CYP1A1, SULT1A1, and SULT1E1 polymorphisms are risk factors for endometrial cancer susceptibility

BACKGROUND: In estrogen biosynthetic pathways, many enzymes are important for metabolism, detoxification, and bioavailability. Polymorphisms in these genes may have an effect on the enzymes' function. For example, higher expression and activation of biosynthetic enzymes and lower expression and activation of conjugation enzymes may lead to high toxicity or carcinogenesis. The authors hypothesized that single nucleotide polymorphisms (single nucleotide polymorphisms) of CYP1A1, CYP1A2, CYP1B1, CYP17, SULT1A1, SULT1E1, and SHBG genes may be risk factors for endometrial cancer. METHODS: DNA samples from 150 cases of endometrial cancer and healthy controls (n = 165) were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to determine the genotypic frequency of 13 different polymorphic loci on the CYP1A1 (m1, m2, m3, m4), CYP1A2 1F, CYP1B1 codon432, COMT codon158, CYP17, SULT1A1 (Arg213His, 14A/G, 85C/T in the 3' flanking region), SULT1E1-64G/A promoter region, and SHBG genes. Genotyping was validated by direct DNA sequencing. The authors also investigated the relation between expression of CYP1A1 in endometrial cancer tissues and genotypes of CYP1A1 m1. RESULTS: A decreased frequency of TC + CC genotype of the CYP1A1 m1 (T/C) polymorphism was observed in endometrial cancer patients compared with controls (OR = 0.42; 95% CI, 0.27-0.69). The T-A haplotype of CYP1A1 m1 and m2 was increased in endometrial cancer patients (P = .017). The frequency of CYP1A1 m1 T/C + C/C was higher in a high CYP1A1 expression group (P = .009). The authors also found that individuals carrying the variants of SULT1A1 codon213 and 2 single nucleotide polymorphisms in the 3' flanking region (14A/G and 85C/T) had an increased risk for endometrial cancer. The frequencies of G-A-C and A-G-T haplotypes of these 3 variants were higher in endometrial cancer patients (P < .0001; P = .0002). In addition, the frequency of combined genotypes (SULT1A1 213 GA + AA and CYP1A1 m1 TT) was higher in endometrial cancer patients. (OR, 4.58; 95% CI, 2.35-8.93). CONCLUSIONS: This is the first report on the combined association of CYP1A1 and SULT gene polymorphisms in endometrial cancer that suggests a decreased single nucleotide polymorphism of CYP1A1 and an increased single nucleotide polymorphism for SULT1A1 and SULT1E1 genes may be risk factors for endometrial cancer in Caucasians.     

Genetic polymorphisms of the CYP19A1 gene and breast cancer survival.

The CYP19A1 protein (aromatase) plays a critical role in estrogen biosynthesis and thus may be related to the progression of breast cancer. We examined the association between CYP19A1 genetic polymorphisms and breast cancer survival in a cohort of 1,136 patients who were recruited as part of a population-based case-control study in Shanghai, China from 1996 to 1998 and who has donated a DNA sample to the study. Patients were followed for cancer recurrence and mortality through July 2005. Nineteen haplotype tagging single-nucleotide polymorphisms (SNP) in the CYP19A1 gene were evaluated. For each of the five SNPs located in haplotype block 2, patients homozygous for the minor alleles had a reduced 5-year disease-free survival rate compared with those carrying the major allele. The age-adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) were 1.5 (1.1-2.1), 2.1 (1.2-3.6), 1.5 (1.1-2.0), 1.4 (1.0-2.0), and 1.4 (1.0-2.0) for hCV1664178, rs12900137, rs730154, rs936306, and rs1902586, respectively. Haplotype analyses showed that the haplotype CCCTA (all minor alleles of the five SNPs in block 2) was associated with decreased disease-free survival (HR, 1.9; 95% CI, 1.1-3.3). The nonsynonymous SNP, rs700519 (Arg264Cys), located in haplotype block 4, was also associated with breast cancer survival. The age-adjusted HR for the Cys/Cys (T/T) genotype was 2.2 (95% CI, 1.2-4.1) for overall survival and 2.1 (95% CI, 1.1-3.9) for disease-free survival, compared with those carrying the Arg (C) allele. These results suggest that polymorphisms in the CYP19A1 gene may have effects on breast cancer prognosis.     

Genetic polymorphisms and metastatic breast cancer survival

Variability of disease progression and survival exists among metastatic breast cancer patients. Treatment efficacy may be dependent on genetic variants in DNA repair and cell-cycle regulatory genes. This study examined three genetic variants in DNA repair and cell-cycle control genes (XRCC1, XRCC3 and CCND1) in 95 patients treated with high-dose chemotherapy. They found that all three were significantly associated with disease progression and survival independently, and that combinations of these variants progressively worsened breast cancer survival. Prior to identifying these genetic variants as prognostic indicators, replication of results in large randomized trials using standard treatment regimens is warranted.     

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 polymorphisms of metastasis suppressor gene NME1 and breast cancer survival

PURPOSE: Ample evidence supports an important role of tumor metastasis suppressor genes in cancer metastatic processes. We evaluated the association of genetic polymorphisms of metastasis suppressor gene NME1 with breast cancer prognosis in a follow-up study of patients with primary breast cancer and further investigated the functions of these polymorphisms. EXPERIMENTAL DESIGN: NME1 genotypes were analyzed in a cohort of 1,134 breast cancer patients recruited as part of the Shanghai Breast Cancer Study who were followed for a median of 7.1 years. In vitro biochemical analyses were carried out to examine the function of NME1 gene polymorphisms. RESULTS: Single nucleotide polymorphisms (SNP) in the promoter region of the NME1 gene were found to be associated with breast cancer prognosis. Patients carrying the C allele in rs16949649 were associated with higher breast cancer-specific mortality [hazard ratio (HR), 1.4; 95% confidence interval (95% CI), 1.1-1.9] compared with those carrying the wild-type allele, and the association was more evident in patients with an early-stage cancer (HR, 1.7; 95% CI, 1.2-2.5). SNP rs2302254 was also associated with breast cancer prognosis, and the association was statistically significant for the risk of breast cancer relapse, metastasis, and death (HR, 1.3; 95% CI, 1.0-1.6). In vitro biochemical analyses showed that minor alleles in rs2302254 and rs3760468, which is in strong linkage disequilibrium with rs16949646, altered nuclear proteins binding capacity and reduced NME1 promoter activity, supporting the results from an association study of these SNPs with breast cancer survival. CONCLUSION: Promoter polymorphisms in the NME1 gene may alter its expression and influence breast cancer survival.     

OGG1 polymorphisms and breast cancer risk.

The role of oxidative stress in breast cancer risk is still unclear. OGG1 encodes an 8-oxoguanine DNA glycosylase/AP lyase that catalyzes the removal of 8-oxodeoxyguanosine from DNA. 8-Oxodeoxyguanosine, the most abundant lesion generated by oxidative stress, is highly mutagenic. Environmental sources of oxidative stress, such as alcohol consumption, cigarette smoking, high body mass index (BMI), and low fruits and vegetables intake, may modify the association of genetic polymorphisms with breast cancer risk. We investigated the association between three genetic polymorphisms in OGG1 (Ser(326)Cys, 7143A/G, and 11657A/G) and breast cancer risk among 1,058 cases and 1,102 controls participating in the Long Island Breast Cancer Study Project. No associations were observed between individual OGG1 polymorphisms, haplotypes, or diplotypes and breast cancer. The association between having at least one variant allele and breast cancer risk was stronger among moderate alcohol drinkers for Ser(326)Cys [odds ratio (OR), 1.82; 95% confidence interval (95% CI), 1.06-3.10] relative to nondrinkers with the wild-type genotype and among those with higher BMI for 7143A/G (OR, 1.47; 95% CI, 1.10-1.96) and for 11657A/G (OR, 1.41; 95% CI, 1.05-1.88), relative to women with BMI < 25 kg/m(2) and the wild-type genotype. However, the patterns were not seen for all three single nucleotide polymorphisms (SNP) nor were there any clear allele dose associations; only one interaction was statistically significant, assuming a multiplicative model (11657A/G, P(interaction) = 0.04). In summary, although we found some differences between the three OGG1 SNPs and breast cancer risk among moderate alcohol drinkers and women with higher BMI, replication of these results is needed to rule out spurious findings. In addition, data on functionality of these polymorphisms are crucial to understand if these modest differences are important.     

CYP17 &; SULT1A1 gene polymorphisms in Indian breast cancer

BACKGROUND: Breast cancer is the most common cancer among women worldwide. Life-time exposure to steroid hormones, especially estrogen, is a major risk factor for breast cancer. Functional polymorphisms in genes encoding steroid metabolizing enzymes may thus be important as biomarkers of individual susceptibility to breast cancer. The CYP17 and SULT1A1 genes encode for two enzymes involved in hormone biosynthesis and metabolism. Single nucleotide polymorphisms of these genes may result in inter-individual variability in steroid hormone biosynthesis and metabolism thus influence the development of breast cancer. METHODS: We tested this hypothesis by conducting a case - control study on a group of 140 breast cancer cases and 140 healthy age-matched controls. Analysis of CYP17 and SULT1A1 genotypes were done by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). RESULTS: The genetic polymorphisms of the estrogen-related genes SULT1A1(OR=2.5, 95% CI=1.28-4.98) and CYP17 (OR=4.1, 95= CI=1.78-9.63) were associated with an increased risk of breast cancer among postmenopausal women. Our data also showed evidence for the genetic regulation of serum 17 beta estradiol (E2) levels as measured by ELISA among the premenopausal women with a significant increase in the serum E2 level for the CYP17 A2 variants. CONCLUSION: These results suggest that both CYP17 and SULT1A1 genotypes could be important determinants of breast cancer risk in Indian women and may help in early identification of high risk subjects. Such genotype analysis resulting in a high-risk profile holds considerable promise for individualizing screening, diagnosis and therapeutic intervention in breast cancer.     

Genetic polymorphisms of ataxia telangiectasia mutated and breast cancer risk.

To evaluate the role of genetic polymorphisms of ataxia telangiectasia mutated (ATM) in the etiology of breast cancer, a hospital-based case-control study was conducted in Korea. Nine-hundred ninety-six histologically confirmed incident breast cancer cases and 1,181 cancer-free controls were recruited in Seoul between 1995 and 2003. Genotypes of the ATM polymorphisms-5144A > T, IVS21 + 1049T > C, IVS33 - 55T > C, IVS34 + 60G > A, and 3393T > G were determined by the 5'-nuclease assay. Individual haplotypes were estimated from genotype data by a Bayesian method. Five ATM alleles were found to be in strong linkage disequilibrium (D' > 0.82; P < 0.001). Haplotype frequencies were significantly different between cases and controls (chi2 test, P < 0.001). The ATM IVS21 + 1049 TC or CC, IVS34 + 60 GA or AA, and 3393 TG or GG genotypes were associated with increased breast cancer risk, particularly in premenopausal women [odds ratios (OR), 1.51; 95% confidence interval (CI), 1.11-2.05; OR, 1.42; 95% CI, 1.08-1.88; and OR, 1.37; 95% CI, 1.04-1.80, respectively]. Compared with diploid of TCCAG:TCCAG, the most common haplotype, the ATTGT:ATTGT was associated with decreased risk of breast cancer with borderline significance (OR, 0.77; 95% CI, 0.58-1.04) and TCCAG:ATCGT and ATTGT:ACCAG were associated with increased breast cancer risk (OR, 2.30; 95% CI, 1.18-4.48 and OR, 2.43; 95% CI, 1.1.07-5.52, respectively) after adjusting for age, education, age at first full-term pregnancy, parity, family history of breast cancer, alcohol consumption, and smoking. As the number of ATTGT haplotype decreased, the risk of breast cancer increased (P for trend < 0.01). Our results thus suggest that genetic polymorphisms of ATM play an important role in the development of breast cancer in Korean women.     

Common germline polymorphisms in COMT,CYP19A1, ESR1, PGR,SULT1E1 and STS and survival after a diagnosis of breast cancer

Although preliminary evidence suggests that germline variation in genes involved in steroid hormone metabolism may alter breast cancer prognosis, this has not been systematically evaluated. We examined associations between germline polymorphisms in 6 genes involved in the steroid hormone metabolism and signaling pathway (COMT, CYP19A1, ESR1, PGR, SULT1E1, STS) and survival among women with breast cancer participating in SEARCH, a population‐based case–control study. Blood samples from up to 4,470 women were genotyped for 4 possible functional SNPs in CYP19A1 and 106 SNPs tagging the common variation in the remainder of the genes. The genotypes of each polymorphism were tested for association with survival after breast cancer diagnosis using Cox regression analysis. Significant evidence of an association was observed for a COMT polymorphism (rs4818 p = 0.016) under the codominant model. This SNP appeared to fit a dominant model better (HR = 0.80 95% CI: 0.69–0.95, p = 0.009); however, the result was only marginally significant after permutation analysis adjustment for multiple hypothesis tests (p = 0.047). To further evaluate this finding, somatic expression microarray data from 8 publicly available datasets were used to test the association between survival and tumor COMT gene expression; no statistically significant associations were observed. A correlated SNP in COMT, rs4860, has recently been associated with breast cancer prognosis in Chinese women in a dominant model. These results suggest that COMT rs4818, or a variant it tags, is associated with breast cancer prognosis. Further study of COMT and its putative association with breast cancer prognosis is warranted. © 2009 UICC     

Genetic polymorphisms in the MMP-7 gene and breast cancer survival

Matrix metalloproteinase-7 (MMP-7) is a small secreted proteolytic enzyme with broad substrate specificity. Its expression has been shown to be associated with tumor invasion, metastasis and survival for a variety of cancers. We systematically evaluated single nucleotide polymorphisms (SNPs) in MMP-7 in relation to breast cancer survival in a large follow-up study. Included were 1,079 breast cancer cases that were recruited from 1996 to 1998 and followed for a median of 7.1 years as part of the Shanghai Breast Cancer Study (SBCS). Eleven SNPs, including 2 known functional promoter SNPs, were analyzed using the Affymetrix Targeted Genotyping System. Associations with survival were evaluated by Cox proportional hazards regression and Kaplan-Meier functions. Statistically significant associations with disease-free and/or overall survival (OS) were found for 5 polymorphisms; these associations were explained primarily by 2 SNPs (rs11568818 and rs11225297) that were in high linkage disequilibrium (LD) with the others. Patients homozygous for the rs11568818 rare allele (G) had a significantly worse prognosis (OS HR: 6.7, 95% CI: 2.4-18.6) than patients homozygous for the common allele (A). Significantly improved survival was seen for patients with the rs11225297 T allele, and this association occurred in a dose-response manner; patients with AT (OS HR: 0.7, 95% CI: 0.5-0.9) and TT (OS HR: 0.3, 95% CI: 0.1-0.8) fared better than patients with AA (p-value for trend: 0.001). Thus, common MMP-7 genetic polymorphisms were found to be significant determinants of survival among Chinese women with breast cancer.     

Association of CYP1B1 polymorphisms and breast cancer risk.

Cytochrome P450 1B1 catalyzes the conversion of 17-beta-estradiol (E2) to thecatechol estrogen metabolites 2-OH-E2 and 4-OH-E2 that have been postulated to be involved in mammary carcinogenesis. We sought to determine whether two common functional polymorphisms in Cytochrome P450 1B1, V432L (m1), and A453S (m2) are related to breast cancer risk. Using a nested case control design within the Nurses' Health Study cohort, we genotyped 453 cases and 456 controls and found no significant association between m1[val/leu and leu/leu versus val/val, OR = 1 (CI, 0.72-1.45)] or m2 [asn/ser and ser/ser versus asn/asn, OR = 0.8 (CI, 0.62-1.15)] and breast cancer risk. However, we did observe women with the Val/Val (m1) genotype to have a higher percentage of estrogen receptor-positive tumors (P = 0.03). We did not observe any correlation with the m2 genotypes and estrogen receptor status. The association of the m1 and m2 genotypes on plasma hormone levels in postmenopausal control women not using hormone replacement therapy was also evaluated. Carriers of the m1 leu and m2 ser alleles had modestly higher estradiol levels but similar estrone and estrone sulfate levels. The results presented do not support a strong association between m1 and m2 and the risk of breast cancer.     

Genetic polymorphisms in base-excision repair pathway genes and risk of breast cancer.

Impaired base-excision repair (BER) function can give rise to the accumulation of DNA damage and initiation of cancer. We evaluated whether genetic variation in six BER pathway genes (XRCC1, ADPRT, APEX1, OGG1, LIG3, and MUTYH) is associated with breast cancer risk in two large population-based case-control studies in the United States (3,368 cases and 2,880 controls) and Poland (1,995 cases and 2,296 controls). A detailed evaluation was first done in a subset of 1,898 cases and 1,514 controls with mouthwash DNA samples in the U.S. study. Significant findings were followed up in the remainder of the U.S. study population that provided cytobrush DNA samples and in the Polish study. Using data from U.S. study participants with mouthwash DNA, we found no significant overall association between breast cancer risk and XRCC1 R280H and R194W, ADPRT V726W, APEX1 D148E, OGG1 S326C, LIG3 R780H, or MUTYH 5' untranslated region. These data suggested a decreased risk for XRCC1Q399R homozygous variants compared with homozygous wild-type in premenopausal women, but these findings were not confirmed when data from cytobrush DNA samples were added [combined odds ratio (OR), 0.8; 95% confidence interval (95% CI), 0.6-1.1] or in the Polish study (OR, 1.0; 95% CI, 0.7-1.5). Meta-analyses based on our data and published data from studies of two single nucleotide polymorphisms in XRCC1 showed no evidence of an overall association between breast cancer risk and homozygous variants versus wild-type for Q399R (OR, 1.1; 95% CI, 1.0-1.2) or R194W (OR, 1.0; 95% CI, 0.7-1.8), although there was a suggestion for an association in Asian populations for Q399R (OR, 1.6; 95% CI, 1.1-2.4; P = 0.02). In conclusion, our results do not support that the polymorphisms evaluated in six BER pathway genes play a major role in breast carcinogenesis, particularly in Caucasian populations.     

Role of estradiol metabolism and CYP1A1 polymorphisms in breast cancer risk.

The endogenous metabolism of estrogens is primarily oxidative and involves hydroxylation of the steroid at either C2 (2-OHE1) or C16 (16-OHE1). While the 2-OHE1 metabolites are essentially devoid of peripheral biological activity, 16-OHE1 is an estrogen agonist. There is evidence of an association between the 2-OHE1/16-OHE1 metabolites ratio and breast cancer risk. The CYP1A1 gene may play a role in the 2-hydroxylation (2-OH) of estradiol. African-American women with the wild-type CYP1A1 gene showed a significant increase in the 2-OHE1/16-OHE1 ratio, from 1.35 +/- 0.56 at baseline to 2.39 +/- 0.98 (p = 0.006) after 5 days of treatment with indole-3-carbinol (400 mg/day), a 2-OHE1 inducer. Women with the Msp1 polymorphism showed no significant increase, (0.37% +/- 0.17%). In a case-control study involving 57 women with breast cancer and 312 female controls, the frequency of the homozygous Msp1 polymorphism was 4.2% in African-American controls and 16% in African-American breast cancer cases. The odds ratio of breast cancer with the Msp1 homozygous variant was 8.4 (95% confidence interval: 1.7-41.7). This association was not observed in Caucasian women. The other CYP1A1 polymorphisms were not associated with breast cancer. The CYP1A1 Msp1 polymorphism may be a marker of altered estradiol metabolism and of increased susceptibility to estrogen-related breast cancer in African-Americans.     

Genetic variation in SIPA1 in relation to breast cancer risk and survival after breast cancer diagnosis

Genetic variation in SIPA1, signal‐induced proliferation‐associated gene 1, has been proposed to be associated with aggressive breast tumor characteristics related to metastasis and worse prognosis in humans and rodents. To test this hypothesis, we genotyped 3 single nucleotide polymorphisms (SNP) located at ?3092 (AT, rs3741378), and exon 14 + 14 (C>T, rs746429), and examined them in relation to breast cancer risk and overall survival, stratified by tumor characteristics in 2 independent case–control studies conducted in Poland (1,995 cases, 2,296 controls) and in Britain (2,142 cases, 2,257 controls). Vital status (n = 396 deaths) was available for 911 Polish and 1,919 British breast cancer cases with an average follow‐up time of 5.5 years. Overall, we found no significant associations between genetic variants of SIPA1 SNPs and breast cancer risk (per allele odds ratios, 95% confidence intervals (CI): rs931127–0.99, 0.93–1.06; rs3741378–1.03, 0.94–1.13; and, rs74642–0.98, 0.92–1.04). In both studies, SIPA1 polymorphisms were not related to overall mortality (per allele hazard ratios, 95% CI: 1.02, 0.88–1.17; 0.90, 0.72–1.11; 1.04, 0.90–1.21, respectively). Our results do not support a relationship between SIPA1 polymorphisms and breast cancer risk or subsequent survival. Published 2008 Wiley‐Liss, Inc.     

Genetic polymorphisms in human SULT1A1 and UGT1A1 genes associate with breast tumor characteristics: a case-series study

Introduction

Estrogens are important in breast cancer development. SULT1A1 and UGT1A1 catalyze estrogen metabolism and are polymorphic. The SULT1A1*2 protein exhibits low activity, and a TA repeat within the UGT1A1 promoter alters the level of expression of the protein. We hypothesized that the SULT1A1*2 allozyme has decreased capacity to sulfate estrogens, that the SULT1A1*2 allele conferred increased capacity of cells to proliferate in response to estrogens, and that individuals with the variant SULT1A1 and UGT1A1 genotypes exhibited different breast tumor characteristics.

Methods

The capacity for SULT1A1*2 to sulfate 17β-estradiol and the capacity for cells expressing SULT1A1*1 or SULT1A1*2 to proliferate in response to 17β-estradiol was evaluated. A case-series study was performed in a total of 210 women with incident breast cancer, including 177 Caucasians, 25 African-Americans and eight women of other ethnic background. The SULT1A1 and UGT1A1 genotypes were determined and a logistic regression model was used to analyze genotype–phenotype associations.

Results

We determined that the SULT1A1*1/*1 high-activity genotype was associated with tumor size ≤2 cm (odds ratio = 2.63, 95% confidence interval = 1.25–5.56, P = 0.02). Individuals with low-activity UGT1A1 genotypes (UGT1A1*28/*28 or UGT1A1*28/*34) were more likely to have an age at diagnosis ≥60 years (odds ratio = 3.70, 95% confidence interval = 1.33–10.00, P = 0.01). Individuals with both SULT1A1 and UGT1A1 high-activity genotypes had low tumor grade (odds ratio = 2.56, 95% confidence interval = 1.04–6.25, P = 0.05). Upon stratification by estrogen receptor status, significant associations were observed predominantly in estrogen receptor-negative tumors.

Conclusion

The data suggest that genetic variation in SULT1A1 and UGT1A1 may influence breast cancer characteristics and might be important for breast cancer prognosis.     

Genetic polymorphisms and cancer risk

While hereditary disease genes have a high lifelong cumulative incidence rate (penetrance), the penetrance for polymorphism genotypes is not high. Polymorphisms relating to cancer incidence are classified into 1. carcinogen metabolizing enzymes (CYPs, GSTs, NQO1, etc.), 2. DNA repair enzymes (OGG1, XRCC1, XPD, etc.), 3. DNA synthesis and methylation (MTHFR, MS, etc.), 4. cytokines and inflammation-related enzymes (IL-1B, TNF-A, MPO, etc.), and 5. sex hormone metabolizing enzymes and the receptors (CYP19, SRD5A2, ER, etc.). Since genotypes cannot be manipulated, they are not the factors subject to prevention. However, the finding that the strength of association between lifestyle and disease occurrence is influenced by genotypes (gene-environment interaction), opens the door to genotype applications for disease prevention practice.     

Genetic polymorphisms in RNA binding proteins contribute to breast cancer survival

The RNA‐binding proteins TTP and HuR control expression of numerous genes associated with breast cancer pathogenesis by regulating mRNA stability. However, the role of genetic variation in TTP (ZFP36) and HuR (ELAVL1) genes is unknown in breast cancer prognosis. A total of 251 breast cancer patients (170 Caucasians and 81 African–Americans) were enrolled and followed up from 2001 to 2011 (or until death). Genotyping was performed for 10 SNPs in ZFP36 and 7 in ELAVL1 genes. On comparing both races with one another, significant differences were found for clinical and genetic variables. The influence of genetic polymorphisms on survival was analyzed by using Cox‐regression, Kaplan‐Meier analysis and the log‐rank test. Univariate (Kaplan‐Meier/Cox‐regression) and multivariate (Cox‐regression) analysis showed that the TTP gene polymorphism ZFP36*2 A > G was significantly associated with poor prognosis of Caucasian patients (HR = 2.03; 95% CI = 1.09–3.76; p = 0.025; log‐rank p = 0.022). None of the haplotypes, but presence of more than six risk genotypes in Caucasian patients, was significantly associated with poor prognosis (HR=2.42; 95% CI = 1.17–4.99; p = 0.017; log‐rank p = 0.007). The effect of ZFP36*2 A > G on gene expression was evaluated from patients' tissue samples. Both TTP mRNA and protein expression was significantly decreased in ZFP36*2 G allele carriers compared to A allele homozygotes. Conversely, upregulation of the TTP‐target gene COX‐2 was observed ZFP36*2 G allele carriers. Through its ability to attenuate TTP gene expression, the ZFP36*2 A > G gene polymorphism has appeared as a novel prognostic breast cancer marker in Caucasian patients.     

A systematic review of genetic polymorphisms and breast cancer risk.

Studies investigating the relationship between common genetic variants and cancer risk are being reported with rapidly increasing frequency. We have identified 46 published case-control studies that have examined the effect of common alleles of 18 different genes on breast cancer risk. Of these, 12 report statistically significant associations, none of which were reported by more than one study. However, many of the studies were small: 10 of the 46 had 80% power or greater to detect a rare allele homozygote relative risk <2.5. We therefore combined the results of individual studies to obtain more precise estimates of risk. Statistically significant differences in genotype frequencies were found in three case-control comparisons of unselected cases. These were for CYP19 (TTTA)n polymorphism [(TTTA)10 carrier odds ratio (OR) = 2.33; P = 0.002], the GSTP1 Ile105Val polymorphism (Val carrier OR = 1.60; P = 0.02), and the TP53 Arg72Pro polymorphism (Pro carrier OR = 1.27; P = 0.03). In addition, the GSTM1 gene deletion was found to be significantly associated with postmenopausal breast cancer (null homozygote OR = 1.33; P = 0.04). There was also some evidence that homozygotes for the PR PROGINS allele are protected against breast cancer, although this result was of borderline statistical significance. For polymorphisms in BRCA1, COMT, CYP17, CYP1A1, NAT1, and NAT2, the best estimate of risk either from the individual studies or the meta-analyses was sufficiently precise to exclude a relative risk of 1.5 or greater. For the polymorphisms in EDH17B2, ER, CYP2D6, CYP2E1, GSTT1, HSP70, and TNFalpha, the risk estimates, although nonsignificant, were insufficiently precise to exclude a moderate risk (>1.5). Precise estimation of the risks associated with these and other as yet untested genes, as well as investigation of more complex risks arising from gene-gene and gene-environment interactions, will require much larger studies.