳腺癌患者和1 592例正常女性对照者CLOCK基因rs3805151位点的基因型,采用SPSS 16.0软件进行数据处理。结果：CLOCK基因CC型、CT型和TT型在病例组和对照组间的分布差异有统计学意义（χ2=9.712,P=0.008）,与CC型相比,杂合型CT可以显著增加乳腺癌的发病风险 （OR=1.41,95% CI：1.07～1.87）,携带T等位基因（CT/TT）的个体乳腺癌风险增加35%（OR=1.35,95% CI：1.04～1.76）。分层分析显示,携带T等位基因绝经后、无肿瘤家族史者、无乳腺良性病史的个体患乳腺癌风险增加。结论：CLOCK基因rs3805151 C>T可增加乳腺癌发病风险,这一结论有待于进一步通过不同种族人群的关联研究以及功能学研究的证实。     

NQO1基因多态性与肺癌遗传易感性

目的：探讨依赖还原型辅酶１／２醌氧化还原的酶基因ｃＤＮＡ６００位Ｃ→Ｔ点突变怕致物基因多态必理否与肺癌遗传多态性有关。方法：采用聚合酶锭反应－限制性片段长度多态性（ＰＣＲ－ＲＦＬＰ）的分析方法分析队列 肺癌病人与１３６例健康成人对照组ＮＱＯ１的基因多态性。结果：Ｔ等位基因频率在肺癌组和对照组分别为５４％、４３％,两组有显著差异（Ｐ＝０．０２４）。基因型分布在肺癌组和组之间差异显著（Ｐ＝０．００８）     

GSTM1基因多态现象与原发性肝癌遗传易感性的关系研究

目的探讨谷胱甘肽Ｓ转移酶Ｍ１（ＧＳＴＭ１）基因多态现象与原发性肝癌遗传易感性的关系。方法应用多重ＰＣＲ方法检测５４例肝癌患者（病例组）和１３６例健康人（对照组）的ＧＳＴＭ１空白基因型。结果病例组ＧＳＴＭ１空白基因型频率为７０．３７％,对照组则为４５．５９％,两者非常显著性差异（Ｐ〈０．０１）,但２组均不存在性别,年龄差异（Ｐ均〉０．０５）;ＯＲ值为２．８３（９５％ＣＩ值为１．４３－５．４２）,ＥＦ     

FGFR3基因单核苷酸多态与绝经前乳腺癌易感性的关联研究

目的 探讨FGFR3基因单核苷酸多态(SNPs)与女性绝经前乳腺癌的风险关系。方法 采用多重单碱基延伸SNP分型技术(Snapshot)检测FGFR3基因的rs2234909和rs3135848的SNP基因型在绝经前乳腺癌患者和绝经前正常女性人群中的频率,并分析不同SNP基因型与绝经前乳腺癌发病的风险关系。结果 FGFR3基因rs2234909和rs3135848的SNP基因型的频率在乳腺癌与对照组间无统计学差异(P＞0.05)。Logistic回归分析结果显示,对于rs2234909位点,相比较于TT基因型,TC和TC+CC基因型和乳腺癌的发病风险无显著相关性(OR=1.035,95% CI:0.680~1.575,P=0.874;OR=0.985,95% CI:0.638~1.521,P=0.945);对于rs3135848位点,相比较于TT基因型,TC、CC和TC+CC基因型与乳腺癌的发病风险无关(OR=1.177,95% CI:0.846~1.636,P=0.333;OR=0.948,95% CI:0.287~3.137,P=0.931;OR=1.162,95% CI:0.548~1.112,P=0.360)。rs2234909位点突变的乳腺癌患者与未突变者相比,组织学分级(显性模型:P=0.032;共显性模型:P=0.024)以及Ki67指数(显性模型:P=0.056;共显性模型:P=0.044)显著增高;rs3135848位点突变及两位点均突变与乳腺癌患者临床病理特征无显著相关性(P＞0.05)。结论 FGFR3基因的rs2234909和rs3135848两位点基因多态性与乳腺癌易感性无明显相关性;而rs2234909位点突变在绝经前乳腺癌患者中与组织学分级和Ki67指数呈正相关,可能提示预后不良。     

SULT1A1基因多态性与女性乳腺癌易感性及他莫昔芬治疗预后相关性研究

目的探讨SULT1A1基因多态性与女性乳腺癌易感性及他莫昔芬治疗预后相关性。方法选择女性乳腺癌患者86例作为研究组,选择同期健康女性80例作为对照组,通过电子病历调查收集其一般资料。采用限制性片段长度多态性聚合酶链反应法检测两组患者外周血SULT1A1基因rs9282861位点多态性,对携带不同基因型患者预后进行比较。结果研究组rs9282861位点GA、AA基因型、A等位基因频率高于对照组(P<0.05),GG基因型、G等位基因频率低于对照组(P<0.05);Logistic回归分析结果显示,与携带GG基因型患者相比,携带GA、AA、GA+AA患者发生乳腺癌风险分别为3.125、3.938、3.450倍,与携带G等位基因患者相比,携带A等位基因患者发生乳腺癌风险为3.008倍,均具有统计学意义(P<0.05);所有患者中位生存期为26个月,rs9282861位点GG、GA、AA基因型中位生存时间分别为30个月、24个月、20个月,差异具有统计学意义(P<0.05)。结论SULT1A1基因rs9282861位点与本地区女性乳腺癌易感性及他莫昔芬治疗预后存在关联,参与了乳腺癌的发生、发展过程。     

乳腺癌易感性相关基因研究状况分析

[目的]了解乳腺癌易感性相关基因的研究现状。[方法]对Embase、Pubmed/Medline和BIOSIS Preview数据库中2001～2010年期间乳腺癌易感性相关基因的研究文献进行文献计量学分析和生物信息学分析。[结果]筛选出相关文献1126篇,近10年文献量呈上升趋势,457个研究机构进行相关研究,涉及基因291个,主要涉及DNA损伤修复、氧化应激反应、细胞生长、增殖和凋亡等通路。[结论]通过文献计量学及生物信息学分析,对乳腺癌易感性相关基因研究现状和发展趋势有了一个系统的认识。     

BRCA1相关A蛋白复合物基因单核苷酸多态性与三阴性乳腺癌易感性研究

背景与目的：BRCA1突变与三阴性乳腺癌发病相关目前已得到学者公认。该研究旨在分析BRCA1相关A蛋白复合物相关基因的单核苷酸多态性(single nucleotide polymorphisms,SNP)与三阴性乳腺癌发病风险的关系,寻找和确定与汉族人群三阴性乳腺癌遗传易感性相关的基因型和单体型。方法：2008年-2011年间414例在复旦大学附属肿瘤医院接受原发性乳腺癌手术的三阴性乳腺癌患者和354例健康妇女进入本病例对照研究。通过对Abraxas、BRE、Rap80、NBA1和BRCC36基因组DNA的37个SNP位点的检测,分析它们与三阴性乳腺癌的相关性。研究者随后检测了652例其他类型乳腺癌和890例健康女性的DNA以证实发现的SNP是否为三阴性特有的遗传相关位点。结果：该研究在第一步研究中发现,NBA1启动子区rs7250266位点突变的G等位基因在三阴性乳腺癌患者中的频率显著低于在正常女性中的频率(0.14 vs 0.19,P<0.01)。对rs7250266位点基因分型显示：与携带CC基因型个体比较,携带GC型个体的三阴性乳腺癌的发病风险显著降低(GC∶OR=0.70,95%CI：0.51~0.97;GG∶OR=0.48,95%CI：0.21~1.07,P=0.03)。单体型分析也证实NBA1基因的不同单体型间三阴性乳腺癌发病风险不同。第二步的研究结果显示,rs7250266位点突变在非三阴性的乳腺癌与正常人群中差异无统计学意义(0.19 vs 0.18,P=0.85)。结论：NBA1基因的rs7250266位点的单核苷酸多态性与汉族女性的三阴性乳腺癌发病风险相关,其突变型等位基因携带者罹患三阴性乳腺癌的风险低于野生型等位基因携带者。     

Expression of the mitotic checkpoint gene MAD2L2 has prognostic significance in colon cancer

Aneuploidy and genetic instability are a hallmark of colorectal cancer and other solid tumors, and they are thought to enhance tumor progression. The gene MAD2L2 (mitotic arrest deficient 2-like 2) encodes the spindle checkpoint protein MAD2L2 (or MAD2B), a key component of a surveillance system that delays anaphase until all chromosomes are correctly oriented. Defects in this mitotic checkpoint are known to contribute to genetic instability, i.e., numerical and structural aberrations of chromosomes. We have previously identified MAD2L2 as significantly upregulated in locally restricted colorectal tumors by gene expression profiling. So far, MAD2L2 has not been reported to play a major role in human cancer in contrast to its homologue MAD2. To address this question, 118 histologically confirmed colorectal lesions were analyzed by quantitative real-time PCR for expression of MAD2L2, and compared to normal colon tissue from 11 patients. Twenty-five out of 118 tumor samples (21%) showed MAD2L2 overexpression of 3-fold or more compared to normal colon, and the fraction of overexpressing tumors increased with tumor stage. Correspondingly, protein levels of MAD2L2 were found to be significantly upregulated in tumors as compared to matched normal tissue. Tumors with upregulated MAD2L2 expression had significantly higher numbers of aberrant mitotic figures (anaphase bridges), an indication of chromosomal instability. Elevated expression of MAD2L2 was significantly correlated with reduced patient survival. By multivariate analysis, MAD2L2 expression was retained as an independent prognostic parameter for patient survival. Thus, our results demonstrate that overexpression of MAD2L2 correlates with bad prognosis in colorectal cancer.     

Genetic variation in the major mitotic checkpoint genes does not affect familial breast cancer risk

Aneuploidy, an aberrant number of chromosomes, is a very common characteristic of many types of cancers, including tumors of the breast. There is increasing evidence that defects in the spindle assembly checkpoint, which controls correct chromosome segregation between two daughter cells, might contribute to tumorigenesis. In the present study we examined the effect of promoter and coding single nucleotide polymorphisms (SNPs) in six major spindle checkpoint genes (BUB1B, BUB3, CENPE, MAD2L1, MAD2L2, TTK) on familial breast cancer (BC) risk. A case–control study was carried out with a total of nine SNPs using 441 German, familial BC cases and 552 controls matched by age, ethnicity and geographical region. Neither the individual SNPs in the studied genes nor the haplotypes in the BUB1B, CENPE and TTK genes caused any significant effect on the risk of BC. We used the multifactor-dimensionality reduction method in order to identify gene-gene interactions among the six mitotic checkpoint genes, but no association was detected. Therefore, our results indicate that the investigated SNPs in the mitotic checkpoint genes do not affect the risk of familial BC.     

Sulfotransferase 1A1 (SULT1A1) polymorphism,PAH-DNA adduct levels in breast tissue and breast cancer risk in a case-control study

Gene–environment interactions are hypothesized to be major contributors to susceptibility to environmental carcinogens and interindividual variability in cancer risk. We present findings on associations between genetic susceptibility due to inherited polymorphisms of the Phase II detoxification enzyme sulfotransferase 1A1 (SULT1A1), breast cancer risk, and polycyclic aromatic hydrocarbon (PAH)-DNA adducts. A hospital based case-control study was conducted at the New York-Presbyterian Medical Center (NYPMC). The study utilized two control groups: one comprised of women with benign breast disease (BBD) and the other comprised of women visiting NYPMC for routine gynecologic checkups (healthy controls). Blood samples were collected from cases and controls; and breast tissue from pathology blocks was collected from cases (tumor and non-tumor tissue) and BBD controls (benign tissue). PAH-DNA adduct levels were measured by immunohistochemistry in breast tissue samples, and the SULT1A1 (Arg/His) polymorphism at codon 213 was determined by PCR RFLP analyses using DNA from white blood cells. Increasing number of His alleles was modestly associated with breast cancer case-control status, when cases were compared to healthy controls (p for trend = 0.08), when cases were compared to BBD controls (p for trend = 0.08) and when cases were compared to both control groups combined (p for trend = 0.07). Contrary to our hypothesis PAH-DNA adduct levels in breast tissue were not associated with SULT1A1 genotype. Our findings are consistent with a prior report that the Arg/His polymorphism in SULT1A1 is associated with breast cancer risk.     

家族性乳腺癌家系成员乳腺癌易感基因突变的研究

目的研究河北省地区家族性乳腺癌家系中的患者及健康一级亲属乳腺癌易感基因1（BRCAl）和乳腺癌易感基因2（BRCA2）突变位点及携带情况。方法研究对象为2002年6月至2008年5月河北医科大学第四医院接诊的乳腺癌患者及其亲属,分别来自12个独立的汉族家族性乳腺癌家系,该家系中有2个及2个以上一级或二级亲属乳腺癌患病史,研究病例包括13例患者及46例健康一级亲属,共59例样本。由外周血提取基因组DNA,采用聚合酶链反应一单链构象多态性分析（PCR—SSCP）和基因测序技术对国内外报告中常见的4个BRCAl／BRCA2突变热点区域（BRCAl：外显子2、11、20;BRCA2外显子11）进行检测。结果发现1个BRCAl突变位点（4193insA）和1个BRCA2突变位点（5329insT）,全部为移码突变;发现4个变异位点（BRCAl：4165T〉A、287G〉C,BRCA2：6251G〉T、5416C〉A）,4193insA、5329insT、287G〉C携带者的家系中均有3例乳腺癌患者。结论BRCAl（4193insA）、BRCA2（5329insT）以及BRCAl：4165T〉A、287G〉C和BRCA2：6251G〉T、5416C〉A可能是河北省家族性乳腺癌相关性突变位点,其携带者家系中乳腺癌发病率明显升高,建议对其一级亲属密切随访或尽早进行手术或药物干预。     

Genetic and epigenetic associations of circadian gene TIMELESS and breast cancer risk

Results from recent molecular epidemiologic studies suggest that the core circadian genes play a role in breast tumorigenesis, possibly by influencing hormone regulation or other pathways relevant to cancer. In order to further evaluate this hypothesis, we conducted a genetic and epigenetic association study of the circadian regulator TIMELESS in breast carcinogenesis. We detected significant associations between two tagging SNPs (rs2291738 and rs7302060) in the TIMELESS gene and breast cancer among 441 breast cancer cases and 479 cancer‐free controls, with apparent effect modification by ER/PR status. The presence of the C allele of rs7302060 was found to be associated with reduced breast cancer risk (OR, 0.54; 95% CI, 0.54–0.99). In addition, both the G/G genotype of rs2291738 and the C/C genotype of rs7302060 were associated with reduced risk of breast cancer among ER‐ or PR‐positive breast cancer cases (OR, 0.46; 95% CI, 0.22–0.97 and OR, 0.36; 95% CI, 0.17–0.78, respectively). We also observed a significant association between stage II, III, and IV breast cancers and TIMELESS promoter hypomethylation in peripheral blood lymphocytes (OR, 0.35; 95% CI, 0.13–0.96) in 80 breast cancer cases and 80 age‐matched controls, which is corroborated by documented overexpression of TIMELESS in breast tumor tissue compared to adjacent normal tissue. Our findings support the hypothesized role of circadian genes in breast tumorigenesis, and identify a set of circadian biomarkers for breast cancer susceptibility. © 2011 Wiley Periodicals, Inc.     

Cytochrome P4501A1 polymorphism as a susceptibility factor for breast cancer in postmenopausal Chinese women in Taiwan.

The incidence of breast cancer has been greatly increasing in Taiwan over the past two decades. Since cytochrome P4501A1 (CYP1A1) is involved in the metabolism of environmental carcinogens or oestrogen, we hypothesized that CYP1A1 genetic polymorphism may be a susceptibility factor for breast cancer. This hypothesis was evaluated in this case control study of 150 breast cancer patients and 150 healthy controls among Chinese women. Two CYP1A1 polymorphisms were studied, one containing a new Msp1 site and the other located in axon 7 and resulting in the replacement of an isoleucine (Ile) residue by a valine (Val). After simultaneously considering the known or significant risk factors for breast cancer, including the age of study participants, positive family history of breast cancer, early menarche (< or = 13 years), nulliparity and late first full-term pregnancy (> or = 30 years), hormone replacement therapy and smoking, the CYP1A1 Msp1 polymorphism was found to be a significant factor in determining the risk of breast cancer. The homozygous variant was the most susceptible genotype with an adjusted odds ratio of 1.98 (95% confidence interval (CI) = 1.01-3.99) compared with the non-homozygous variants (the homozygous wild-type and the heterozygous variant). In contrast, the CYP1A1 Ile/Val polymorphism was not significantly associated with breast cancer development (adjusted OR = 1.07, 95% CI = 0.64-1.78). Interestingly, the Msp1 polymorphism was especially significant in postmenopausal women, but not in premenopausal women. Further stratification analysis in postmenopausal women who were non-smokers and with no history of hormone replacement therapy showed the cancer risk due to the Msp1 variant to be more significant in women with early menarche. We conclude that CYP1A1 polymorphism is a susceptibility factor for breast cancer in postmenopausal Chinese women in Taiwan. Further study with a large sample size should be considered to address issues of interactions between CYP1A1 and other risk factors.     

Genetic polymorphisms in uridine diphospho-glucuronosyltransferase 1A1 and breast cancer risk in Africans

The UDP-glucuronosylatransferase 1A1 (UGT1A1) gene is involved in the metabolism of estrogen and detoxification of potential carcinogens. The number of TA repeats in the promoter region of UGT1A1 has been linked to breast cancer risk, but results varied by race. We performed a comprehensive assessment of genetic polymorphisms in the UGT1A1 gene, and examined these polymorphisms and TA repeats in relation to breast cancer risk in a case-control study in Nigeria. 512 breast cancer cases and 226 community controls were genotyped for UGT1A1. Compared with high-activity TA repeat genotypes, the odds ratios (OR) for low-activity and moderate-activity genotypes were 0.47 (95% confidence interval CI, 0.26-0.83) and 0.64 (95% CI, 0.39-1.06), respectively, in premenopausal women (P = 0.009 for trend), but no association was observed in postmenopausal women (P = 0.24). The effect of TA repeats was also differentiated by age: the OR was 0.39 (95% CI 0.21-0.71) for low-activity genotypes and 0.58 (95% CI 0.33-1.00) for moderate-activity genotypes in women <45 years old (P = 0.002 for trend), but no association was observed in women >/=45 years old (P = 0.15). Haplotype analysis showed that UGT1A1 haplotypes were highly diverse with blocked structures. We found a specific haplotype in block 2 that was significantly associated with a 2.1-fold elevated risk (95% CI 1.05-4.39; P = 0.04). In contrast with previous studies, we found low-activity TA repeat alleles were protective against breast cancer among premenopausal indigenous Africans, suggesting that the role of UGT1A1 in breast cancer development may vary by population, presumably due to different environmental and genetic modifier effects.     

Genetic variants and haplotype analyses of the ZBRK1/ZNF350 gene in high-risk non BRCA1/2 French Canadian breast and ovarian cancer families

The E6 and E7 proteins of human papillomaviruses (HPV) play a crucial role in the pathogenesis of malignant tumors. E6 protein of high-risk mucosal papillomaviruses targets a number of proteins for proteosomal degradation through complex formation with ubiquitin ligase E6AP. These proteins include, amongst others, p53, paxillin and PDZ-domain proteins e.g. Dlg and MAGUK. The mechanism by which the E6 protein of cutaneous HPV types interacts with cellular proteins to induce either benign or malignant cutaneous lesions, has not been elucidated, although extensive ultraviolet exposure and mutated p53 (hot-spot mutations) are known to be associated with non-melanoma skin cancer. We demonstrate two mechanisms in which HPV20E6 may be involved in the infected cell. One pathway is the wtp53 mediated degradation of HPV20E6 through caspase-3. Mutated p53R248W and Delta Np63 alpha, as well as other unknown proteins involved in proteosome-dependent degradation, convey a protective effect on HPV20E6 under these conditions. This unveils a remarkable opposite regulation to the well-known mechanism of E6-E6AP mediated degradation of p53 for mucosal HPV types. In a second interaction, ectopically expressed HPV20E6 induces cleavage of procaspase-3 to active caspase-3. We demonstrate, in addition, in vivo binding of HPV20E6 to the intermediate filament vimentin.     

GSTM1 and GSTT1 polymorphisms and postmenopausal breast cancer risk

Glutathione S-transferases (GSTs) are a family of important enzymes involved in the detoxification of a wide variety of known and suspected carcinogens, including potential mammary carcinogens identified in charred meats and tobacco smoke. A substantial proportion of the Caucasian population has a homozygous deletion (null) of the GSTM1 or GSTT1 gene, which results in lack of production of these isoenzymes. We conducted a case-control study in a cohort of postmenopausal Iowa women who in 1986 completed a mailed questionnaire on lifestyle factors including information on cigarette smoking and breast cancer risk factors. DNA samples and information related to charred meat intake were obtained, in the case-control study, from breast cancer cases diagnosed during 1992–1994, and a random sample of cancer-free cohort members. Included in this study were 202 cases and 481 controls who were genotyped for GSTM1 or GSTT1 gene polymorphisms. Compared to women who had both GSTM1 and GSTT1 genes, a 60% elevated risk (95% CI = 1.0–2.5) was observed among those whose GSTM1 or GSTT1 gene was deleted. When stratified by meat eating habits, the risk of breast cancer associated with null GSTM1 or GSTT1 genotype was observed primarily among women who ate meats consistently well- or very well-done. Women who carried either one of the null genotypes and consumed meat consistently well- or very well-done had a 3.4-fold elevated risk of developing breast cancer (95% CI = 1.6–7.1). Cigarette smoking was not a risk factor for breast cancer among women who had either the GSTM1 or GSTT1 genes. Among those with the null GSTT1 genotype, however, a significantly elevated risk of breast cancer was associated with cigarette smoking (OR = 2.5, 95% CI = 1.1–5.4) and the association was stronger among former (OR = 4.4, 95% CI = 1.5–12.8) than current smokers (OR = 1.3, 95% CI = 0.4–4.1). This study suggests that certain null GST genotypes may be associated with an elevated risk of breast cancer and the association may be modified by charred meat intake and cigarette smoking.