Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium.

BACKGROUND: Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer. METHODS: We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype. RESULTS: Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ⩾35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant. CONCLUSIONS: Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.

Coffee, ADORA2A, and CYP1A2: the caffeine connection in Parkinson's disease.

BACKGROUND AND PURPOSE: In 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine animal models of Parkinson's disease (PD), caffeine protects neurons by blocking the adenosine receptor A2A (ADORA2A). Caffeine is primarily metabolized by cytochrome P450 1A2 (CYP1A2). Our objective was to examine whether ADORA2A and CYP1A2 polymorphisms are associated with PD risk or modify the caffeine-PD association. METHODS: Parkinson's Epidemiology and Genetic Associations Studies in the United States (PEGASUS) included five population-based case-control studies. One laboratory genotyped four ADORA2A and three CYP1A2 polymorphisms in 1325 PD cases and 1735 age- and sex-matched controls. Information regarding caffeine (coffee) consumption and other lifestyle factors came from structured in-person or telephone interviews. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression. RESULTS: Two ADORA2A polymorphisms were inversely associated with PD risk - rs71651683, a 5' variant (adjusted allelic OR = 0.51, 95% CI 0.33-0.80, permutation-adjusted P = 0.015) and rs5996696, a promoter region variant (adjusted OR for AC and CC genotypes compared with the AA wild-type genotype were 0.76 (95% CI 0.57-1.02) and 0.37 (95% CI 0.13-1.01), respectively (permutation-adjusted P for trend = 0.04). CYP1A2 polymorphisms were not associated with PD risk; however, the coffee-PD association was strongest among subjects homozygous for either variant allele rs762551 (P(interaction) = 0.05) or rs2470890 (P(interaction) = 0.04). CONCLUSION: In this consortium study, two ADORA2A polymorphisms were inversely associated with PD risk, but there was weak evidence of interaction with coffee consumption. In contrast, the coffee-PD association was strongest among slow metabolizers of caffeine who were homozygous carriers of the CYP1A2 polymorphisms.

Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer.

Low-moderate risk alleles that are relatively common in the population may explain a significant proportion of the excess familial risk of ovarian cancer (OC) not attributed to highly penetrant genes. In this study, we evaluated the risks of OC associated with common germline variants in five oncogenes (BRAF, ERBB2, KRAS, NMI and PIK3CA) known to be involved in OC development. Thirty-four tagging SNPs in these genes were genotyped in approximately 1800 invasive OC cases and 3000 controls from population-based studies in Denmark, the United Kingdom and the United States. We found no evidence of disease association for SNPs in BRAF, KRAS, ERBB2 and PIK3CA when OC was considered as a single disease phenotype; but after stratification by histological subtype, we found borderline evidence of association for SNPs in KRAS and BRAF with mucinous OC and in ERBB2 and PIK3CA with endometrioid OC. For NMI, we identified a SNP (rs11683487) that was associated with a decreased risk of OC (unadjusted P(dominant)=0.004). We then genotyped rs11683487 in another 1097 cases and 1792 controls from an additional three case-control studies from the United States. The combined odds ratio was 0.89 (95% confidence interval (CI): 0.80-0.99) and remained statistically significant (P(dominant)=0.032). We also identified two haplotypes in ERBB2 associated with an increased OC risk (P(global)=0.034) and a haplotype in BRAF that had a protective effect (P(global)=0.005). In conclusion, these data provide borderline evidence of association for common allelic variation in the NMI with risk of epithelial OC.

Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium.

The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.

Evidence of association between plasma high-density lipoprotein cholesterol and risk factors for breast cancer.

Females in western societies have higher plasma levels of high-density lipoprotein cholesterol (HDL-C) than males. The difference in plasma lipids between the sexes is believed to contribute to differences in risk of heart disease. The evidence reviewed here demonstrates that plasma levels of HDL-C are also associated with factors influencing risk of breast cancer, a leading cause of death in women in western societies. Both breast cancer risk and HDL-C levels are higher in women who live in northern European countries than in those who live in Asia, in women who have never been pregnant compared with those who have, and in women of higher socioeconomic status. HDL-C levels are also affected by several other known or suspected factors in breast cancer risk; these include dietary fat intake, alcohol consumption, endogenous hormones, and premenopausal leanness. Increases in any of these factors are known to increase the level of HDL-C. Preliminary work has also shown HDL-C levels to be higher in subjects with mammographic dysplasia and a family history of breast cancer. Further, in serum-free culture systems, HDL-C appears to possess biologic properties that may be relevant to carcinogenesis. In other areas, evidence of a relationship between increased HDL-C levels and increased breast cancer risk is either incomplete or contradictory. These areas include obesity (in the risk of postmenopausal breast cancer), use of exogenous hormones (oral contraceptives or postmenopausal estrogens), and physical exercise. In addition, both elevated and depressed levels of HDL-C have been reported in women with breast cancer. Our findings suggest an association between high HDL-C levels and the epidemiology of breast cancer risk. We recommend additional studies of plasma lipid level as a possible risk factor for this disease.

Genetic ablation of placental sinusoidal trophoblast giant cells causes fetal growth restriction and embryonic lethality.

A specialized subtype of trophoblast giant cells (TGCs) line the torturous sinusoids of the murine placental labyrinth, and can be distinguished from most other TGCs by the expression of Ctsq. We generated a transgenic mouse line expressing Cre recombinase from the Ctsq promoter. Crosses with Cre-inducible tdTomato reporter mice indicated Cre activity was restricted to the sinusoidal TGCs of the labyrinth, as well as the recently characterized channel TGCs. When crossed with Cre-inducible DTA transgenic mice, ablation of sinusoidal TGCs was achieved in double transgenic embryos, resulting in fetal growth restriction by E16.5, and embryonic lethality by term.

The possible role of lipid peroxidation in breast cancer risk.

Breast cancer remains the commonest cause of death from cancer in women in most of the Western world. There is considerable evidence that breast cancer risk is influenced by environmental factors and can therefore potentially be modified. In this paper we describe evidence suggesting a relationship of lipid peroxidation to breast cancer risk, and propose that the method used to generate this information might usefully be applied to other disease states, and make some suggestions for further work. We have compared the urinary excretion of the mutagen malonaldehyde (MDA) in premenopausal women at different risks for breast cancer as determined by the appearance of the breast parenchyma on mammography. MDA was measured in 24-h urine samples from both groups and excretion in 30 women with mammographic dysplasia (high risk) was found to be approximately double that of 16 women without these radiological changes (p less than 0.02). These results suggest that mammographic dysplasia may be associated with lipid peroxidation. Further study of environmental factors associated with states that precede the development of breast and other cancers may lead to the identification of factors that can be modified and that may prevent the development of malignant disease.

Methods for dealing with fats of unknown type in dietary surveys: the Lipid Research Clinic Population Study.

The design of the nutrition analysis tables adopted by the Lipid Research Clinics program of the National Heart Lung Blood Institute provides a specialized opportunity for assessing the fat component of 1-day dietary recalls. When the fat added during preparation of foods was unknown, rules were adopted for imputing composition. In order to investigate the effect that unknown fats produce on the apparent fatty acid composition of the diet, a detailed examination was made of 923 one-day dietary recalls from three clinics within the program. Total fat per recall from this sample averaged 107.6 g as calculated from visit 2 information. The average amount of unknown fat per recall at these three clinics was about 15.5%. About half the unknown fat at one clinic (Toronto-McMaster) could be identified and characterized through a procedure elected under Lipid Research Clinics protocol, "postinterview enquiry." Using this information, hypothetical "composite values," based on weighted means derived from the relative frequency of known use of fats and oils, were substituted for the unknown fat designations. Comparison of these composite values with values for known fats supports this approach and suggests the recommendation that postinterview information be collected for each region at the time of the inception of a new nutrition trial.

Compliance in a randomized clinical trial of dietary fat reduction in patients with breast dysplasia.

Dietary compliance was studied in 57 women participating for 1 y in a randomized clinical trial of dietary fat reduction. Nutrient analysis of food records, collected at 0, 6, and 12 mo, was compared with changes observed in lipid profiles and with chemical analysis of duplicate diets. Both food records and duplicate meals showed a significant decrease in fat intake (from 36 to 23% of total calories, p less than 0.0001) and a significant increase in carbohydrate (from 43 to 56% of total calories, p less than 0.0001) in the intervention group. The calculated nutrient intake from food records tended to overestimate the intake of protein, fat, and carbohydrate compared with the chemically analyzed method. The mean level of plasma cholesterol in the intervention group was significantly reduced (7.3%, p less than 0.01) in the first 6 mo after a reduction in dietary fat but the levels observed did not differ significantly between the groups at any time.

Source of variance in 24-hour dietary recall data: implications for nutrition study design and interpretation. Carbohydrate sources, vitamins, and minerals.

Beaton et al (Am J Clin Nutr 1979;32:2546-59) reported on the partitioning of variance in 1-day dietary data for the intake of energy, protein, total carbohydrate, total fat, classes of fatty acids, cholesterol, and alcohol. Using the same food intake data and the expanded National Heart, Lung and Blood Institute food composition data base, these analyses of sources of variance have been expanded to include classes of carbohydrate, vitamin A, vitamin C, thiamin, riboflavin, niacin, calcium, iron, total ash, caffeine, and crude fiber. The analyses relate to observed intakes (replicated six times) of 30 adult males and 30 adult females obtained under a paired Graeco-Latin square design with sequence of interview, interviewer, and day of the week as determinants. Neither sequence nor interviewer made consistent contribution to variance. In females, day of the week had a significant effect for several nutrients. The major partitioning of variance was between interindividual variation (between subjects) and intraindividual variation (within subjects) which included both true day-to-day variation in intake and methodological variation. For all except caffeine, the intraindividual variability of 1-day data was larger than the interindividual variability. For vitamin A, almost all of the variance was associated with day-to-day variability. One day data provide a very inadequate estimate of usual intake of individuals. In the design of nutrition studies it is critical that the intended use of dietary data be a major consideration in deciding on methodology. There is no "ideal" dietary method. There may be preferred methods for particular purposes.

Leguminous seeds in the dietary management of hyperlipidemia.

Seven male hyperlipidemic patients substituted approximately 140g dried beans daily for other sources of starch in their diet over a 4-month period. After this, mean fasting serum triglyceride levels were reduced by 25 +/- 5% (p less than 0.01) while total serum cholesterol levels were 7 +/- 2% (p less than 0.5) lower than the values measured during the previous five clinic attendances (12 +/- 2.5 months). However, low- and high-density lipoprotein cholesterol levels remained unaltered. While taking beans a nonsignificant fall (0.7 kg) was seen in body weight. Nevertheless no change was seen in macronutrient intake determined by 1-wk diet histories recorded both before and four times during the study, although cholesterol intake decreased by 80 mg (p less than 0.02). Reintroduction of dried leguminous seeds into a Western diet may be a useful adjunct to the management of hyperlipidemia.

Risk of amyotrophic lateral sclerosis and history of physical activity: a population-based case-control study.

OBJECTIVE: To assess in greater detail than previous studies the purported association between a history of physical activity and amyotrophic lateral sclerosis (ALS). METHODS: A population-based case-control study was used to identify risk factors for ALS. Case patients were from 3 counties of western Washington State who were newly diagnosed as having ALS by a neurologist. Two control subjects matched with each case patient for sex and age within 5 years were identified by random digit telephone dialing or random selection from Medicare eligibility lists. All subjects underwent an in-person structured interview including detailed information about physical activity before a reference date, which was the month and year the case patient was diagnosed as having ALS. Various measures of physical activity both at work and leisure time were evaluated using conditional logistic regression taking into account the matching for sex and age. RESULTS: One hundred seventy-four case patients and 348 control subjects participated in the study. Physical activity was not significantly different between case patients and controls--whether at work, leisure time or both combined, and whether during a person's lifetime (from 10 years before reference date back to age 15 years) or during specific decades before reference date. An exception was that case patients reported having participated in organized sports in high school slightly more frequently than control subjects (odds ratio, 1.52; 95% confidence interval, 1.03-2.25). CONCLUSION: A history of physical activity has little, if any, effect on the risk of ALS.

Incidence of amyotrophic lateral sclerosis in three counties in western Washington state.

We conducted a population-based study of amyotrophic lateral sclerosis (ALS) in King, Pierce, and Snohomish counties in western Washington state. Between April 1, 1990 and March 31, 1995, neurologists diagnosed 235 patients with ALS, including 127 men (54%) and 108 women (46%). The incidence rate, age-adjusted to the 1990 total U.S. population, was higher for men at 2.1 per 100,000 per year (95% CI, 1.3 to 2.9) than for women at 1.9 (95% CI, 1.1, 2.7) and increased with age for both men and women. These incidence rates are consistent with other studies from northern latitudes.

Evidence of lipid peroxidation in premenopausal women with mammographic dysplasia.

We have compared the urinary excretion of the mutagen malonaldehyde in premenopausal women at different risks for breast cancer as determined by the appearance of the breast parenchyma on mammography. Thirty women with extensive mammographic densities were compared with 16 controls without these radiological changes. Malonaldehyde was measured in 24-h urine samples from both groups and excretion in 30 women with mammographic dysplasia (high risk) was found to be approximately double that of 16 women without these radiological changes (P less than 0.02). These results suggest that mammographic dysplasia may be associated with lipid peroxidation and raise the possibility that mutagenic products generated by this process may influence breast cancer risk.

A review of the methods used by studies of dietary measurement.

Studying the association between diet and disease requires reliable and valid methods for the assessment of diet. The authors reviewed the literature concerned with the assessment of these aspects of the measurement of dietary intake. Studies were examined for the stated purpose and scope of the dietary instrument, for a description of the instrument itself, for any methods employed to train individuals in its use and for the methods used to assess its reliability and validity. Of the 59 studies reviewed, 54% described fully the dietary method used. Of the 39 studies that described the results using questionnaires, 51% gave specific information on questions asked and only 18% included the questionnaire itself. Reliability was assessed in 26 studies and 74% (19) used the test-retest reliability and 22% (6) used proxies to assess reliability. Validity was assessed in 46 studies and 83% (38) used indirect methods that compared the results of one dietary method (e.g. 24 hr recall) with another more extensive one (e.g. diet history). Thirty five percent (16) used biochemical and 15% (7) used other methods. This review suggests several directions that might be usefully followed in conducting and reporting further research in the development of methods to assess diet.

Short-term chorionic villi and amniotic fluid cultures.

Prenatal diagnosis of genetic disorders associated with specific biochemical, chromosomal, or molecular characteristics can be achieved from amniotie fluid (AF) or placenta (chorionic villus: CV) samples. Chorion material is usually obtained by sampling the placenta at the implantation site, during the first trimester (i. e., 9-12 wk), using either the transcervical or transabdominal route. The first method entails access to the placenta via the cervical canal, with aspiration through a metal cannula or a flexible catheter. Alternatively, the chorionic villi may be aspirated using a needle, which is passed through the abdominal wall. In both these methods, the positioning of the aspirating device must be made with the help of ultrasound scanning. Later pregnancies can only be sampled by the transabdominal route. Amniocentesis is usually performed at 16-18 wk of gestation by the transabdominal method.

Comparative studies of triacylglycerol structure of very low density lipoproteins and chylomicrons of normolipemic subjects and patients with type II hyperlipoproteinemia.

The triacylglycerols of very low density lipoproteins (VLDL) and of chylomicrons were analyzed in the fasting and postabsorptive states from normolipemic subjects and patients with Frederickson's Type II hyperlipoproteinemia, who subsisted on free choice diets, standard diets excluding lard, or were given a breakfast enriched in lard. The VLDL and chylomicrons were obtained by conventional ultracentrifugation, and the triacylglycerols were isolated by thin-layer chromatography (TLC). Representative sn-1,2-, sn-2-3- and sn-1,3-diacylglycerols were generated by partial Grignard degradation of the triacylglycerols and a stereospecific hydrolysis by phospholipase C of the mixed sn-1,2(2,3)-diacyl phosphatidylcholines prepared as intermediates. Representative sn-2-acylglycerols were obtained by hydrolysis with pancreatic lipase. Positional distribution of the fatty acids was established by subtracting in turn the fatty acid composition of the sn-2-position from the fatty acid composition of the sn-1,2- and sn-2,3-diacylglycerols. The molecular association of the fatty acids in the diacylglycerol moieties was determined by gas-liquid chromatography with mass spectrometry (GC/MS) of the tertiary-butyldimethylsilyl (t-BDMS) ethers. The molecular association of the fatty acids in the triacylglycerols was determined by 1-random 2-random 3-random calculation following experimental validation of the distribution. The results confirm a marked asymmetry in the positional distribution of the fatty acids in all triacylglycerol samples, with the palmitic acid predominantly in the sn-1-position, the unsaturated acids about equally divided between the sn-2- and sn-3-positions, and the stearic acid divided about equally between the sn-1- and sn-3-positions. The overall structure of the VLDL and chylomicron triacylglycerols from patients and control subjects was characterized by a non-correlative distribution of fatty acids under all dietary conditions.