Sex steroid hormones and genetic susceptibility to breast and prostate cancer.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
R K Ross
Publications and source records attributed to R K Ross.
Breastfeeding experience and breast cancer risk among postmenopausal women.
Results of studies of breastfeeding and postmenopausal breast cancer risk have been inconsistent, with many investigators concluding that breastfeeding does not influence risk. We examined whether breastfeeding reduces postmenopausal breast cancer risk as well as the details of this relationship, including possible modification in risk by the age that a woman first breastfed a child and the number of children she breastfed. This population-based case-control study compared 974 women who were residents of Los Angeles County and newly diagnosed with breast cancer to 973 women with no history of breast cancer who were matched to patients by age (within 3 years) and neighborhood of residence. Subjects were parous and postmenopausal. Breast cancer patients were ages 55-64 years at diagnosis. Women who breastfed at least 16 months experienced a reduced odds of breast cancer relative to women who never breastfed (odds ratio, 0.73; 95% confidence interval, 0.52-1.01). Risk decreased as the number of children breastfed increased, but the association was attenuated after accounting for lifetime duration of breastfeeding. Breast cancer risk was 30% lower among women ages 20-24 years at first breastfeeding than women who had never breastfed (odds ratio, 0.69; 95% confidence interval, 0.54-0.88), independent of the effect of age at first birth. This study provides some evidence that the protective effect of breastfeeding persists into the postmenopausal years. The potential for nondifferential error in recall of breastfeeding habits among postmenopausal patients and controls may explain the inconsistent results observed across studies and underscores the need for careful assessment of this relationship.
Adolescent↗
Tobacco use in relation to renal cell carcinoma.
The modest effect of cigarette smoking on renal cell carcinoma (RCC) requires a study with a large number of subjects to definitively answer the question of whether smoking is causally related to RCC. A population-based case-control study was conducted in Los Angeles, California that involved 1204 RCC patients and an equal number of neighborhood controls who were matched to the index cases by sex, date of birth (within 5 years), and race. Detailed information on tobacco use was collected through in-person interviews. Cigarette smoking was associated with a statistically significant 35% increase in the risk of RCC [odds ratio (OR), 1.35; 95% confidence interval (CI), 1.14-1.60]. The risk increased with increasing number of cigarettes smoked per day (two-sided P < 0.001, linear trend test). Former smokers (OR, 1.24; 95% CI, 1.02-1.50) had a lower risk of RCC than current smokers (OR, 1.53; 95% CI, 1.23-1.90). Compared with current smokers, those who quit smoking 10 or more years ago experienced a statistically significant 30% reduction in the risk of RCC. Current smokers who smoked 40 or more cigarettes/day experienced a nearly 2-fold increase in the risk of RCC compared with lifelong nonsmokers. The association between cigarette smoking and RCC was similar in men and women. There were no measurable differences in the risk of RCC between filtered and nonfiltered cigarette smokers or between those who inhaled cigarette smoke deeply and those who inhaled lightly after adjustment for the number of cigarettes smoked per day and current smoking status. After the effect of cigarette smoking was accounted for, heavy cigar smokers (14 or more cigars/week) exhibited a statistically significant 70% increase in the risk of RCC, but no increased risk of RCC was observed for the use of pipes or smokeless tobacco. Seventeen percent of RCC (21% in men and 11% in women) in Los Angeles, California can be attributed to cigarette smoking.
Adult↗
Absence of the glutathione S-transferase M1 gene increases cytochrome P4501A2 activity among frequent consumers of cruciferous vegetables in a Caucasian population.
The cancer protective effect of cruciferous vegetables has been attributed to induction of phase II enzymes. But cruciferous vegetables also induce cytochrome P4501A2 (CYP1A2), which catalyzes the metabolic activation of various procarcinogens, including aromatic amines in tobacco. Thus, frequent intake of cruciferous vegetables could also result in cancer-enhancing effects. GSTM1 is involved in the detoxification of various carcinogens, but it also enhances the excretion of isothiocyanates and possibly other enzyme inducers in cruciferous vegetables. We, therefore, hypothesized that GSTM1 null genotype might be associated with increased CYP1A2 activity among frequent consumers of cruciferous vegetables because the excretion of CYP1A2 inducers contained in these vegetables may be partially inhibited in the absence of the GSTM1 enzyme. Three hundred twenty-eight non-Hispanic white residents of Los Angeles County (265 males and 63 females) were genotyped for the presence or absence of GSTM1 alleles and phenotyped for CYP1A2 activity. Information on usual dietary habits was obtained from these subjects through in-person interviews. Among frequent (at least once a week) consumers of broccoli, GSTM1 null individuals exhibited a 21% higher geometric mean level of CYP1A2 activity relative to GSTM1 non-null individuals (5.24 versus 4.32, two-sided P = 0.01). No such difference was observed in subjects who consumed broccoli less frequently (two-sided P = 0.39). This interactive effect of GSTM1 genotype and vegetable intake on CYP1A2 activity also was observed when overall intake of the five cruciferous vegetables under study (broccoli, cabbage, cauliflower, Brussels sprouts, and mustard greens) was examined. Among weekly consumers of cruciferous vegetables, GSTM1 null individuals showed a 16% higher geometric mean level of CYP1A2 activity relative to GSTM1 non-null individuals (5.03 versus 4.33, two-sided P = 0.02), whereas no difference was evident among those who consumed cruciferous vegetables less frequently (two-sided P = 0.35). Our results suggest that cruciferous vegetables contain CYP1A2 inducers, which are deactivated in the presence of GSTM1.
Brassicaceae↗
Genetic variation of 3 beta-hydroxysteroid dehydrogenase type II in three racial/ethnic groups: implications for prostate cancer risk.
BACKGROUND: Elevated prostatic dihydrotestosterone (DHT) has been suggested to increase the risk of prostate cancer. The HSD3B2 gene encodes the type II 3 beta-hydroxysteroid dehydrogenase: one of two enzymes that initiate the inactivation of DHT. Thus, the HSD3B2 gene is a candidate gene for predisposition to prostate cancer. METHODS: We have determine the distribution of a complex dinucleotide repeat in the HSD3B2 gene in high-risk African-Americans, intermediate-risk Euro-Americans, and low-risk Asians. Genomic DNA from 312 individuals was amplified by polymerase chain reaction (PCR) and analyzed by electrophoresis on denaturing polyacrylamide gels. RESULTS: We have found that certain alleles are either unique to or much more common in either African-Americans, Asians, or Euro-Americans. Our data also substantially expand the number of alleles reported for the complex dinucleotide repeat polymorphism in the HSD3B2 gene. CONCLUSIONS: Our report demonstrates substantial genetic variation in the HSD3B2 gene. We hypothesize that allelic variants of the HSD3B2 gene may play a role in predisposition to prostate cancer, and in explaining the substantial racial/ethnic variation in risk.
3-Hydroxysteroid Dehydrogenases↗
Prospective evaluation of dietary and other predictors of fatal stroke in Shanghai, China.
BACKGROUND: Although a number of risk factors for fatal stroke are well established in Western populations, this is less true for Asian countries, many of which have stroke mortality rates that are historically high. In a prospective study in Shanghai, China, we determined whether the same factors predict risk for fatal stroke as in the West. We also studied a number of potential dietary associations, particularly those with dietary antioxidants because these have been suggested to reduce atherogenesis. METHODS AND RESULTS: Between 1986 and 1989, 18 244 men aged 45 to 64 years living in four geographically defined areas of Shanghai, China were recruited to participate in a prospective study of diet and cancer. All participants completed an in-person, structured interview and provided blood and urine samples. As of March 1994, fatal stroke accounted for 245 of the 980 observed deaths. The most important risk factor for stroke mortality was a history of hypertension (multivariate relative risk, 4.5; 95% confidence interval, 3.3, 6.2). Cigarette smoking was not strongly associated with risk, and alcohol consumption increased risk only in the extreme categories of lifetime consumption. Educational level was strongly, inversely associated with fatal stroke, and this could not be explained by adjustment for any other risk factors. No macronutrient was associated with risk, including total energy, fat consumption, or any component of fat. There also were no significant inverse associations for stroke mortality with several micronutrients of interest, including vitamin C, carotene, vitamin E, riboflavin, or calcium. CONCLUSIONS: Our data demonstrate that hypertension is by far the most important contributor to stroke mortality in Shanghai and that among dietary factors, only alcohol consumption shows any evidence whatsoever of being a risk factor.
Alcohol Drinking↗
An explanation for the increasing incidence of testis cancer: decreasing age at first full-term pregnancy.
Explore the source record for details and available documents.
Adult↗
A prevalent missense substitution that modulates activity of prostatic steroid 5alpha-reductase.
Prostate cancer is the most common serious cancer diagnosed in men in the United States. This disease is also characterized by a striking racial/ethnic variation in incidence: highest in African-Americans, intermediate in Caucasians, slightly lower in Latinos, and lowest in Asians. Ample biochemical and epidemiological evidence suggests a role for androgens, particularly testosterone and dihydrotestosterone, in prostate cancer etiology. We have analyzed a candidate gene for prostate cancer, SRD5A2, encoding prostatic steroid 5alpha-reductase type II, which converts testosterone into the more bioactive dihydrotestosterone, for mutations. We report here one amino acid substitution, V89L, which replaces valine at codon 89 with leucine. This substitution is a "germline" (constitutional) DNA polymorphism, and it is common, panethnic, and reduces in vivo steroid 5alpha-reductase activity. This substitution is particularly common among Asians and may explain the low risk for prostate cancer in this population.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
A polymorphism in the CYP17 gene increases the risk of breast cancer.
We conducted a case-control study to determine whether a polymorphism in the CYP17 gene was associated with risk of breast cancer. We found an increased risk of advanced breast cancer in women carrying an A2 allele. The odds ratio was 2.5 [95% confidence interval (CI), 1.07-5.94] for regional or metastatic disease. Among controls, the A1/A1 genotype was associated with a later age at menarche. The reduced risk of breast cancer associated with a later age of menarche was largely limited to A1/A1 women: odds ratio, 0.47 (CI, 0.22-0.98) for breast cancer and later age at menarche among A1 homozygotes compared with 0.80 (CI, 0.51-1.27) for A1/A2 and A2/A2 genotypes. These findings suggest that the CYP17 genotype may be a biomarker for the onset of ovulation and advanced breast cancer risk.
Aged↗
Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor.
BACKGROUND: Prostate cancer is an increasingly common disease for which there are few well-established risk factors. Family history data suggest a genetic component; however, the majority of prostate cancer cases cannot be explained by a single-gene model. Prostate cell division is influenced by two steroid hormones, testosterone and vitamin D, the action of each being mediated by its respective receptor. The genes for the two receptors are candidates in a multigenic model for prostate cancer susceptibility. PURPOSE: We examined genetic polymorphisms in two steroid receptors, the androgen receptor (AR) and the vitamin D receptor (VDR), in a case-control pilot study of prostate cancer. METHODS: Fifty-seven non-Hispanic white case patients with prostate cancer and 169 non-Hispanic white control subjects were genotyped for a previously described microsatellite (CAG repeats) in the AR gene and for a newly discovered poly-A microsatellite in the 3'-untranslated region (3'UTR) of the VDR gene. To compare genotypes with respect to prostate cancer risk, we estimated odds ratios (ORs) by using logistic regression. ORs were also estimated separately for advanced and localized cases of disease. All P values resulted from two-sided tests. RESULTS: Both the AR and the VDR polymorphisms were associated, individually and after mutual adjustment, with prostate cancer. Adjusted ORs (95% confidence intervals [CIs]) for prostate cancer were 2.10 (95% CI = 1.11-3.99) for individuals carrying an AR CAG allele with fewer than 20 repeats versus an allele with 20 or more repeats and 4.61 (95% CI = 1.34-15.82) for individuals carrying at least one long (A18 to A22) VDR poly-A allele versus two short (A14 to A17) poly-A alleles. For both the AR and VDR genes, the at-risk genotypes were more strongly associated with advanced disease than with localized disease. CONCLUSIONS: In this pilot study, genetic variation in both the VDR and the AR genes was associated with prostate cancer, and both genes appear to preferentially confer risk for advanced disease. These two genetic risk factors, if confirmed, are among the strongest risk factors yet identified for prostate cancer. IMPLICATIONS: These results are consistent with a multigenic model of prostate cancer susceptibility. On the basis of the joint effect of several genetic loci, one might ultimately be able to construct a risk profile to predict advanced disease, so that men whose disease is unlikely to progress to an advanced stage can possibly be spared aggressive treatment.
Alleles↗
Follow up study of moderate alcohol intake and mortality among middle aged men in Shanghai, China.
OBJECTIVE: To assess the risk of death associated with various patterns of alcohol intake. DESIGN: Prospective study of mortality in relation to alcohol consumption at recruitment, with active annual follow up. SETTING: Four small, geographically defined communities in Shanghai, China. SUBJECTS: 18,244 men aged 45-64 years enrolled in a prospective study of diet and cancer during January 1986 to September 1989. MAIN OUTCOME MEASURE: All cause mortality. RESULTS: By 28 February 1995, 1198 deaths (including 498 from cancer, 269 from stroke, and 104 from ischaemic heart disease) had been identified. Compared with lifelong non-drinkers, those who consumed 1-14 drinks a week had a 19% reduction in overall mortality (relative risk 0.81; 95% confidence interval 0.70 to 0.94) after age, level of education, and cigarette smoking were adjusted for. This protective effect was not restricted to any specific type of alcoholic drink. Although light to moderate drinking (28 or fewer drinks per week) was associated with a 36% reduction in death from ischaemic heart disease (0.64; 0.41 to 0.998), it had no effect on death from stroke, which is the leading cause of death in this population. As expected, heavy drinking (29 or more drinks per week) was significantly associated with increased risks of death from cancer of the upper aerodigestive tract, hepatic cirrhosis, and stroke. CONCLUSIONS: Regular consumption of small amounts of alcohol is associated with lower overall mortality including death from ischaemic heart disease in middle aged Chinese men. The type of alcoholic drink does not affect this association.
Alcohol Drinking↗
Presence of antibodies to the hepatitis B surface antigen is associated with an excess risk for hepatocellular carcinoma among non-Asians in Los Angeles County, California.
Hepatocellular carcinoma (HCC) exhibits a more than 50-fold variation in incidence worldwide. High-risk regions include East Asia and sub-Saharan Africa, while non-Asians in the United States constitute a low-risk population. We assessed 111 cases of histologically confirmed HCC and 128 community control subjects among non-Asians of Los Angeles County for the presence in serum of hepatitis B surface antigen (HBsAg), antibodies to HBsAg (anti-HBs), antibodies to the hepatitis B core antigen (anti-HBc), HBV DNA, and antibodies to the hepatitis C virus (anti-HCV). Anti-HCV positivity was significantly associated with a 12.6-fold increase in HCC risk (95% confidence limits = 4.7, 33.6). As expected, the presence of serum HBsAg and the presence of anti-HBc in the absence of anti-HBs were both positively associated with the risk of HCC. But most interestingly, among our study subjects, the presence of anti-HBs in the absence of HBsAg and HBV DNA (indicative of a resolved infection) was significantly related to a 4.7-fold increased risk for HCC (95% confidence limits = 2.2, 9.4). Overall, any serological evidence of prior HBV exposure was associated with a 9.4-fold elevation in HCC risk (95% confidence limits = 4.7, 18.7). The data also demonstrate a synergistic effect of HBV and HCV infections on the risk of HCC. We estimate that about 55% of HCC cases occurring in non-Asians of Los Angeles can be attributed to infection by the hepatitis B and/or C viruses.
Adolescent↗
Variations in treatment of rectal cancer: the influence of hospital type and caseload.
PURPOSE: Surgical options for the treatment of rectal cancer may involve sphincter-sparing procedures (SSP) or abdominoperineal resection (APR). We sought to examine variations in the surgical treatment of rectal cancer for a large, well-defined patient population and specifically to determine if differences exist in management and survival based on hospital type and surgical caseload. METHODS: The Cancer Surveillance Program database for Los Angeles County was used to retrospectively retrieve data on all patients who underwent SSP or APR for rectal adenocarcinoma between 1988 and 1992. RESULTS: A total of 2,006 patients with adenocarcinoma of the rectum underwent SSP or APR during the study period. Overall, 55 percent underwent SSP, and the remaining 45 percent underwent APR. Use of SSP remained relatively constant for each year of the five-year period. Substantial variability was seen in the use of SSP at various hospital types. For localized disease, this varied from as low as 52 percent at teaching hospitals to as high as 78 percent at hospitals approved by the American College of Surgeons (P = 0.067). To examine the role of caseload experience, hospitals were divided into those completing an average of five or fewer rectal cancer cases per year vs. those completing an average of more than five cases per year. For localized disease, hospitals with higher caseloads performed SSP in significantly more cases, 69 vs. 63 percent (P = 0.049). Survival was seen to be significantly improved for patients operated on at hospitals with higher caseloads, in cases of both localized and regional diseases (P < 0.001). CONCLUSION: Surgical choices in the treatment of rectal cancer may vary widely, even in a well-defined geographic region. Although the reasons for this variability are multifactorial, hospital environment and surgical caseload experience seem to have a significant role in the choice of surgical procedure and on survival.
Adenocarcinoma↗
Breastfeeding history, pregnancy experience and risk of breast cancer.
Epidemiological evidence suggests that breastfeeding protects against breast cancer. Whether an effect of age at first breastfeeding is independent of an effect of age at first birth is unclear. We hypothesized that nausea and vomiting in pregnancy, which are associated with elevated serum oestradiol levels during pregnancy, may increase risk. Cases were 452 parous, premenopausal women, 40 years or younger, diagnosed with breast cancer in Los Angeles County from July 1983 to December 1988. Control subjects were matched to cases on age, race, parity and neighbourhood. Pregnancy and breastfeeding histories were obtained from in-person interviews. Odds of breast cancer among women who breastfed for at least 16 months relative to those among women who did not breastfeed was 0.66 [95% confidence interval (CI) 0.41-1.05]. Number of children breastfed was not associated with risk. Risk was lower in women who first breastfed at older ages. Having ever been treated for nausea or vomiting during pregnancy was associated with an increased risk, especially in women experiencing recent pregnancies (OR = 2.03, 95% CI 1.05-3.92). These results support a protective role of breastfeeding and an adverse role of nausea or vomiting during pregnancy in the development of premenopausal breast cancer, especially in the years immediately following pregnancy.
Adult↗
A pilot study of urinary estrogen metabolites (16alpha-OHE1 and 2-OHE1) in postmenopausal women with and without breast cancer.
The two main pathways for metabolizing estrogen are via 16alpha-hydroxylation and 2-hydroxylation. The 16alpha-hydroxy metabolites are biologically active; the 2-hydroxy metabolites are not. It is suggested that women who metabolize a larger proportion of their endogenous estrogen via the 16alpha-hydroxy pathway may be at significantly elevated risk of breast cancer compared with women who metabolize proportionally more estrogen via the 2-hydroxy pathway. In particular, it is suggested that the ratio of urinary 2-hydroxyestrone (2-OHE1) to 16alpha-hydroxyestrone (16alpha-OHE1) is an index of reduced breast cancer risk. This pilot study compared this ratio in postmenopausal women diagnosed with breast cancer to those of healthy controls. Urinary concentrations of estrone (E1), 17beta-estradiol (E2) and estriol (E3) were also quantified. White women who were subjects in a previous breast cancer case-control study at our institution were eligible for inclusion. All participants provided a sample of their first morning urine. The results from the first 25 cases and 23 controls are presented here. The ratio of 2-OHE1 to 16alpha-OHE1 was 12% lower in the cases (p=0.58). However, urinary E1 was 30% higher (p=0.10), E2 was 58% higher (p=0.07), E3 was 15% higher (p=0.48), and the sum of E1, E2, and E3 was 22% higher (p=0.16) in the cases. These preliminary results do not support the hypothesis that the ratio of the two hydroxylation metabolites (2-OHE1/16alpha-OHE1) is an important risk factor for breast cancer or that it is a better predictor of breast cancer risk than levels of E1, E2 and E3 measured in urine.
Breast Neoplasms↗
Strength of linkage disequilibrium between two vitamin D receptor markers in five ethnic groups: implications for association studies.
Markers in the 3' end of the vitamin D receptor gene have recently been associated with prostate cancer risk. To evaluate the adequacy of the commonly used BsmI restriction fragment length polymorphism as a marker of this locus, we genotyped 627 individuals from five ethnic groups for this marker, as well as for a polymorphic site in the 3' untranslated region of this gene. At the latter site, we identified 12 alleles, A13 to A24, of a poly(A) microsatellite. Allele size followed a bimodal distribution with distinct short (A13-A17) and long (A18-A24) allele populations. Poly(A) allele frequency differed by ethnicity, with the frequency of short alleles being highest in non-Hispanic whites (41%), intermediate in Hispanics and African-Americans (31 and 29%, respectively), and lowest in Japanese-Americans and Chinese (8 and 9%, respectively). In each of the ethnic groups, some degree of coupling was observed between BsmI B and short poly(A) alleles and between BsmI b and long poly(A) alleles. However, the strength of the linkage disequilibrium varied by ethnicity, with departures from complete disequilibrium producing disagreement between the BsmI and poly(A) genotypes. Genotypic disagreement was lowest in Japanese-Americans and non-Hispanic whites (6 and 7%, respectively), intermediate in Chinese and Hispanics (11 and 19%, respectively), and highest among African-Americans (37%), indicating that BsmI is not a good marker for the vitamin D receptor 3' untranslated region genotype in all populations. This finding may explain contradictory results from recent association studies using the BsmI marker.
Asian↗
Androgens in serum and the risk of prostate cancer: a nested case-control study from the Janus serum bank in Norway.
We tested the hypothesis that serum levels of testosterone (T), dihydrotestosterone (DHT), and the DHT metabolite 3 alpha,17 beta-androstanediol glucuronide are positively associated with the risk of prostate cancer. This nested case-control study was based on the cohort of men who donated blood to the Janus serum bank at Oslo University Hospital (Oslo, Norway) between 1973 and 1994. Cancer incidence was ascertained through linkage with the Norwegian Cancer Registry. The study included sera from 59 men who developed prostate cancer (cases) subsequent to blood donation and 180 men who were free of any diagnosed cancer (controls) in 1994 and were of similar age (+/- 1 year) and had similar blood storage time (+/- 6 months) to the cases. Neither T, DHT, nor the ratio T:DHT was associated with risk of developing prostate cancer. Compared to the bottom quartile, the odds ratio (OR) associated with the top quartile of T was 0.83 [95% confidence interval (CI), 0.36-1.93]; the OR for the top (compared to the bottom) quartile of DHT was 0.83 (95% CI, 0.36-1.94), and the equivalent OR for T:DHT was 1.31 (95% CI, 0.58-2.97). Similarly, 3 alpha,17 beta-androstanediol glucuronide showed no association with prostate cancer risk; the OR for the top (compared to the bottom) quartile was 1.10 (95% CI, 0.41-2.90). These results showed no association, positive or negative, between androgens measured in serum and the subsequent risk of developing prostate cancer.
Adult↗
An apparent lack of association between Helicobacter pylori infection and risk of gastric cancer in China.
Several prospective studies have shown a significant association between Helicobacter pylori seropositivity and the risk of gastric cancer. Only a small proportion of H. pylori-infected individuals will, however, develop gastric cancer, and it is unclear what effects other factors, such as diet, might have on the risk of cancer. Eighty-seven subjects with gastric cancer were identified during the first 6 years of follow-up (mean 2.4 years) of a cohort of middle-aged men from Shanghai, China. They were matched with 261 cancer-free controls, and serum samples from all subjects, obtained at recruitment, were assayed for anti-H. pylori IgG antibodies. Questionnaire data provided information on a wide range of socio-demographic life-style and dietary variables. H. pylori seropositivity rates in the cases and controls were 54% and 56%, respectively. Neither the overall risk of developing gastric cancer nor the risk of developing non-cardia gastric cancer was significantly associated with prior M. pylori seropositivity. Adjustment for any of the other medical, dietary or life-style variables studied had little effect on the risk of developing non-cardia gastric cancer; simultaneous adjustment for all of these factors yielded an odds ratio of 1.17. The results do not support the hypothesis that H. pylori plays a role in the process of gastric carcinogenesis in China. It is possible that this is an artefact resulting from the relatively short follow-up period to date.
Antibodies, Bacterial↗