Faculty Bibliography
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333
Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome
To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
PMCID:4909985
PMID: 27291797
ISSN: 2041-1723
CID: 2143242
Alcohol consumption and breast cancer risk by estrogen receptor status: in a pooled analysis of 20 studies
BACKGROUND: Breast cancer aetiology may differ by estrogen receptor (ER) status. Associations of alcohol and folate intakes with risk of breast cancer defined by ER status were examined in pooled analyses of the primary data from 20 cohorts. METHODS: During a maximum of 6-18 years of follow-up of 1 089 273 women, 21 624 ER+ and 5113 ER- breast cancers were identified. Study-specific multivariable relative risks (RRs) were calculated using Cox proportional hazards regression models and then combined using a random-effects model. RESULTS: Alcohol consumption was positively associated with risk of ER+ and ER- breast cancer. The pooled multivariable RRs (95% confidence intervals) comparing >/= 30 g/d with 0 g/day of alcohol consumption were 1.35 (1.23-1.48) for ER+ and 1.28 (1.10-1.49) for ER- breast cancer (Ptrend /= 0.26). Dietary (from foods only) and total folate intakes were not associated with risk of overall, ER+ and ER- breast cancer; pooled multivariable RRs ranged from 0.98 to 1.02 comparing extreme quintiles. Following-up US studies through only the period before mandatory folic acid fortification did not change the results. The alcohol and folate associations did not vary by tumour subtypes defined by progesterone receptor status. CONCLUSIONS: Alcohol consumption was positively associated with risk of both ER+ and ER- breast cancer, even among women with high folate intake. Folate intake was not associated with breast cancer risk.
PMCID:5005939
PMID: 26320033
ISSN: 1464-3685
CID: 1761582
Premenopausal Circulating Androgens and Risk of Endometrial Cancer: results of a Prospective Study
Endometrial cancer risk is increased by estrogens unopposed by progesterone. In premenopausal women, androgen excess is often associated with progesterone insufficiency, suggesting that premenopausal androgen concentrations may be associated with risk. In a case-control study nested within three cohorts, we assessed the relationship between premenopausal androgens and risk of endometrial cancer (161 cases and 303 controls matched on age and date of blood donation). Testosterone, DHEAS, androstenedione, and SHBG were measured in serum or plasma. Free testosterone was calculated from testosterone and SHBG. We observed trends of increasing risk across tertiles of testosterone (ORT3-T1 = 1.59, 95 % CI = 0.96, 2.64, p = 0.08) and free testosterone (ORT3-T1 = 1.76, 95 % CI = 1.01, 3.07, p = 0.047), which were not statistically significant after adjustment for body mass index (BMI). There was no association for DHEAS, androstenedione, or SHBG. There were significant interactions by age at diagnosis (<55 years, n = 51 cases; >/=55 years, n = 110 cases). Among women who were >/=55 years of age (predominantly postmenopausal) at diagnosis, the BMI-adjusted OR was 2.08 (95 % CI = 1.25, 3.44, p = 0.005) for a doubling in testosterone and 1.55 (95 % CI = 1.04, 2.31, p = 0.049) for a doubling in free testosterone. There was no association among women aged <55 years at diagnosis, consistent with the only other prospective study to date. If pre- and post-menopausal concentrations of androgens are correlated, our observation of an association of premenopausal androgens with risk among women aged >/=55 years at diagnosis could be due to the effect on the endometrium of postmenopausal androgen-derived estrogens in the absence of progesterone, which is no longer secreted.
PMCID:4860027
PMID: 26925952
ISSN: 1868-8500
CID: 2009252
Plasma anti-Mullerian hormone concentrations and risk of breast cancer among premenopausal women in the Nurses' Health Studies
BACKGROUND: Anti-Mullerian hormone (AMH) is a member of the transforming growth factor-beta family of growth and differentiation factors with a key role in regulating folliculogenesis. In experimental studies, using supraphysiologic concentrations, AMH inhibits breast cancer growth. However, high levels of AMH were associated with increased breast cancer risk in two prior prospective epidemiologic studies. METHODS: We conducted a nested case-control study of premenopausal plasma AMH and breast cancer risk within the Nurses' Health Study (NHS) and NHSII. In NHS, 32,826 women donated blood samples in 1989-90; in NHSII, 29,611 women donated samples in 1996-99. After blood collection and before February 2004 (NHS) or July 2010 (NHSII), 539 cases were diagnosed among women premenopausal at diagnosis, and were matched 1:1 to controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression, adjusting for matching and breast cancer risk factors. RESULTS: Higher plasma levels of AMH were associated with increased breast cancer risk (top vs. bottom quintile multivariate OR=2.20, 95%CI (1.34-3.63), p-trend=0.001). The association did not vary by invasive vs. in situ disease or by estrogen receptor status. Associations were not significantly different by age at blood or diagnosis. Further adjustment for plasma estradiol or testosterone yielded similar results. CONCLUSIONS: Higher circulating AMH levels are associated with increased breast cancer risk among premenopausal women. IMPACT: The significant positive association between premenopausal plasma AMH levels and subsequent breast cancer risk before menopause suggests AMH may be useful as a marker of breast cancer risk in younger women.
PMCID:4873319
PMID: 26961996
ISSN: 1538-7755
CID: 2024412
Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes
Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 x 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 x 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk.
PMCID:4854019
PMID: 27008888
ISSN: 1460-2083
CID: 2051542
Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 x 10(-11)), 6p25.2 (rs73718779, SERPINB6, P=1.97 x 10(-8)) and 3q28 (rs9815073, LPP, P=3.62 x 10(-8)), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 x 10(-11)) in the combined analysis. We find suggestive evidence (P<5 x 10(-7)) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 x 10(-8)) and 3p22.2 (rs1274963, CSRNP1, P=2.12 x 10(-7)). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.
PMCID:4786871
PMID: 26956414
ISSN: 2041-1723
CID: 2023532
Anthropometric Factors and Thyroid Cancer Risk by Histological Subtype: Pooled Analysis of 22 Prospective Studies
BACKGROUND: Greater height and body mass index (BMI) have been associated with an increased risk of thyroid cancer, particularly papillary carcinoma, the most common and least aggressive subtype. Few studies have evaluated these associations in relation to other, more aggressive histologic types or thyroid cancer-specific mortality. METHODS: This large pooled analysis of 22 prospective studies (833,176 men and 1,260,871 women) investigated thyroid cancer incidence associated with greater height, BMI at baseline and young adulthood, and adulthood BMI gain (difference between young-adult and baseline BMI), overall and separately by sex and histological subtype using multivariable Cox proportional hazards regression models. Associations with thyroid cancer mortality were investigated in a subset of cohorts (578,922 men and 774,373 women) that contributed cause of death information. RESULTS: During follow-up, 2996 incident thyroid cancers and 104 thyroid cancer deaths were identified. All anthropometric factors were positively associated with thyroid cancer incidence: hazard ratios (HR) [confidence intervals (CIs)] for height (per 5 cm) = 1.07 [1.04-1.10], BMI (per 5 kg/m(2)) = 1.06 [1.02-1.10], waist circumference (per 5 cm) = 1.03 [1.01-1.05], young-adult BMI (per 5 kg/m(2)) = 1.13 [1.02-1.25], and adulthood BMI gain (per 5 kg/m(2)) = 1.07 [1.00-1.15]. Associations for baseline BMI and waist circumference were attenuated after mutual adjustment. Baseline BMI was more strongly associated with risk in men compared with women (p = 0.04). Positive associations were observed for papillary, follicular, and anaplastic, but not medullary, thyroid carcinomas. Similar, but stronger, associations were observed for thyroid cancer mortality. CONCLUSION: The results suggest that greater height and excess adiposity throughout adulthood are associated with higher incidence of most major types of thyroid cancer, including the least common but most aggressive form, anaplastic carcinoma, and higher thyroid cancer mortality. Potential underlying biological mechanisms should be explored in future studies.
PMCID:4754509
PMID: 26756356
ISSN: 1557-9077
CID: 1935282
Serum Taurine and Stroke Risk in Women: A Prospective, Nested Case-Control Study
BACKGROUND: Taurine (2-aminoethanesulfonic acid), a conditionally essential sulfur-containing amino acid, is mainly obtained from diet in humans. Experimental studies have shown that taurine's main biological actions include bile salt conjugation, blood pressure regulation, anti-oxidation, and anti-inflammation. METHODS: We conducted a prospective case-control study nested in the New York University Women's Health Study, a cohort study involving 14,274 women enrolled since 1985. Taurine was measured in pre-diagnostic serum samples of 241 stroke cases and 479 matched controls. RESULTS: There was no statistically significant association between serum taurine and stroke risk in the overall study population. The adjusted ORs for stroke were 1.0 (reference), 0.87 (95% CI, 0.59-1.28), and 1.03 (95% CI, 0.69-1.54) in increasing tertiles of taurine (64.3-126.6, 126.7-152.9, and 153.0-308.5 nmol/mL, respectively). A significant inverse association between serum taurine and stroke risk was observed among never smokers, with an adjusted OR of 0.66 (95% CI, 0.37-1.18) and 0.50 (95% CI, 0.26-0.94) for the second and third tertile, respectively (p for trend = 0.01), but not among past or current smokers (p for interaction < 0.01). CONCLUSIONS: We observed no overall association between serum taurine and stroke risk, although a protective effect was observed in never smokers, which requires further investigation. Taurine, Stroke, Epidemiology, Prospective, Case-control study, NYUWHS.
PMCID:4750934
PMID: 26866594
ISSN: 1932-6203
CID: 1948722
Cancer prevention research (Philadelphia, Pa.). 2015:8(12):1156-62.DOI: 10.1158/1940-6207.CAPR-15-0126
NSAID use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: The Liver Cancer Pooling Project
Chronic inflammation plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), the two most common types of liver cancer. A number of prior experimental studies have suggested that non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and ibuprofen, may potentially protect against liver cancer. However, no observational study has examined the association between aspirin duration and dose or other over-the-counter non-aspirin NSAIDs, such as ibuprofen, and liver cancer incidence. Furthermore, the association between NSAID use and risk of ICC is unclear. As part of the Liver Cancer Pooling Project, we harmonized data on 1,084,133 individuals (HCC=679, ICC=225) from ten US-based prospective cohort studies. Cox proportional hazards regression models were used to evaluate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Current aspirin use, versus nonuse, was inversely associated with HCC (HR=0.68, 95% CI=0.57-0.81), which persisted when restricted to individuals not using non-aspirin NSAIDs and in a 5 and 10-year lag analysis. The association between aspirin use and HCC risk was stronger for users who reported daily use, longer duration use, and lower dosage. Ibuprofen use was not associated with HCC risk. Aspirin use was associated with a reduced ICC risk in men (HR=0.64, 95% CI=0.42-0.98) but not women (HR=1.34, 95% CI=0.89-2.01, pinteraction=0.01). The observed inverse association between aspirin use and liver cancer in our study, together with previous data, suggest the merit of future intervention studies of aspirin and other agents that affect chronic inflammatory pathways for HCC and possibly ICC.
PMCID:4704448
PMID: 26391917
ISSN: 1940-6215
CID: 1786742
Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types
BACKGROUND: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. METHODS: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. RESULTS: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE =0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. CONCLUSION: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
PMCID:4806328
PMID: 26464424
ISSN: 1460-2105
CID: 1909402
