Faculty Bibliography
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333
Demographic, lifestyle, and other factors in relation to antimullerian hormone levels in mostly late premenopausal women
OBJECTIVE: To identify reproductive, lifestyle, hormonal, and other correlates of circulating antimullerian hormone (AMH) concentrations in mostly late premenopausal women. DESIGN: Cross-sectional study. SETTING: Not applicable. PATIENT(S): A total of 671 premenopausal women not known to have cancer. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Concentrations of AMH were measured in a single laboratory using the picoAMH ELISA. Multivariable-adjusted median (and interquartile range) AMH concentrations were calculated using quantile regression for several potential correlates. RESULT(S): Older women had significantly lower AMH concentrations (>/=40 [n = 444] vs. <35 years [n = 64], multivariable-adjusted median 0.73 ng/mL vs. 2.52 ng/mL). Concentrations of AMH were also significantly lower among women with earlier age at menarche (<12 [n = 96] vs. >/=14 years [n = 200]: 0.90 ng/mL vs. 1.12 ng/mL) and among current users of oral contraceptives (n = 27) compared with never or former users (n = 468) (0.36 ng/mL vs. 1.15 ng/mL). Race, body mass index, education, height, smoking status, parity, and menstrual cycle phase were not significantly associated with AMH concentrations. There were no significant associations between AMH concentrations and androgen or sex hormone-binding globulin concentrations or with factors related to blood collection (e.g., sample type, time, season, and year of blood collection). CONCLUSION(S): Among premenopausal women, lower AMH concentrations are associated with older age, a younger age at menarche, and currently using oral contraceptives, suggesting these factors are related to a lower number or decreased secretory activity of ovarian follicles.
PMCID:5426228
PMID: 28366409
ISSN: 1556-5653
CID: 2519352
Biomarkers of folate and vitamin B12 and breast cancer risk: Report from the EPIC cohort
Epidemiological studies have reported inconsistent findings for the association between B vitamins and breast cancer (BC) risk. We investigated the relationship between biomarkers of folate and vitamin B12 and the risk of BC in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Plasma concentrations of folate and vitamin B12 were determined in 2,491 BC cases individually matched to 2,521 controls among women who provided baseline blood samples. Multivariable logistic regression models were used to estimate odds ratios by quartiles of either plasma B vitamin. Subgroup analyses by menopausal status, hormone receptor status of breast tumors (ER, PR, and HER2), alcohol intake, and MTHFR polymorphisms (677C>T and 1298A>C) were also performed. Plasma levels of folate and vitamin B12 were not significantly associated with the overall risk of BC or by hormone receptor status. A marginally positive association was found between vitamin B12 status and BC risk in women consuming above the median level of alcohol (ORQ4-Q1 = 1.26; 95% CI 1.00-1.58; Ptrend = 0.05). Vitamin B12 status was also positively associated with BC risk in women with plasma folate levels below the median value (ORQ4-Q1 = 1.29; 95% CI 1.02-1.62; Ptrend = 0.03). Overall, folate and vitamin B12 status was not clearly associated with BC risk in this prospective cohort study. However, potential interactions between vitamin B12 and alcohol or folate on the risk of BC deserve further investigation
PMID: 27905104
ISSN: 1097-0215
CID: 2329392
Human chorionic gonadotropin does not correlate with risk for maternal breast cancer: results from the Finnish maternity cohort
Human chorionic gonadotropin (hCG) is necessary for the maintenance of early pregnancy and promotes normal breast cell differentiation. Administered hCG reduces risk of carcinogen-induced breast cancer in animal models, and higher circulating hCG concentrations were associated with significantly lower long-term risk of breast cancer in a prior nested case-control study. In this study, we investigated early pregnancy hCG concentrations and subsequent breast cancer risk. We conducted a nested case-control study with 1,191 cases and 2,257 controls (matched on age and date at blood collection) in the Finnish Maternity Cohort (FMC), a cohort with serum samples from 98% of pregnancies registered in Finland since 1983. This study included women with a serum sample collected early (<140 days gestation) in their first pregnancy resulting in a live, term birth. Breast cancer cases were identified via the Finnish Cancer Registry. Age at breast cancer diagnosis ranged from 22-58 years (mean: 41 years). hCG was measured using a solidphase competitive chemiluminescence assay. Odds ratios (ORs) were calculated using conditional logistic regression. We observed no association between hCG and breast cancer risk, overall (Quartile 4 vs. 1, OR: 1.14 95% confidence interval [0.94-1.39], by estrogen and progesterone receptor status, or by ages at first term birth or diagnosis. Associations did not differ by time between pregnancy and diagnosis (e.g., <5 years, ORQ4 vs. Q1: 1.10 [0.64-1.89]; {greater than or equal to}15 years, ORQ4 vs. Q1: 1.36 [0.86-2.13]; pheterogeneity=0.62). This large prospective study does not support an inverse relationship between early pregnancy serum hCG concentrations and breast cancer risk.
PMCID:5270509
PMID: 27784743
ISSN: 1538-7445
CID: 2288752
Lupus-related single nucleotide polymorphisms and risk of diffuse large B-cell lymphoma
Objective/UNASSIGNED:Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods/UNASSIGNED:GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results/UNASSIGNED:Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions/UNASSIGNED:These data suggest several plausible genetic links between DLBCL and SLE.
PMCID:5715504
PMID: 29214033
ISSN: 2053-8790
CID: 2838152
Serum biomarkers of polyomavirus infection and risk of lung cancer in never smokers
BACKGROUND: Lung cancer in never smokers is a significant contributor of cancer mortality worldwide. In this analysis, we explored the role of nine human polyomaviruses, including JC virus (JCV), BK virus (BKV) and Merkel cell virus (MCV), in lung cancer development in never smokers as there are data to support that polyomaviruses are potentially carcinogenic in the human lung. METHODS: We used multiplex serology to detect serum antibodies to polyomaviruses in a nested case-control design combining lung cancer cases and controls from four cohort studies - NYU Women's Health Study (NYU-WHS), Janus Serum Bank, Shanghai Women's Health Study and Singapore Chinese Health Study (SCHS). RESULTS: The final analyses included 511 cases and 508 controls. Seroprevalence for each polyomavirus showed significant heterogeneity by study, but overall there were no statistically significant differences between cases and controls. In total, 69.1% of the cases and 68.7% of the controls were seropositive for JCV VP1 antibody. Seropositivity for BKV was higher at 89.0% in cases and 89.8% in controls and lower for MCV at 59.3% in cases and 61.6% in controls. Similar results were obtained after adding an additional retrospective case-control study (Xuanwei study) to the analysis. CONCLUSIONS: Our results do not support the hypothesis that seropositivity for polyomaviruses is associated with increased lung cancer risk in never smokers. Future research to evaluate relationship between polyomavirus infection and lung carcinogenesis should focus more on evaluating the presence of virus or viral nucleic acids (DNA or RNA) in lung tumour samples.British Journal of Cancer advance online publication, 15 September 2016; doi:10.1038/bjc.2016.285 www.bjcancer.com.
PMCID:5117783
PMID: 27632373
ISSN: 1532-1827
CID: 2247082
Body Mass Index, Waist Circumference, Diabetes, and Risk of Liver Cancer for U.S. Adults
Incidence rates for liver cancer have increased 3-fold since the mid-1970s in the United States in parallel with increasing trends for obesity and type II diabetes mellitus. We conducted an analysis of baseline body mass index (BMI), waist circumference (WC), and type II diabetes mellitus with risk of liver cancer. The Liver Cancer Pooling Project maintains harmonized data from 1.57 million adults enrolled in 14 U.S.-based prospective studies. Cox regression estimated HRs and 95% confidence intervals (CI) adjusted for age, sex, study center, alcohol, smoking, race, and BMI (for WC and type II diabetes mellitus). Stratified analyses assessed whether the BMI-liver cancer associations differed by hepatitis sera-positivity in nested analyses for a subset of cases (n = 220) and controls (n = 547). After enrollment, 2,162 incident liver cancer diagnoses were identified. BMI, per 5 kg/m2, was associated with higher risks of liver cancer, more so for men (HR = 1.38; 95% CI, 1.30-1.46) than women (HR = 1.25; 95% CI, 1.17-1.35; Pinteraction = 0.02). WC, per 5 cm, was associated with higher risks of liver cancer, approximately equally by sex (overall, HR = 1.08; 95% CI, 1.04-1.13). Type II diabetes mellitus was associated with higher risk of liver cancer (HR = 2.61; 95% CI, 2.34-2.91). In stratified analyses, there was a null association between BMI and liver cancer risk for participants who were sera-positive for hepatitis. This study suggests that high BMI, high WC, and type II diabetes mellitus are associated with higher risks of liver cancer and that the association may differ by status of viral hepatitis infection. Cancer Res; 76(20); 6076-83. (c)2016 AACR.
PMCID:5141518
PMID: 27742674
ISSN: 1538-7445
CID: 2278632
Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21
Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10-15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10-9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10-8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L-TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10-8). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10-4-2.0x10-3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.
PMCID:5340084
PMID: 27579533
ISSN: 1949-2553
CID: 2232522
Ovarian Cancer Risk Factors by Histologic Subtype: An Analysis From the Ovarian Cancer Cohort Consortium
PURPOSE: An understanding of the etiologic heterogeneity of ovarian cancer is important for improving prevention, early detection, and therapeutic approaches. We evaluated 14 hormonal, reproductive, and lifestyle factors by histologic subtype in the Ovarian Cancer Cohort Consortium (OC3). PATIENTS AND METHODS: Among 1.3 million women from 21 studies, 5,584 invasive epithelial ovarian cancers were identified (3,378 serous, 606 endometrioid, 331 mucinous, 269 clear cell, 1,000 other). By using competing-risks Cox proportional hazards regression stratified by study and birth year and adjusted for age, parity, and oral contraceptive use, we assessed associations for all invasive cancers by histology. Heterogeneity was evaluated by likelihood ratio test. RESULTS: Most risk factors exhibited significant heterogeneity by histology. Higher parity was most strongly associated with endometrioid (relative risk [RR] per birth, 0.78; 95% CI, 0.74 to 0.83) and clear cell (RR, 0.68; 95% CI, 0.61 to 0.76) carcinomas (P value for heterogeneity [P-het] < .001). Similarly, age at menopause, endometriosis, and tubal ligation were only associated with endometrioid and clear cell tumors (P-het
PMCID:5012665
PMID: 27325851
ISSN: 1527-7755
CID: 2159102
Hormone concentrations throughout uncomplicated pregnancies: a longitudinal study
BACKGROUND: Evidence suggests that the hormonal milieu of pregnancy is an important determinant of subsequent cancer and other chronic diseases in both the mother and the offspring. Many of the existing maternity and birth cohorts include specimens drawn only once during pregnancy. How well a single blood specimen collected during a pregnancy characterizes exposure to these hormones throughout gestation, and also in subsequent pregnancies, is not well understood. METHODS: We used serial serum samples from 71 pregnant women (25 primiparous, 25 multiparous, and 21 with two consecutive pregnancies) with natural, complication-free pregnancies and a healthy offspring at term who participated in a population-based screening trial for congenital infections in Finland between January 1st, 1988 and June 30, 1989 and provided a blood sample in each trimester. RESULTS: Hormone levels were more strongly correlated between consecutive trimesters of a pregnancy than between the 1st and 3rd trimester (e.g., estradiol, rT1 vs. T2 = 0.51 and rT2 vs. T3 = 0.60, p < 0.01; rT1 vs. T3 = 0.32, p < 0.05). Concentrations of sRANKL remained stable throughout gestation, whereas estradiol, estrone, progesterone, testosterone, prolactin, and osteoprotegerin increased throughout pregnancy. First trimester hormone concentrations explained less of the variation in the third trimester on their own than second trimester hormone levels (e.g. estradiol R(2) T1 = 16 % and R(2) T2 = 42 %). Addition of maternal (e.g., smoking) and/or child characteristics (e.g., sex) improved the accuracy of the 3rd trimester estimates for some of the hormones. CONCLUSIONS: One hormone measurement in early pregnancy, in conjunction with maternal and fetal characteristics, permits estimation of 3rd trimester hormone concentrations. Therefore, single hormone measurements available from maternity cohorts are suitable to quantify hormone exposure during pregnancy. To our knowledge, we provide the first data on correlations between hormone concentrations both across trimesters of a single pregnancy, as well as between two subsequent pregnancies.
PMCID:4932669
PMID: 27377060
ISSN: 1471-2393
CID: 2178962
Calibration and seasonal adjustment for matched case-control studies of vitamin D and cancer
Vitamin D measurements are influenced by seasonal variation and specific assay used. Motivated by multicenter studies of associations of vitamin D with cancer, we formulated an analytic framework for matched case-control data that accounts for seasonal variation and calibrates to a reference assay. Calibration data were obtained from controls sampled within decile strata of the uncalibrated vitamin D values. Seasonal sine-cosine series were fit to control data. Practical findings included the following: (1) failure to adjust for season and calibrate increased variance, bias, and mean square error and (2) analysis of continuous vitamin D requires a variance adjustment for variation in the calibration estimate. An advantage of the continuous linear risk model is that results are independent of the reference date for seasonal adjustment. (3) For categorical risk models, procedures based on categorizing the seasonally adjusted and calibrated vitamin D have near nominal operating characteristics; estimates of log odds ratios are not robust to choice of seasonal reference date, however. Thus, public health recommendations based on categories of vitamin D should also define the time of year to which they refer. This work supports the use of simple methods for calibration and seasonal adjustment and is informing analytic approaches for the multicenter Vitamin D Pooling Project for Breast and Colorectal Cancer. Published 2016. This article has been contributed to by US Government employees and their work is in the public domain in the USA.
PMCID:4853926
PMID: 27133461
ISSN: 1097-0258
CID: 2100752
