Biomedical subjects

Malcolm C Pike

Publications and source records attributed to Malcolm C Pike.

At least 19 recordsLinked to original sources

PubMed2007

Body size, hormone therapy and risk of breast cancer in Asian-American women.

Historically, breast cancer rates have been low in Asia but rates have increased substantially in Asian-Americans for reasons that are not well understood. The authors conducted a population-based case-control study of breast cancer in Los Angeles County, which included 1,277 (450 Chinese, 352 Japanese, 475 Filipinos) women with incident, histologically confirmed breast cancer and 1,160 control subjects (486 Chinese, 311 Japanese, 363 Filipinos). A detailed in-person interview was conducted, which included questions on menopausal hormone therapy (HT) use, height, weight in each decade of life and reproductive factors. Breast cancer risk increased with increasing recent weight in postmenopausal women (p trend = 0.015). There was a significant 16% (95% CI = 2-35%) increase in risk per 10 kg of body weight in postmenopausal women. In both premenopausal and postmenopausal women, risk increased with increasing waist to hip ratio; this remained statistically significant after adjustment for recent weight in all subjects combined (p trend = 0.042). The increased risk associated with high recent weight in postmenopausal women was more apparent for women with high waist to hip ratio (p trend = 0.013). Use of HT was a significant risk factor; risk increased 26% per 5 years of current use of estrogen and progestin therapy (p trend = 0.017). The increased risk associated with high body weight was observed irrespective of HT use. Use of HT and high body size might have contributed to the rapid increase of breast cancer in Asian-Americans.

Adult↗

PubMed2006

A systematic assessment of common genetic variation in CYP11A and risk of breast cancer.

CYP11A catalyzes the rate-limiting step in the biosynthesis of sex-steroid hormones. In this study, we employed a systematic approach that involved gene resequencing and a haplotype-based analysis to investigate the relationship between common variation in CYP11A and breast cancer risk among African-Americans, Latinas, Japanese-Americans, Native Hawaiians, and Whites in the Multiethnic Cohort Study. Resequencing in a multiethnic panel of 95 advanced breast cancer cases revealed no common missense variant (> or =5% frequency). Common haplotype patterns were assessed by genotyping 36 densely spaced single nucleotide polymorphisms (SNPs) spanning 67 kb of the CYP11A locus in a multiethnic panel of subjects (n = 349; 1 SNP/1.86 kb on average). We identified one to two regions of strong linkage disequilibrium in these populations. Twelve tagging SNPs were selected to predict the common haplotypes (> or =5% frequency) in these regions with high probability (average R(h)(2) = 0.94) and were examined in a breast cancer case-control study in the Multiethnic Cohort Study (1,615 cases and 1,962 controls). A global test for differences in risk according to common haplotypes over the locus was statistically significant (P = 0.006), as were associations with haplotypes in each block (block 1 global test, P = 0.008; haplotype 1D, effect per haplotype copy, odds ratios, 1.23; 95% confidence interval, 1.03-1.48) and block 2 (global test, P = 0.016; haplotype 2F odds ratios, 1.52; 95% confidence interval, 1.15-2.01). These haplotypes were most common in Japanese-Americans and Native Hawaiians, followed by Whites then Latinas, and were rare in African-Americans (<5% frequency); the haplotype effects on risk across each group were homogeneous. Based on these findings, CYP11A deserves further consideration as a candidate breast cancer susceptibility gene.

Breast Neoplasms↗

PubMed2006

Racial/ethnic differences in endometrial cancer risk: the multiethnic cohort study.

Few studies have examined differences in endometrial cancer risk among ethnic groups in the United States. The authors assessed the extent to which known risk factors for endometrial cancer explain the racial/ethnic differences in risk among 46,933 postmenopausal African-American, Native-Hawaiian, Japanese-American, Latina, and White women recruited to the prospective Multiethnic Cohort Study in 1993-1996. During a 7.3-year follow up period, 321 incident endometrial cancer cases were identified among these women. Data on known/suspected risk factors were obtained from baseline questionnaires, and comparisons of endometrial cancer incidence across racial/ethnic groups were estimated using log-linear proportional hazard models. Later age at menopause, unopposed estrogen therapy use, and obesity were associated with increased risk, while increasing parity and increasing duration of oral contraceptive use were associated with decreased risk. The relative risks for endometrial cancer (vs. Whites) were 0.76 (95% confidence interval (CI): 0.53, 1.08) for African Americans, 0.92 (95% CI: 0.58, 1.46) for Native Hawaiians, 0.61 (95% CI: 0.46, 0.83) for Japanese Americans, and 0.63 (95% CI: 0.46, 0.87) for Latinas. After adjustment for the risk factors, the relative risks were 0.68 (95% CI: 0.47, 0.98) for African Americans, 0.91 (95% CI: 0.56, 1.46) for Native Hawaiians, 0.74 (95% CI: 0.54, 1.01) for Japanese Americans, and 0.65 (95% CI: 0.47, 0.92) for Latinas. Results from this study show that the interethnic differences in endometrial cancer risk do not appear to be explained by differences in the distribution of known risk factors among women of different races/ethnicities.

Aged↗

PubMed2006

BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50.

BACKGROUND: Understanding the effect of oral contraceptives on risk of breast cancer in BRCA1 or BRCA2 mutation carriers is important because oral contraceptive use is a common, modifiable practice. METHODS: We studied 497 BRCA1 and 307 BRCA2 mutation carriers, of whom 195 and 128, respectively, had been diagnosed with breast cancer. Case-control analyses were conducted using unconditional logistic regression with adjustments for family history and familial relationships and were restricted to subjects with a reference age under 50 years. RESULTS: For BRCA1 mutation carriers, there was no significant association between risk of breast cancer and use of oral contraceptives for at least 1 year [odds ratio (OR), 0.77; 95% confidence interval (95% CI), 0.53-1.12] or duration of oral contraceptive use (P(trend) = 0.62). For BRCA2 mutation carriers, there was no association with use of oral contraceptives for at least 1 year (OR, 1.62; 95% CI, 0.90-2.92); however, there was an association of elevated risk with oral contraceptive use for at least 5 years (OR, 2.06; 95% CI, 1.08-3.94) and with duration of use (OR(trend) per year of use, 1.08; P = 0.008). Similar results were obtained when we considered only use of oral contraceptives that first started in 1975 or later. CONCLUSIONS: We found no evidence overall that use of oral contraceptives for at least 1 year is associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers before age 50. For BRCA2 mutation carriers, use of oral contraceptives may be associated with an increased risk of breast cancer among women who use them for at least 5 years. Further studies reporting results separately for BRCA1 and BRCA2 mutation carriers are needed to resolve this important issue.

Adult↗

PubMed2006

Dense breast stromal tissue shows greatly increased concentration of breast epithelium but no increase in its proliferative activity.

INTRODUCTION: Increased mammographic density is a strong risk factor for breast cancer. The reasons for this are not clear; two obvious possibilities are increased epithelial cell proliferation in mammographically dense areas and increased breast epithelium in women with mammographically dense breasts. We addressed this question by studying the number of epithelial cells in terminal duct lobular units (TDLUs) and in ducts, and their proliferation rates, as they related to local breast densities defined histologically within individual women. METHOD: We studied deep breast tissue away from subcutaneous fat obtained from 12 healthy women undergoing reduction mammoplasty. A slide from each specimen was stained with the cell-proliferation marker MIB1. Each slide was divided into (sets of) areas of low, medium and high density of connective tissue (CT; highly correlated with mammographic densities). Within each of the areas, the numbers of epithelial cells in TDLUs and ducts, and the numbers MIB1 positive, were counted. RESULTS: The relative concentration (RC) of epithelial cells in high compared with low CT density areas was 12.3 (95% confidence interval (CI) 10.9 to 13.8) in TDLUs and 34.1 (95% CI 26.9 to 43.2) in ducts. There was a much smaller difference between medium and low CT density areas: RC = 1.4 (95% CI 1.2 to 1.6) in TDLUs and 1.9 (95% CI 1.5 to 2.3) in ducts. The relative mitotic rate (RMR; MIB1 positive) of epithelial cells in high compared with low CT density areas was 0.59 (95% CI 0.53 to 0.66) in TDLUs and 0.65 (95% CI 0.53 to 0.79) in ducts; the figures for the comparison of medium with low CT density areas were 0.58 (95% CI 0.48 to 0.70) in TDLUs and 0.66 (95% CI 0.44 to 0.97) in ducts. CONCLUSION: Breast epithelial cells are overwhelmingly concentrated in high CT density areas. Their proliferation rate in areas of high and medium CT density is lower than that in low CT density areas. The increased breast cancer risk associated with increased mammographic densities may simply be a reflection of increased epithelial cell numbers. Why epithelium is concentrated in high CT density areas remains to be explained.

Breast↗

PubMed2006

Haplotype analysis of the HSD17B1 gene and risk of breast cancer: a comprehensive approach to multicenter analyses of prospective cohort studies.

The 17beta-hydroxysteroid dehydrogenase 1 gene (HSD17B1) encodes 17HSD1, which catalyzes the final step of estradiol biosynthesis. Despite the important role of HSD17B1 in hormone metabolism, few epidemiologic studies of HSD17B1 and breast cancer have been conducted. This study includes 5,370 breast cancer cases and 7,480 matched controls from five large cohorts in the Breast and Prostate Cancer Cohort Consortium. We characterized variation in HSD17B1 by resequencing and dense genotyping a multiethnic sample and identified haplotype-tagging single nucleotide polymorphisms (htSNP) that capture common variation within a 33.3-kb region around HSD17B1. Four htSNPs, including the previously studied SNP rs605059 (S312G), were genotyped to tag five common haplotypes in all cases and controls. Conditional logistic regression was used to estimate odds ratios (OR) for disease. We found no evidence of association between common HSD17B1 haplotypes or htSNPs and overall risk of breast cancer. The OR for each haplotype relative to the most common haplotype ranged from 0.98 to 1.07 (omnibus test for association: X2 = 3.77, P = 0.58, 5 degrees of freedom). When cases were subdivided by estrogen receptor (ER) status, two common haplotypes were associated with ER-negative tumors (test for trend, Ps = 0.0009 and 0.0076; n = 353 cases). HSD17B1 variants that are common in Caucasians are not associated with overall risk of breast cancer; however, there was an association among the subset of ER-negative tumors. Although the probability that these ER-negative findings are false-positive results is high, these findings were consistent across each cohort examined and warrant further study.

17-Hydroxysteroid Dehydrogenases↗

PubMed2006

Ethnic and racial differences in the smoking-related risk of lung cancer.

BACKGROUND: There is remarkable variation in the incidence of lung cancer among ethnic and racial groups in the United States. METHODS: We investigated differences in the risk of lung cancer associated with cigarette smoking among 183,813 African-American, Japanese-American, Latino, Native Hawaiian, and white men and women in the Multiethnic Cohort Study. Our analysis included 1979 cases of incident lung cancer identified prospectively over an eight-year period, between baseline (1993 through 1996) and 2001. RESULTS: The risk of lung cancer among ethnic and racial groups was modified by the number of cigarettes smoked per day. Among participants who smoked no more than 30 cigarettes per day, African Americans and Native Hawaiians had significantly greater risks of lung cancer than did the other groups. Among those who smoked no more than 10 and those who smoked 11 to 20 cigarettes per day, relative risks ranged from 0.21 to 0.39 (P<0.001) among Japanese Americans and Latinos and from 0.45 to 0.57 (P<0.001) among whites, as compared with African Americans. However, at levels exceeding 30 cigarettes per day, these differences were not significant. Differences in risk associated with smoking were observed among both men and women and for all histologic types of lung cancer. CONCLUSIONS: Among cigarette smokers, African Americans and Native Hawaiians are more susceptible to lung cancer than whites, Japanese Americans, and Latinos.

Black or African American↗

PubMed2006

Prostate cancer incidence and intake of fruits, vegetables and related micronutrients: the multiethnic cohort study* (United States).

OBJECTIVE: To describe the relationship between the intake of fruits, vegetables, and related vitamins and antioxidants, and the risk of prostate cancer in male participants in a large multiethnic cohort study. METHODS: Food and nutrient intakes in 1993-1996 were calculated from a detailed food frequency questionnaire (FFQ) designed to account for the food and nutrient intake of the ethnic groups represented in the study (82,486 African-American, Japanese-American, Native-Hawaiian, Latino and White males included here). Follow-up for incident cancers utilized local SEER registries. Vital status was ascertained using state death files. Data on PSA utilization from a later questionnaire was also examined. RESULTS: A total of 3,922 incident cancer cases were ascertained during follow-up. Modestly increased risks of prostate cancer were observed in relation to higher intakes of several food items including light green lettuce and dark leafy green vegetables. Notably, no significant protective associations of any foods were seen, including tomato intake; and intakes of two complex foods containing tomato sauce (pizza and Spanish rice) were associated with modest increases in risk. PSA test use was significantly and positively related to intake of some of these same items, implying a degree of disease detection-bias. Analysis of non-localized and high grade disease (1,345 cases) showed no significant protective associations with overall fruits and vegetables intake, related micronutrients, or with intake of selected complex food items. CONCLUSIONS: We found no statistically significant evidence of a protective effect against prostate cancer of higher levels of intake of any of these foods, associated micronutrients or supplements. A possible explanation for the positive associations with risk of several of the foods normally considered to be healthy is detection bias, since "healthy" dietary intake was related to greater use of the PSA test.

Black or African American↗

PubMed2006

Reproductive factors and breast cancer risk according to joint estrogen and progesterone receptor status: a meta-analysis of epidemiological studies.

INTRODUCTION: Although reproductive factors have been known for decades to be associated with breast cancer risk, it is unclear to what extent these associations differ by estrogen and progesterone receptor (ER/PR) status. This report presents the first meta-analysis of results from epidemiological studies that have investigated parity, age at first birth, breastfeeding, and age at menarche in relation to ER+PR+ and ER-PR- cancer risk. MATERIALS AND METHODS: We calculated summary relative risks (RRs) and corresponding 95% confidence intervals (CIs) using a fixed effects model. RESULTS: Each birth reduced the risk of ER+PR+ cancer by 11% (RR per birth = 0.89, 95% CI = 0.84-0.94), and women who were in the highest age at first birth category had, on average, 27% higher risk of ER+PR+ cancer compared with women who were in the youngest age at first birth category (RR = 1.27, 95% CI = 1.07-1.50). Neither parity nor age at first birth was associated with the risk of ER-PR- cancer (RR per birth = 0.99, 95% CI = 0.94-1.05; RR of oldest versus youngest age at first birth category = 1.01, 95% CI = 0.85-1.20). Breastfeeding and late age at menarche decreased the risk of both receptor subtypes of breast cancer. The protective effect of late age at menarche was statistically significantly greater for ER+PR+ than ER-PR- cancer (RR = 0.72 for ER+PR+ cancer; RR = 0.84 for ER-PR- cancer, p for homogeneity = 0.006). CONCLUSION: Our findings suggest that breastfeeding (and age at menarche) may act through different hormonal mechanisms than do parity and age at first birth.

Age Factors↗

PubMed2006

A comprehensive analysis of the androgen receptor gene and risk of breast cancer: results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3).

INTRODUCTION: Androgens have been hypothesised to influence risk of breast cancer through several possible mechanisms, including their conversion to estradiol or their binding to the oestrogen receptor and/or androgen receptor (AR) in the breast. Here, we report on the results of a large and comprehensive study of the association between genetic variation in the AR gene and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). METHODS: The underlying genetic variation was determined by first sequencing the coding regions of the AR gene in a panel of 95 advanced breast cancer cases. Second, a dense set of markers from the public database was genotyped in a panel of 349 healthy women. The linkage disequilibrium relationships (blocks) across the gene were then identified, and haplotype-tagging single nucleotide polymorphisms (htSNPs) were selected to capture the common genetic variation across the locus. The htSNPs were then genotyped in the nested breast cancer cases and controls from the Cancer Prevention Study II, European Prospective Investigation into Cancer and Nutrition, Multiethnic Cohort, Nurses' Health Study, and Women's Health Study cohorts (5,603 breast cancer cases and 7,480 controls). RESULTS: We found no association between any genetic variation (SNP, haplotype, or the exon 1 CAG repeat) in the AR gene and risk of breast cancer, nor were any statistical interactions with known breast cancer risk factors observed. CONCLUSION: Among postmenopausal Caucasian women, common variants of the AR gene are not associated with risk of breast cancer.

Aged↗

PubMed2005

Genetic variation in the HSD17B1 gene and risk of prostate cancer.

Steroid hormones are believed to play an important role in prostate carcinogenesis, but epidemiological evidence linking prostate cancer and steroid hormone genes has been inconclusive, in part due to small sample sizes or incomplete characterization of genetic variation at the locus of interest. Here we report on the results of a comprehensive study of the association between HSD17B1 and prostate cancer by the Breast and Prostate Cancer Cohort Consortium, a large collaborative study. HSD17B1 encodes 17beta-hydroxysteroid dehydrogenase 1, an enzyme that converts dihydroepiandrosterone to the testosterone precursor Delta5-androsterone-3beta,17beta-diol and converts estrone to estradiol. The Breast and Prostate Cancer Cohort Consortium researchers systematically characterized variation in HSD17B1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNPs) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,290 prostate cancer cases and 9,367 study-, age-, and ethnicity-matched controls. We found no evidence that HSD17B1 htSNPs (including the nonsynonymous coding SNP S312G) or htSNP haplotypes were associated with risk of prostate cancer or tumor stage in the pooled multiethnic sample or in U.S. and European whites. Analyses stratified by age, body mass index, and family history of disease found no subgroup-specific associations between these HSD17B1 htSNPs and prostate cancer. We found significant evidence of heterogeneity in associations between HSD17B1 haplotypes and prostate cancer across ethnicity: one haplotype had a significant (p < 0.002) inverse association with risk of prostate cancer in Latinos and Japanese Americans but showed no evidence of association in African Americans, Native Hawaiians, or whites. However, the smaller numbers of Latinos and Japanese Americans in this study makes these subgroup analyses less reliable. These results suggest that the germline variants in HSD17B1 characterized by these htSNPs do not substantially influence the risk of prostate cancer in U.S. and European whites.

17-Hydroxysteroid Dehydrogenases↗

PubMed2005

The association of endogenous sex steroids and sex steroid binding proteins with mammographic density: results from the Postmenopausal Estrogen/Progestin Interventions Mammographic Density Study.

Mammographic density is an independent risk factor for breast cancer. In postmenopausal women, higher levels of endogenous sex steroids are associated with an increased risk of breast cancer. Limited prior data suggest that endogenous sex steroids either are not associated (total estradiol and progesterone) or are negatively associated (free estradiol) with higher mammographic density. To analyze the associations between endogenous sex steroids and mammographic density, the authors conducted a 1998-2005 cross-sectional analysis of baseline clinical trial data from the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial for US women who had not used hormone therapy for at least 3.1 months prior to baseline. In models adjusted for age, body mass index, parity, prior use of hormone therapy, time since last use of hormone therapy, and the interaction between prior hormone therapy use and time since last hormone therapy use, higher levels of estrone (beta = 0.0013, p = 0.014), estradiol (beta = 0.0009, p = 0.009), and bioavailable estradiol (beta = 0.0021, p = 0.018) were statistically significantly related to greater mammographic density. (Beta coefficients express the increment in mammographic density per-unit increment (pg/ml) of each hormone.) These results suggest that some sex steroids may increase the risk of breast cancer by stimulating breast epithelial or stromal proliferation, which appears on a mammogram as higher density.

Breast↗

PubMed2005

Greatly increased occurrence of breast cancers in areas of mammographically dense tissue.

INTRODUCTION: Mammographic density is a strong, independent risk factor for breast cancer. A critical unanswered question is whether cancers tend to arise in mammographically dense tissue (i.e. are densities directly related to risk or are they simply a marker of risk). This question cannot be addressed by studying invasive tumors because they manifest as densities and cannot be confidently differentiated from the densities representing fibrous and glandular tissue. We addressed this question by studying ductal carcinoma in situ (DCIS), as revealed by microcalcifications. METHOD: We studied the cranio-caudal and the mediolateral-oblique mammograms of 28 breasts with a solitary DCIS lesion. Two experienced radiologists independently judged whether the DCIS occurred in a mammographically dense area, and determined the density of different areas of the mammograms. RESULTS: It was not possible to determine whether the DCIS was or was not in a dense area for six of the tumors. Of the remaining 22 lesions, 21 occurred in dense tissue (test for difference from expected taken as the percentage of density of the 'mammographic quadrant' containing DCIS; P < 0.0001). A preponderance of DCIS (17 out of 28) occurred in the mammographic quadrant with the highest percentage density. CONCLUSION: DCIS occurs overwhelmingly in the mammographically dense areas of the breast, and pre-DCIS mammograms showed that this relationship was not brought about by the presence of the DCIS. This strongly suggests that some aspect of stromal tissue comprising the mammographically dense tissue directly influences the carcinogenic process in the local breast glandular tissue.

Breast↗

PubMed2005

Cell-nonautonomous induction of ovarian and uterine serous cystadenomas in mice lacking a functional Brca1 in ovarian granulosa cells.

Women with germline mutations in BRCA1 have a 40% risk of developing ovarian cancer by age 70 and are also predisposed to cancers of the fallopian tubes. Given that ovulatory activity is a strong risk factor for sporadic ovarian cancer, we hypothesized that reduced BRCA1 expression might predispose to gynecological cancers indirectly, by influencing ovarian granulosa cells. These cells secrete sex steroids that control the ovulatory cycle and influence the growth of ovarian epithelial tumors. Granulosa cells also secrete mullerian inhibiting substance (MIS), a hormone that inhibits both the formation of female reproductive organs in male embryos and the proliferation of ovarian epithelial tumor cells. We tested this hypothesis by using the Cre-lox system to inactivate the Brca1 gene in mouse ovarian granulosa cells. A truncated form of the Fsh receptor promoter served as the Cre driver. Here, we show that indeed, inactivation of the Brca1 gene in granulosa cells led to the development of cystic tumors in the ovaries and uterine horns. These tumors carried normal Brca1 alleles, supporting the view that Brca1 may influence tumor development indirectly, possibly through an effector secreted by granulosa cells.

Animals↗

PubMed2005

Polymorphisms in genes involved in estrogen and progesterone metabolism and mammographic density changes in women randomized to postmenopausal hormone therapy: results from a pilot study.

INTRODUCTION: Mammographic density is a strong independent risk factor for breast cancer, and can be modified by hormonal exposures. Identifying genetic variants that determine increases in mammographic density in hormone users may be important in understanding hormonal carcinogenesis of the breast. METHODS: We obtained mammograms and DNA from 232 postmenopausal women aged 45 to 75 years who had participated in one of two randomized, double-blind clinical trials with estrogen therapy (104 women, taking 1 mg/day of micronized 17beta-estradiol, E2), combined estrogen and progestin therapy (34 women, taking 17beta-estradiol and 5 mg/day of medroxyprogesterone acetate for 12 days/month) or matching placebos (94 women). Mammographic percentage density (MPD) was measured on baseline and 12-month mammograms with a validated computer-assisted method. We evaluated polymorphisms in genes involved in estrogen metabolism (catechol-O-methyltransferase (COMT (Val158Met)), cytochrome P450 1B1 (CYP1B1 (Val432Leu)), UDP-glucuronosyltransferase 1A1 (UGT1A1 (<7/>or= 7 TA repeats))) and progesterone metabolism (aldo-keto reductase 1C4 (AKR1C4 (Leu311Val))) with changes in MPD. RESULTS: The adjusted mean change in MPD was +4.6% in the estrogen therapy arm and +7.2% in the combined estrogen and progestin therapy arm, compared with +0.02% in the placebo arm (P = 0.0001). None of the genetic variants predicted mammographic density changes in women using estrogen therapy. Both the AKR1C4 and the CYP1B1 polymorphisms predicted mammographic density change in the combined estrogen and progestin therapy group (P < 0.05). In particular, the eight women carrying one or two low-activity AKR1C4 Val alleles showed a significantly greater increase in MPD (16.7% and 29.3%) than women homozygous for the Leu allele (4.0%). CONCLUSION: Although based on small numbers, these findings suggest that the magnitude of the increase in mammographic density in women using combined estrogen and progestin therapy may be greater in those with genetically determined lower activity of enzymes that metabolize estrogen and progesterone.

Aged↗

PubMed2005

Clarifying the PROGINS allele association in ovarian and breast cancer risk: a haplotype-based analysis.

BACKGROUND: The PROGINS allele of the progesterone receptor (PGR) gene has been associated with an increased risk of ovarian cancer and a decreased risk of breast cancer. We set out to refine the association between common variation at the PGR gene locus and these two diseases. METHODS: We characterized the haplotype structure of the PGR gene by genotyping 54 single-nucleotide polymorphisms (SNPs) in 349 women. We then selected a subset of 17 haplotype-tagging SNPs that captured variation across the locus and typed them in 267 ovarian cancer case patients and 397 control subjects from two case-control studies and in 1715 breast cancer case patients and 2505 control subjects from a cohort study. RESULTS: The PGR locus was characterized by four blocks of strong linkage disequilibrium. Two SNPs in block 4 were associated with an increased risk of ovarian cancer among homozygous carriers as compared with noncarriers: rs1042838 (PROGINS allele; odds ratio [OR] = 3.23, 95% confidence interval [CI] = 1.19 to 8.75, P = .022) and rs608995 (minor allele; OR = 3.10, 95% CI = 1.63 to 5.89, P<.001). The PROGINS allele was observed on a subset of chromosomes carrying the minor allele at rs608995, and its association with ovarian cancer was fully explained by its association with rs608995. In addition, rs608995 fell on two common haplotypes (4-D and 4-E), whose association with ovarian cancer was the same as that of rs608995. These same two haplotypes were associated with a non-statistically significantly reduced risk of breast cancer. CONCLUSIONS: Variation in PGR was associated with ovarian cancer risk, although the strongest result was not with the PROGINS allele. Instead, any causal allele(s) are likely in or downstream of block 4 and carried on haplotypes 4-D and 4-E. There was some evidence that the same variation was associated with a reduced risk of breast cancer, but the association was not statistically significant.

Adult↗

PubMed2005

Ethnic differences in neuroendocrine cell expression in normal human prostatic tissue.

OBJECTIVES: To determine whether any differences exist in neuroendocrine (NE) cell differentiation in normal prostates among various ethnic groups because the incidence and mortality from prostate cancer vary across racial groups. METHODS: Archived paraffin-embedded prostate samples not containing any malignancy were obtained from cystoprostatectomy specimens. Prostatic tissue was obtained from 15 African Americans, 13 Hispanics, 15 Asians, and 16 whites. NE cells were identified based on immunoreactivity for chromogranin A. The mean number of NE cells per high power field (HPF) for each patient was determined using a visual quantitative method by two observers who were unaware of the race of the patients. RESULTS: The geometric mean number of NE cells was 6.1/HPF for Asians, 5.6/HPF for whites, 4.0/HPF for Hispanics, and 0.7/HPF for African Americans. A highly significant difference was observed in the distribution of NE cells between African Americans and each of the other races (P < or =0.003). A trend toward greater NE expression was noted in Asians and whites compared with Hispanics; however, this difference did not reach statistical significance. CONCLUSIONS: We found a fivefold to eightfold difference in the distribution of NE cells in the normal prostates of African-American men compared with that of other races. The comparatively low NE cell expression in African-American men may play a role in the greater rate of prostate carcinogenesis seen in this ethnic group.

Black or African American↗

PubMed2005

The role of mammographic density in evaluating changes in breast cancer risk.

The Women's Health Initiative (WHI) study showed that postmenopausal continuous combined estrogen-progestogen therapy (EPT) significantly increases the risk of breast cancer, thus confirming the results from large epidemiological studies. These results were predicted approximately 15 years previously based on the epidemiology of breast cancer and the relationship of ovarian hormone levels to breast cell proliferation. However, the prediction had little effect on prescribing habits due to its theoretical nature. Many questions remain regarding menopausal therapy and breast cancer risk, especially the effects of other schedules and regimens. Epidemiological case-control studies and randomized clinical trials with breast cancer as the outcome cannot answer these questions in an appropriate timeframe. Some intermediate marker of breast cancer risk must therefore be used as a basis of rational prescribing. There is considerable evidence in support of using changes in mammographic densities as such a marker. For example, measurement of changes in mammographic density in the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial showed that EPT was likely to be associated with a notably greater risk than estrogen therapy alone, that sequential EPT regimens are likely to increase the risk as much as continuous regimens (if the total progestin dose is similar), and that replacing medroxyprogesterone acetate with progesterone is unlikely to significantly alter the additional risk.

Biomarkers↗