Association of breast cancer risk with a common functional polymorphism (Asp327Asn) in the sex hormone-binding globulin gene.

Sex hormones play a central role in the development of breast cancer. Sex hormone-binding globulin (SHBG) modulates the bioavailability of circulating sex hormones and regulates their signaling system in the breast tissue. We evaluated the association of a common functional polymorphism (Asp327Asn) in the SHBG gene with breast cancer risk in a population-based case-control study (1,106 cases and 1,180 controls) conducted in Shanghai, China. The variant Asn allele was associated with a reduced breast cancer risk in postmenopausal women [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.53-0.99], but not in premenopausal women (OR, 1.03; 95% CI, 0.82-1.27). The protective association was much stronger in postmenopausal women with a low body mass index (BMI; OR, 0.46; 95% CI, 0.29-0.75) or waist-to-hip ratio (OR, 0.51; 95% CI, 0.32-0.83) than those with a high BMI or waist-to-hip ratio (P for interaction < 0.05). Furthermore, the association was stronger for estrogen receptor-positive (OR, 0.64; 95% CI, 0.42-0.98) than for estrogen receptor-negative breast cancer (OR, 0.85; 95% CI, 0.50-1.45). Among postmenopausal controls, blood SHBG levels were 10% higher in carriers of the variant Asn allele than noncarriers (P = 0.06). Postmenopausal control women with the Asn allele and low BMI or waist-to-hip ratio had 20% higher SHBG levels (P < 0.05). This study suggests that the Asn allele in the SHBG gene may be related to a reduced risk of breast cancer among postmenopausal women by increasing their blood SHBG levels.     

Estrogen metabolism genotypes, use of long-term hormone replacement therapy and risk of postmenopausal breast cancer

Association between long-term hormone replacement therapy (HRT) use and increased risk of breast cancer is still under debate. Functionally relevant genetic variants within the estrogen metabolic pathway may alter exposure to exogenous sex hormones and affect the risk of postmenopausal breast cancer. We investigated the associations of common polymorphisms in 4 genes encoding key proteins of the estrogen metabolic pathway, duration of HRT use and their interactions with breast cancer risk. We studied 530 breast cancer cases and 270 controls of the same age and ethnicity participating in a case-control study of postmenopausal women. Duration of HRT use was ascertained through a postal questionnaire. Genotyping was conducted for CYP1B1 (rs1056836), COMT (rs4680), GSTP1 (rs1695) and MnSOD (rs4880) polymorphisms by PCR-based RFLP and TaqMan? allelic discrimination method. Adjusted odds ratios and 95% confidence intervals were calculated using logistic regression analysis. HRT use was significantly associated with decreased breast cancer risk (p<0.001). None of the polymorphisms studied was associated with breast cancer risk. A significant interaction was observed between MnSOD 47T>C and HRT use (pinteraction=0.036); the risk of breast cancer associated with long-term vs. short-term HRT use was decreased in women homozygous for the wild-type allele and increased in women with at least one variant allele of the MnSOD 47T>C polymorphism. Our results suggest that MnSOD 47T>C polymorphism in interaction with long-term HRT use may modify the risk of breast cancer.     

Body mass index and colon cancer: an evaluation of the modifying effects of estrogen (United States)

Objective: The association between body mass index (BMI) and colon cancer has been reported to be different for men and women. No prior literature has examined if estrogen influences these differences. Methods: Using data from an incident population-based case (n = 1972) and control (n = 2386) study of colon cancer we evaluated if estrogen modifies the association between BMI and risk of colon cancer. Results: Women who were estrogen-negative (postmenopausal women not taking hormone replacement therapy, HRT) were at increased risk of colon cancer regardless of indicator of estrogen status used (i.e. estrogen-negative compared to estrogen-positive women defined as either being premenopausal or postmenopausal women using HRT, OR 1.54, 95% CI 1.23–1.93; no recent exposure to estrogens compared to current or HRT use within the past 2 years, OR 1.58, 95% CI 1.24–2.00; postmenopausal women not currently using HRT compared to postmenopausal women taking HRT, OR 1.65, 95% CI 1.29–2.12). BMI (kg/m²) was not associated with an increased risk of colon cancer among women who were estrogen-negative. However, women who were estrogen-positive experienced a greater than two-fold increase in colon cancer risk if they had a BMI of > 30 relative to those who had a BMI of <23 (for estrogen-positive, OR, 2.50, 95% CI 1.51–4.13; premenopausal, OR 2.19, 95% CI 0.94–5.07; postmenopausal using HRT, OR 3.36, 95% CI 1.58–7.13). Among men the colon cancer risk associated with BMI decreased with advancing age. Physical activity modified the increased colon cancer risk associated with a large BMI. Conclusions: These data suggest the importance of estrogen in colon cancer etiology. Being estrogen-negative resulted in a significant increased risk of colon cancer. However, BMI significantly increased the risk of colon cancer among women who were estrogen-positive. We hypothesize that estrogen up-regulates IGF-I receptors and IRS-I levels in the colon, which in turn increases susceptibility to obesity-induced increased levels of insulin. We further hypothesize that androgens may have similar effects in men given the decline in colon cancer risk associated with BMI with advancing age.     

Polymorphisms in CYP1A1 and breast carcinoma risk in a population-based case-control study of Chinese women

BACKGROUND: Cytochrome P450 1A1 (CYP1A1) is involved in the 2-hydroxylation of estrogen, the hormone that plays a critical role in the etiology of breast carcinoma. METHODS: The authors evaluated common polymorphisms in the CYP1A1 gene in relation to breast carcinoma risk in a large population-based case-control study among Chinese women, the Shanghai Breast Cancer Study. Because the CYP1A1*3 and CYP1A1*4 alleles were not detected in the study population, analyses were performed for CYP1A1*2A (T-->C transition in the 3' noncoding region) and CYP1A1*2C (A-->G transition in exon 7, resulting in a substitution of Val for Ile) in 1134 patients with breast carcinoma and 1227 controls. RESULTS: The frequencies of the variant allele were 38.3% and 38.8% among cases and controls (P = 0.91), respectively, for the CYP1A1*2A polymorphism, and 23.1% and 24.8% (P = 0.26) for the CYP1A1*2C polymorphism. Homozygosity for both variant alleles in these 2 polymorphic sites (CYP1A1*2B) was associated with a borderline significant odds ratio (OR) of 0.71 (95% confidence interval [CI], 0.47-1.06). The reduced risk was more pronounced among postmenopausal women with long duration (> 30 yrs) of menstruation (OR = 0.43; 95% CI, 0.19-0.99) or among women with a low waist-to-hip ratio (OR = 0.52; 95% CI, 0.28-0.94). CONCLUSIONS: Results from the current study suggest that homozygosity for the CYP1A1*2A and CYP1A1*2C alleles in the CYP1A1 gene may be associated with a reduced risk for breast carcinoma, particularly among lean women with long-term endogenous estrogen exposure.     

Urinary hydroxyestrogens and breast cancer risk among postmenopausal women: a prospective study.

BACKGROUND: It has been suggested that a low level of the 2-hydroxyestrogen metabolites (2-OHE) and a high level of 16alpha-hydroxyestrone (16alpha-OHE1) are associated with an enhanced risk of breast cancer. We examined the association between the metabolite levels and breast cancer in a nested case-control study, which also addressed hormone replacement therapy (HRT) and estrogen receptor status of the tumors. METHODS: 24,697 postmenopausal Danish women were enrolled in the "Diet, Cancer and Health" cohort. During follow-up, 426 breast cancer cases were identified and controls were matched by age at diagnosis, baseline age, and HRT use. The concentrations of 2-OHE and 16alpha-OHE1 in spot urine were measured by an enzyme immunoassay. Incidence rate ratios (IRR) and 95% confidence intervals (95% CI) were estimated for total and estrogen receptor-specific breast cancer and were stratified according to HRT use. RESULTS: A higher incidence of estrogen receptor-positive breast cancer with an enhanced 2-OHE level was observed among current HRT users, IRR per doubling = 1.30 (95% CI, 1.02-1.66), whereas no association was seen among nonusers of HRT, IRR per doubling = 1.00 (95% CI, 0.69-1.45). The association between estrogen receptor-positive breast cancer and the 16alpha-OHE1 metabolite level was in the opposite direction but slightly weaker and statistically insignificant. For estrogen receptor-negative breast cancer, no significant associations were seen. CONCLUSIONS: The risk of breast cancer, in particular the estrogen receptor-positive type, was enhanced among postmenopausal women using estradiol-based HRT and among those who had a high 2-OHE concentration.     

The CYP19 gene codon 39 Trp/Arg polymorphism increases breast cancer risk in subsets of premenopausal Japanese.

The production of estrogen from androgen via the estrogen biosynthesis pathway is catalyzed by aromatase P450 (CYP19). To assess the association between breast cancer risk and a polymorphism at codon 39 Trp/Arg of the encoding gene, a case-control study was conducted at Aichi Cancer Center Hospital in Japan. Subjects were 248 histologically confirmed breast cancer patients and 603 hospital controls without cancer. Odds ratios (OR) and 95% confidence intervals (95% CI) were determined by logistic regression analysis. The allele frequency among controls was 3.8% for the C allele, and the OR (95% CI) of the polymorphism relative to TT genotype was 1.21 (0.69-2.14) for TC/CC genotypes combined. There was no association between CYP19 gene polymorphism and breast cancer risk in the study group as a whole, but homozygous and heterozygous carriers of the variant Arg allele showed a significantly increased risk of breast cancer among premenopausal women with a late age at first full-term pregnancy (OR 7.31, 95% CI 1.88-28.5) or a high body mass index (OR 2.77, 95% CI 1.12-6.87). Additional larger studies should be done to confirm that the rare CYP19 variant increases the risk of breast cancer among premenopausal Japanese women.     

The relationship between a polymorphism in CYP17 with plasma hormone levels and breast cancer

The A2 allele of CYP17 has been associated with polycystic ovarian syndrome, elevated levels of certain steroid hormones in premenopausal women, and increased breast cancer risk. We prospectively assessed the association between the A2 allele of CYP17 and breast cancer risk in a case-control study nested within the Nurses' Health Study cohort. We also evaluated associations between this CYP17 genotype and plasma steroid hormone levels among postmenopausal controls not using hormone replacement to assess the biological significance of this genetic variant. Women with the A2 allele were not at an increased risk of incident breast cancer [OR (odds ratio), 0.85; 95% CI (confidence interval), 0.65-1.12] or advanced breast cancer (OR, 0.84; 95% CI, 0.54-1.32). We did observe evidence that the inverse association of late age at menarche with breast cancer may be modified by the CYP17 A2 allele. The protective effect of later age at menarche was only observed among women without the A2 allele (A1/A1 genotype: for age at menarche > or =13 versus <13; OR, 0.57; 95% CI, 0.36-0.90; A1/A2 and A2/A2 genotypes: OR, 1.05; 95% CI, 0.76-1.45; P for interaction = 0.07). Among controls, we found women with the A2/A2 genotype to have elevated levels of estrone (+14.3%, P = 0.01), estradiol (+13.8%, P = 0.08), testosterone (+8.6%, P = 0.34), androstenedione (+17.1%, P = 0.06), dehydroepiandrosterone (+14.4%, P = 0.02), and dehydroepiandrosterone sulfate (+7.2%, P = 0.26) compared with women with the A1/A1 genotype. These data suggest that the A2 allele of CYP17 modifies endogenous hormone levels, but is not a strong independent risk factor for breast cancer.     

Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin

BACKGROUND: Hormone replacement therapy (HRT) given as unopposed estrogen replacement therapy (ERT) gained widespread popularity in the United States in the 1960s and 1970s. Recent prescribing practices have favored combination HRT (CHRT), i.e., adding a progestin to estrogen for the entire monthly cycle (continuous combined replacement therapy [CCRT]) or a part of the cycle (sequential estrogen plus progestin therapy [SEPRT]). Few data exist on the association between CHRT and breast cancer risk. We determined the effects of CHRT on a woman's risk of developing breast cancer in a population-based, case-control study. METHODS: Case subjects included those with incident breast cancers diagnosed over 4(1/2) years in Los Angeles County, CA, in the late 1980s and 1990s. Control subjects were neighborhood residents who were individually matched to case subjects on age and race. Case subjects and control subjects were interviewed in person to collect information on known breast cancer risk factors as well as on HRT use. Information on 1897 postmenopausal case subjects and on 1637 postmenopausal control subjects aged 55-72 years who had not undergone a simple hysterectomy was analyzed. Breast cancer risks associated with the various types of HRT were estimated as odds ratios (ORs) after adjusting simultaneously for the different forms of HRT and for known risk factors of breast cancer. All P values are two-sided. RESULTS: HRT was associated with a 10% higher breast cancer risk for each 5 years of use (OR(5) = 1.10; 95% confidence interval [CI] = 1.02-1.18). Risk was substantially higher for CHRT use (OR(5) = 1.24; 95% CI = 1.07-1.45) than for ERT use (OR(5) = 1. 06; 95% CI = 0.97-1.15). Risk estimates were higher for SEPRT (OR(5) = 1.38; 95% CI = 1.13-1.68) than for CCRT (OR(5) = 1.09; 95% CI = 0. 88-1.35), but this difference was not statistically significant. CONCLUSIONS: This study provides strong evidence that the addition of a progestin to HRT enhances markedly the risk of breast cancer relative to estrogen use alone. These findings have important implications for the risk-benefit equation for HRT in women using CHRT.     

Hormone replacement therapy and breast carcinoma risk in Hispanic and non-Hispanic women

BACKGROUND: Hormone replacement therapy (HRT) alleviates menopausal symptoms and prevents osteoporosis, but there is concern that long-term use may have an adverse impact on breast carcinoma risk. Epidemiologic studies report inconsistent findings regarding the relationship between HRT and postmenopausal breast carcinoma risk and there is little information on the HRT-associated risk among minority women. METHODS: To investigate the effects of HRT on breast carcinoma risk among Hispanic women, we examined data from the New Mexico Women's Health Study (NMWHS), a statewide case-control study comprising 366 postmenopausal women with breast carcinoma and 403 controls. Conditional logistic regression was used to estimate the odds ratios (OR) and 95% confidence intervals (95% CI). RESULTS: After adjustment for sociodemographic, medical, and reproductive factors, we found an increased risk associated with long-term users of estrogen replacement therapy (ERT; OR for ERT use longer than 140 months was 2.57, 95%CI, 1.25-5.28, compared with ERT use shorter than 17 months). In addition, there was a positive trend with the duration of ERT use (P < 0.01). Hispanic postmenopausal women appeared to be at a significantly greater risk than non-Hispanic white women (OR for ERT use longer than 140 months in Hispanics was 5.53, 95%CI, 1.47-20.87; OR in non-Hispanics was 2.65, 95%CI, 0.95-7.34, compared with ERT use shorter than 17 months). In contrast, no significant association was observed for combined estrogen-progesterone use in either Hispanic or non-Hispanic women. CONCLUSIONS: The results of this study indicated that postmenopausal women had significantly increased breast carcinoma risk for long-term ERT use. The risks among Hispanic women were substantially higher than among non-Hispanic white women although they were not statistically significant.     

A population-based case-control study of the Arg399Gln polymorphism in DNA repair gene XRCC1 and risk of breast cancer.

XRCC1 (X-ray repair cross-complementing group 1) is a base excision repair protein that plays a central role in the repair of DNA base damage and strand breaks. A common polymorphism (Arg-->Gln) at codon 399 of the XRCC1 gene has been previously linked to functional changes of the gene product and risk of cancers. We evaluated the association between XRCC1 Arg399Gln polymorphism and breast cancer risk in the population-based Shanghai Breast Cancer Study involving 1088 cancer patients and 1182 community controls. Genomic DNA from peripheral blood was used in genotyping assays, and exposure information and anthropometrics were collected through in-person interview. Plasma estrogen and sex hormone-binding globulin (SHBG) levels were measured for 190 postmenopausal breast cancer patients who had donated a pretreatment blood sample and 407 postmenopausal controls. Conditional logistic regression model was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusting potential confounders. Approximately 27% of controls carried the variant allele (Gln), and cases and controls had a similar distribution for both allele type and genotype of this polymorphism. We found that 7.8% of cases and 6.3% of controls were homozygous for the variant allele, resulting in an OR of 1.20 (95% CI, 0.85-1.69). The OR was slightly higher among younger women [<45 years of age (OR, 1.39; 95% CI, 0.82-2.36)] than older women [> or = 45 years of age (OR, 1.07; 95% CI, 0.68-1.67)], but neither OR was statistically significant. No modifying effect of major breast cancer risk factors, including years of menstruation, body mass index, waist:hip ratio, and blood estrogen levels, was noted. Homozygosity for the variant Gln allele was associated with an elevated risk of postmenopausal breast cancer among subjects with a higher blood level of SHBG (OR, 3.27; 95% CI, 1.16-9.20) and a reduced risk among those with a lower level of SHBG (OR, 0.60; 95% CI, 0.18-1.97). The overall results of the study suggest that Arg399Gln polymorphism of the XRCC1 gene alone may not play a substantial role in the risk of breast cancer among Chinese women.     

Cytochrome P450 1B1 and catechol-O-methyltransferase polymorphisms and endometrial cancer susceptibility

Estrogen production and metabolism play critical roles in the development and pathogenesis of endometrial carcinoma. Cytochrome P450 1B1 (CYP1B1) and catechol-O-methyltransferase (COMT) are two key enzymes in the estrogen metabolism pathway that result in the hydroxylation and conjugation of estradiol, respectively. We evaluated the association between the CYP1B1 Leu432Val and CYP1B1 Asn453Ser polymorphisms and the COMT Val158Met polymorphism and invasive endometrial cancer risk in a case-control study nested within the Nurses' Health Study (n = 222 cases, 666 controls). We also evaluated whether body mass index (BMI), postmenopausal hormone (PMH) use and cigarette smoking modified the associations of the CYP1B1 and COMT genotypes and endometrial cancer risk. Conditional logistic regression was used to calculate the adjusted odds ratios (OR) and 95% confidence intervals (CI) to quantify the risk of endometrial cancer among subjects who had at least one variant allele compared with subjects who were homozygous for the wild-type allele. Carriers of the CYP1B1 Ser allele had a statistically significant decreased risk of endometrial cancer (OR = 0.62; 95% CI, 0.42-0.91); there was no significant association between the CYP1B1 Val allele and endometrial cancer risk (OR = 1.10; 95% CI, 0.75-1.59). Compared with the COMT Val/Val wildtype genotype, the adjusted OR of endometrial cancer for women with the COMT Val/Met or COMT Met/Met genotype was 0.96 (95% CI, 0.65-1.43). We did not observe any effect modification by BMI, PMH use and cigarette smoking for the CYP1B1 and COMT genotypes. Our data suggest, that the CYP1B1 Ser allele may decrease endometrial cancer risk by altering the production of catechol estrogens. However, further studies are warranted to elucidate the role of CYP1B1 in endometrial cancer.     

Risk of endometrial cancer and estrogen replacement therapy history by CYP17 genotype

Common variants among genes coding for enzymes in sex steroid biosynthetic pathways may influence the risk of endometrial cancer. We examined the association between endometrial cancer risk and estrogen replacement therapy (ERT) by CYP17 genotype using 51 incident cases and 391 randomly selected controls from a multiethnic cohort in Hawaii and Los Angeles, California. The relative risk of endometrial cancer was calculated for ever use versus never use of ERT by CYP17 genotype (TT, TC, and CC). We found that women who reported ever taking ERT were more than twice as likely to develop endometrial cancer as women who never took ERT [odds ratio (OR), 2.24; 95% confidence interval (CI), 1.19-4.23]. Among these women, the risk of endometrial cancer was higher for women homozygous for the CYP17 T allele (OR, 4.10; 95% CI, 1.64-10.3), but not for women with the C allele (OR, 1.31; 95% CI, 0.53-3.21). These preliminary findings suggest that CYP17 or other variants in estrogen biosynthesis or metabolism pathways may be potential markers of endometrial cancer susceptibility due to ERT.     

HSD17B1 and CYP17 polymorphisms and breast cancer risk among Chinese women in Singapore

Reasons for the recent trend of increasing breast cancer incidence among Chinese and other Asian women are not well understood. Endogenous estrogen levels are strongly associated with breast cancer risk and its determinants include both genetic and lifestyle factors. We conducted a nested case-control study to investigate, within the Singapore Chinese Health Study Cohort, the relationships between polymorphisms in 2 genes involved in estrogen metabolism, CYP17 and HSD17B1, and the risk of breast cancer. For this analysis, 188 incident breast cancer cases and 671 female cohort control subjects were compared. When the HSD17B1 A allele was considered as the "putative high-risk" allele, there was a modest increased risk (adjusted relative risk, RR=1.37, 95% CI=0.90-2.07 for HSD17B1 AA vs. other); this association was statistically significant in analysis restricted to postmenopausal women (RR=1.86, 95% CI=1.14-3.03). There was no significant association between the CYP17 MspAI polymorphism and risk in all subjects (RR=1.06, 95% CI=0.65-1.74 for CYP17 A2A2 vs. CYP17 A1A1) or in postmenopausal women only. When we evaluated breast cancer risk in relation to the joint stratification of CYP17 and HSD17B1 genotypes and according to the combined number of putative high-risk alleles (range, 0-4), we observed an elevated joint effect of the CYP17 and HSD17B1 genes on risk. Women who possessed all 4 putative high-risk alleles of both genes (CYP17 A2A2 and HSD17B1 AA) vs. less displayed a nearly 2-fold increased risk (RR=1.83, 95% CI=0.97-3.44); this finding was statistically significant in postmenopausal women (RR=2.31, 95% CI=1.07-4.98). Risk of breast cancer was similar among women possessing the other genotypes (i.e., less than 4 putative high-risk alleles in the joint CYP17/HSD17B1 genotypes). In addition, the significant increased risk of breast cancer associated with nulliparity or late age at first live birth (age 31 years or older) was largely limited to women with the high-risk CYP17 A1A2/A2A2 or HSD17B1 AA genotypes (RR=2.41, 95% CI=1.56-3.72; RR=4.39, 95% CI=1.71-11.30, respectively). The latter gene-parity effects were especially pronounced in postmenopausal women.     

Hormone replacement therapy in relation to breast carcinoma incidence rate ratios: a prospective Danish cohort study

BACKGROUND: The goal of the current study was to investigate the relation between hormone replacement therapy (HRT) and breast carcinoma in a prospective study cohort. Particular attention was paid to the type of HRT used and to the association of HRT type with estrogen receptor status and tumor histology. METHODS: Between 1993 and 1997, a total of 29,875 women were enrolled in the Danish Cancer Society's prospective "Diet, Cancer and Health" study. Among 23,618 women who were assumed to be postmenopausal and for whom information on HRT use was available, we identified 423 cases of breast carcinoma over a median follow-up period of 4.8 years. Statistical analyses were based on the Cox proportional hazards model, with age serving as the time parameter. RESULTS: The breast carcinoma incidence rate ratio (IRR) was 2.22 (95% confidence interval [CI], 1.80-2.75) for users of HRT at baseline compared with women who never received HRT. Among HRT users (relative to nonusers), the IRR for estrogen receptor-positive tumors (2.38; 95% CI, 1.84-3.06) was greater than the IRR for estrogen receptor-negative tumors (1.56; 95% CI, 1.00-2.43). HRT use at baseline also was analyzed in relation to the incidence of lobular carcinoma and the incidence of ductal carcinoma; the adjusted IRR associated with HRT use was 3.53 (95% CI, 1.94-6.41) for lobular carcinoma and 2.10 (95% CI, 1.64-2.70) for ductal carcinoma. The likelihood of developing estrogen receptor-positive breast carcinoma was found to depend significantly on the type of HRT regimen used (P = 0.03), with women receiving continuous therapy having the greatest probability of developing estrogen receptor-positive disease. CONCLUSIONS: An increased breast carcinoma IRR was found to be associated with current HRT use. In addition, relative to other types of HRT regimens, continuous estrogen + progestin regimens were found to be associated with an increased risk of breast carcinoma, and particularly estrogen receptor-positive breast carcinoma.     

Polymorphisms and haplotypes in the cytochrome P450 17A1, prolactin, and catechol-O-methyltransferase genes and non-Hodgkin lymphoma risk.

Expression of prolactin and of prolactin and estrogen receptors in lymphocytes, bone marrow, and lymphoma cell lines suggests that hormonal modulation may influence lymphoma risk. Prolactin and estrogen promote the proliferation and survival of B cells, factors that may increase non-Hodgkin lymphoma risk, and effects of estrogen may be modified by catechol-O-methyltransferase (COMT), an enzyme that alters estrogenic activity. Cytochrome P450 17A1 (CYP17A1), a key enzyme in estrogen biosynthesis, has been associated with increased cancer risk and may affect lymphoma susceptibility. We studied the polymorphisms prolactin (PRL) -1149G>T, CYP17A1 -34T>C, and COMT 108/158Val>Met, and predicted haplotypes among a subset of participants (n = 308 cases, n = 684 controls) in a San Francisco Bay Area population-based non-Hodgkin lymphoma study (n = 1,593 cases, n = 2,515 controls) conducted from 1988 to 1995. Oral contraceptive and other hormone use also was analyzed. Odds ratios (OR) for non-Hodgkin lymphoma and follicular lymphoma were reduced for carriers of the PRL -1149TT genotype [OR, 0.64; 95% confidence interval (95% CI), 0.41-1.0; OR, 0.53; 95% CI, 0.26-1.0, respectively]. Diffuse large-cell lymphoma risk was increased for those with CYP17A1 polymorphisms including CYP17A1 -34CC (OR, 2.0; 95% CI, 1.1-3.5). ORs for all non-Hodgkin lymphoma and follicular lymphoma among women were decreased for COMT IVS1 701A>G [rs737865; variant allele: OR, 0.53; 95% CI, 0.34-0.82; OR, 0.42; 95% CI, 0.23-0.78, respectively]. Compared with never users of oral contraceptives, a 35% reduced risk was observed among oral contraceptive users in the total population. Reduced ORs for all non-Hodgkin lymphoma were observed with use of exogenous estrogens among genotyped women although 95% CIs included unity. These results suggest that PRL, CYP17A1, and COMT may be relevant genetic loci for non-Hodgkin lymphoma and indicate a possible role for prolactin and estrogen in lymphoma pathogenesis.     

CYP17 (T- 34C), CYP19 (Trp39Arg), and FGFR2 (C-906T) Polymorphisms and the Risk of Breast Cancer in South Indian Women

Breast cancer is initiated by exposure to endogenous and exogenous estrogens. A case-control (n=250-500)study was undertaken to investigate the role of Single Nucleotide Polymorphisms (SNP’s) in CYP17 (T-34C),CYP19 (Trp39Arg) and FGFR2(C-906T). Genotyping was done using the Taqman allelic discrimination assayfor CYP17 (T-34C) and FGFR2 (T-906C) and PCR-CTPP for CYP19 (Trp39Arg). There was a significantprotective association of the (TT/CC) genotype of the CYP17 gene against the risk of developing breast cancer(OR=0.68, 95% CI: 0.49-0.96), which was more significant in postmenopausal women (OR=0.56, 95% CI: 0.35-0.89) (p=0.015). CYP19 (Trp39Arg) is a rare polymorphism and all the cases were homozygous for the wild typeTrp allele (100%); this was also the case for 99.2% of the controls. We were unable to detect any variant form ofthe CYP19 gene in south Indian women. There was no significant association between the risk of breast cancerand FGFR2 (C-906T). These results suggest that the CYP17 TT/CC genotype is associated with decreased riskfor breast cancer, especially in post menopausal women.     

Estrogen receptor genotypes and haplotypes associated with breast cancer risk

Nearly one in eight US women will develop breast cancer in their lifetime. Most breast cancer is not associated with a hereditary syndrome, occurs in postmenopausal women, and is estrogen and progesterone receptor-positive. Estrogen exposure is an epidemiologic risk factor for breast cancer and estrogen is a potent mammary mitogen. We studied single nucleotide polymorphisms (SNPs) in estrogen receptors in 615 healthy subjects and 1011 individuals with histologically confirmed breast cancer, all from New York City. We analyzed 13 SNPs in the progesterone receptor gene (PGR), 17 SNPs in estrogen receptor 1 gene (ESR1), and 8 SNPs in the estrogen receptor 2 gene (ESR2). We observed three common haplotypes in ESR1 that were associated with a decreased risk for breast cancer [odds ratio (OR), approximately O.4; 95% confidence interval (CI), 0.2-0.8; P < 0.01]. Another haplotype was associated with an increased risk of breast cancer (OR, 2.1; 95% CI, 1.2-3.8; P < 0.05). A unique risk haplotype was present in approximately 7% of older Ashkenazi Jewish study subjects (OR, 1.7; 95% CI, 1.2-2.4; P < 0.003). We narrowed the ESR1 risk haplotypes to the promoter region and first exon. We define several other haplotypes in Ashkenazi Jews in both ESR1 and ESR2 that may elevate susceptibility to breast cancer. In contrast, we found no association between any PGR variant or haplotype and breast cancer. Genetic epidemiology study replication and functional assays of the haplotypes should permit a better understanding of the role of steroid receptor genetic variants and breast cancer risk.     

Hormone replacement therapy and breast cancer in former users of oral contraceptives--The Norwegian Women and Cancer study

Combined estrogen-progestin menopausal therapy (HRT) and combined estrogen-progestin contraceptives (OC) both increase breast cancer risk during current use and a few years after. We investigated risk of breast cancer in women who were users of HRT dependant on former history of OC use in a large, national population-based cohort study, the Norwegian Women and Cancer study (NOWAC). Exposure information was collected through postal questionnaires. Based on follow-up of 30,118 postmenopausal women by linkage to national registers of cancer, deaths, and emigration we revealed 540 incident breast cancer cases between 1996 and 2004. Compared to never users of either drugs current use of HRT gave a significant (p = 0.002) higher risk of breast cancer in former OC users, RR = 2.45 (95% CI 1.92-3.12), than among never users of OCs, RR = 1.67 (1.32-2.12). Relative risk of current use of HRT was similar for estrogen only and combinations with progestin added in ever users of OCs. The increased risk of breast cancer in current HRT users with a history of former OC use could have potential great impact on postmenopausal breast cancer risk as the proportion of postmenopausal women with former OC use will continue to increase.     

Cytochrome P4501A1 genetic polymorphisms and breast cancer risk in Nigerian women

Summary In this case-control study based on 250 women with breast cancer and 250 age-matched controls, we sought to evaluate the role of four polymorphic variants in the CYP1A1 gene in breast cancer susceptibility in Nigerian women. Heterozygosity for the CYP1A1 M1 genotype (CYP1A1 M1 [T/C]) was associated with a 21% reduced risk of breast cancer (OR=0.79, 95% CI 0.46–1.40) while homozygosity for the genotype (CYP1A1 M1 [C/C]) conferred a non-significant 9% reduced risk of breast cancer. These risk profiles were not significantly altered in subgroup analysis by menopausal status. While heterozygosity for the CYP1A1 M3 genotype (T/C) conferred a non-significant 24% reduced risk of breast cancer (OR=0.76, 95% CI 0.47–1.22), homozygosity for the variant was associated a non-significant 1.95-fold increased risk of breast cancer (OR=1.95, 95% CI 0.24–6.01). Subgroup analysis showed a non-significant 11% reduced risk in premenopausal heterozygous carriers (OR=0.89, 95% CI 0.45–1.44) and a non-significant 6% increased risk of postmenopausal breast cancer for carriers of the CYP1A1 M3 (T/C) genotype. The CYP1A1 M2 (isoleucine to valine) polymorphism in exon 7 and CYP1A1 M4 (threonine to asparagine) variant in codon 461 of the CYP1A1 gene were found to be very rare in our study subjects. This study has shown that while the CYP1A1 M1 polymorphism conferred reduced risk of breast cancer, homozygosity for the CYP1A1 M3 (C/C) was associated with increased risk of breast cancer although these risks did not attain statistical significance.