Aditi H | Harvard University (original) (raw)

Papers by Aditi H

Background: Experimental evidence has demonstrated an antineoplastic role for vitamin D in the co... more Background: Experimental evidence has demonstrated an antineoplastic role for vitamin D in the colon, and higher circulating 25-hydroxyvitamin D [25(OH)D] levels are consistently associated with a lower risk of colorectal cancer. Genome-wide association studies have identified loci associated with levels of circulating 25(OH)D. The identified single-nucleotide polymorphisms (SNPs) from four gene regions collectively explain approximately 5% of the variance in circulating 25(OH)D.Methods: We investigated whether five polymorphisms in GC, CYP2R1, CYP24A1, and DHCR7/NADSYN1, genes previously shown to be associated with circulating 25(OH)D levels, were associated with colorectal cancer risk in 10,061 cases and 12,768 controls drawn from 13 studies included in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry (CCFR). We conducted a meta-analysis of crude and multivariate-adjusted logistic regression models to calculate odds ratios and ...

Cells

Identification of a unique genomic biomarker in de novo inflammatory breast cancer (IBC) may prov... more Identification of a unique genomic biomarker in de novo inflammatory breast cancer (IBC) may provide an insight into the biology of this aggressive disease. The goal of our study was to elucidate biomarkers associated with IBC. We examined breast biopsies collected from Dana–Farber Cancer Institute patients with IBC prior to initiating preoperative systemic treatment (30 samples were examined, of which 14 were eligible). Patients without available biopsies (n = 1), with insufficient tumor epithelial cells (n = 10), or insufficient DNA yield (n = 5) were excluded from the analysis. Molecular subtype and tumor grade were abstracted from a medical records’ review. Ten IBC tumors were estrogen-receptor-positive (ER+) and human epidermal growth factor receptor 2 (HER2)-negative (n = 10 out of 14). Sufficient RNA and DNA were simultaneously extracted from 14 biopsy specimens using the Qiagen AllPrep Kit. RNA was amplified using the Sensation kit and profiled using the Affymetrix Human Tra...

Contemporary Clinical Trials

by LINE-1 methylation in a database of 869 tumors

Human Molecular Genetics, 2011

In genome-wide association studies (GWAS) of common genetic variants associated with circulating ... more In genome-wide association studies (GWAS) of common genetic variants associated with circulating alpha- and gamma-tocopherol concentrations in two adult cohorts comprising 5006 men of European descent, we observed three loci associated with alpha-tocopherol levels, two novel single-nucleotide polymorphisms (SNPs), rs2108622 on 19pter-p13.11 (P= 1.7 × 10−8) and rs11057830 on 12q24.31 (P= 2.0 × 10−8) and confirmed a previously reported locus marked by rs964184 on 11q23.3 (P= 2.7 × 10−10). The three SNPs have been reported to be associated with lipid metabolism and/or regulation. We replicated these findings in a combined meta-analysis with two independent samples, P= 7.8 × 10−12 (rs964184 on 11q23.3 near BUD13, ZNF259 and APOA1/C3/A4/A5), P= 1.4 × 10−10 (rs2108622 on 19pter-p13.11 near CYP4F2) and P= 8.2 × 10−9 (rs11057830 on 12q24.31 near SCARB1). Combined, these SNPs explain 1.7% of the residual variance in log alpha-tocopherol levels. In one of the two male GWAS cohorts (n= 992), n...

JAMA Network Open

IMPORTANCE Epidemiologic and trial data suggest that vitamin D supplementation may reduce metasta... more IMPORTANCE Epidemiologic and trial data suggest that vitamin D supplementation may reduce metastatic cancer and cancer mortality, reflecting shared biological pathways. OBJECTIVE To follow up on the possible reduction in cancer death in the Vitamin D and Omega-3 Trial (VITAL) with an evaluation of whether vitamin D reduces the incidence of advanced (metastatic or fatal) cancer and an examination possible effect modification by body mass index. DESIGN, SETTING, AND PARTICIPANTS VITAL is a randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial of vitamin D 3 (cholecalciferol, 2000 IU/d) and marine omega-3 fatty acids (1 g/d). This multicenter clinical trial was conducted in the United States; participants included men

As the United States prepares to return to work and open up the economy in the midst of the COVID... more As the United States prepares to return to work and open up the economy in the midst of the COVID-19 pandemic without an available vaccine or effective therapy, testing and contact tracing are essential to contain and limit the spread of the COVID-19 virus. In response to the urgent public health need for accurate, effective, low-cost, and scalable COVID-19 testing technology, we evaluated and identified diagnostic solutions with potential for use as an at-home product. We conducted a deep horizon scan for antigen and serology-based diagnostics and down-selected to the most promising technologies. A total of 303 candidate products (138 antibody and 44 antigen tests) were identified. Product evaluations were based entirely on company-provided data. 73 serology-based antibody tests passing an initial scoring algorithm based on specificity and sensitivity data were then further evaluated using a second scoring algorithm. This second algorithm included a review of additional technical s...

NPJ breast cancer, 2018

Sex steroid hormone signaling is critical in the development of breast cancers, although the role... more Sex steroid hormone signaling is critical in the development of breast cancers, although the role of the androgen receptor remains unclear. This study evaluated androgen receptor (AR) expression in normal breast tissue as a potential marker of breast cancer risk. We conducted a nested case-control study of women with benign breast disease (BBD) within the Nurses' Health Studies. Epithelial AR expression was assessed by immunohistochemistry in normal tissue from the BBD biopsy and the percent of positive nuclei was estimated in ordinal categories of 10% for 78 breast cancer cases and 276 controls. Logistic regression models adjusting for the matching factors and BBD lesion type were used to calculate odds ratios (ORs) for the association between AR expression (tertiles: ≤10%, 11-30%, and >30%) and breast cancer risk. AR expression in normal breast tissue was not associated with subsequent breast cancer risk (OR = 0.9, 95% CI = 0.4-1.8, trend = 0.68). In comparison with low AR/...

Breast cancer research : BCR, Jan 12, 2017

Alcohol consumption is an established risk factor for breast cancer and the association generally... more Alcohol consumption is an established risk factor for breast cancer and the association generally appears stronger among estrogen receptor (ER)-positive tumors. However, the biological mechanisms underlying this association are not completely understood. We analyzed messenger RNA (mRNA) microarray data from both invasive breast tumors (N = 602) and tumor-adjacent normal tissues (N = 508) from participants diagnosed with breast cancer in the Nurses' Health Study (NHS) and NHSII. Multivariable linear regression, controlling for other known breast cancer risk factors, was used to identify differentially expressed genes by pre-diagnostic alcohol intake. For pathway analysis, we performed gene set enrichment analysis (GSEA). Differentially expressed genes or enriched pathway-defined gene sets with false discovery rate (FDR) <0.1 identified in tumors were validated in RNA sequencing data of invasive breast tumors (N = 166) from The Cancer Genome Atlas. No individual genes were sign...

Breast cancer research and treatment, Jan 8, 2017

Ki67 is a proliferation marker commonly assessed by immunohistochemistry in breast cancer, and it... more Ki67 is a proliferation marker commonly assessed by immunohistochemistry in breast cancer, and it has been proposed as a clinical marker for subtype classification, prognosis, and prediction of therapeutic response. However, the clinical utility of Ki67 is limited by the lack of consensus on the optimal cut point for each application. We assessed Ki67 by immunohistochemistry using Definiens digital image analysis (DIA) in 2653 cases of incident invasive breast cancer diagnosed in the Nurses' Health Study from 1976 to 2006. Ki67 was scored as continuous percentage of positive tumor cells, and dichotomized at various cut points. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression models for distant recurrence, breast cancer-specific mortality and overall mortality in relation to luminal subtypes defined with various Ki67 cut points, adjusting for breast cancer prognostic factors, clinico-pathologic features and treatment. DIA was...

PloS one, 2017

We investigate 71 single nucleotide polymorphisms (SNPs) identified in meta-analytic studies of g... more We investigate 71 single nucleotide polymorphisms (SNPs) identified in meta-analytic studies of genome-wide association studies (GWAS) of breast cancer, the majority of which are located in intergenic or intronic regions. To explore regulatory impacts of these variants we conducted expression quantitative loci (eQTL) analyses on tissue samples from 376 invasive postmenopausal breast cancer cases in the Nurses' Health Study (NHS) diagnosed from 1990-2004. Expression analysis was conducted on all formalin-fixed paraffin-embedded (FFPE) tissue samples (and on 264 adjacent normal samples) using the Affymetrix Human Transcriptome Array. Significance and ranking of associations between tumor receptor status and expression variation was preserved between NHS FFPE and TCGA fresh-frozen sample sets (Spearman r = 0.85, p<10^-10 for 17 of the 21 Oncotype DX recurrence signature genes). At an FDR threshold of 10%, we identified 27 trans-eQTLs associated with expression variation in 217 d...

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, Jun 23, 2017

Epigenetic disturbances are crucial in cancer initiation, potentially with pleiotropic effects, a... more Epigenetic disturbances are crucial in cancer initiation, potentially with pleiotropic effects, and may be influenced by the genetic background. In a subsets (ASSET) meta-analytic approach, we investigated associations of genetic variants related to epigenetic mechanisms with risks of breast, lung, colorectal, ovarian and prostate carcinomas using 51,724 cases and 52,001 controls. False-discovery-rate corrected p-values (q-values < 0.05) were considered statistically significant. Among 162,887 imputed or genotyped variants in 555 candidate genes, SNPs in eight genes were associated with risk of more than one cancer type. For example, variants in BABAM1 were confirmed as a susceptibility locus for squamous cell lung, overall breast, ER-negative breast, overall prostate, overall and serous ovarian cancer; the most significant variant was rs4808076 (odds ratio (OR)=1.14, 95% confidence interval (CI)=1.10-1.19, q=6.87*10-5). DPF1 rs12611084 was inversely associated with ER-negative b...

Cancer research, Sep 20, 2016

Identifying genetic variants with pleiotropic associations can uncover common pathways influencin... more Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-staged approach to conduct genome-wide association studies for lung, ovary, breast, prostate and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple c...

Hormones & cancer, Jan 18, 2015

In epidemiologic studies, alcohol consumption appears more strongly associated with risk of estro... more In epidemiologic studies, alcohol consumption appears more strongly associated with risk of estrogen receptor (ER)-positive than ER-negative breast cancer. However, this association has not been assessed by other potentially relevant tumor markers, such as androgen receptor (AR) or insulin receptor (IR). In the prospective Nurses' Health Study cohort, we evaluated alcohol consumption and breast cancer risk by individual tumor marker expression (i.e., ER, progesterone receptor [PR], AR, and IR) while controlling for other markers and also assessed the joint effect of these receptors. During 26 years follow-up of 106,037 women, 2552 invasive breast cancers contributed to the analysis. When all four markers were considered simultaneously, no significant heterogeneity of the alcohol and breast cancer association was observed by any of the markers. However, each increment in one drink per day was associated with 10 % (95 % confidence interval [CI] = 4 %, 15 %) and 9 % (95 % CI = 4 %,...

Applied Immunohistochemistry & Molecular Morphology, 2015

Carcinogenesis, Jan 12, 2015

Although genome-wide association studies have separately identified many genetic susceptibility l... more Although genome-wide association studies have separately identified many genetic susceptibility loci for ulcerative colitis (UC), Crohn's disease (CD), and colorectal cancer (CRC), there has been no large-scale examination for pleiotropy, or shared genetic susceptibility, for these conditions. We used logistic regression modeling to examine the associations of 181 UC and CD susceptibility variants previously identified by GWAS with risk of CRC using data from the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. We also examined…

Breast Cancer Research, 2015

Introduction: Breast cancer in situ (BCIS) diagnoses, a precursor lesion for invasive breast canc... more Introduction: Breast cancer in situ (BCIS) diagnoses, a precursor lesion for invasive breast cancer, comprise about 20 % of all breast cancers (BC) in countries with screening programs. Family history of BC is considered one of the strongest risk factors for BCIS. Methods: To evaluate the association of BC susceptibility loci with BCIS risk, we genotyped 39 single nucleotide polymorphisms (SNPs), associated with risk of invasive BC, in 1317 BCIS cases, 10,645 invasive BC cases, and 14,006 healthy controls in the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). Using unconditional logistic regression models adjusted for age and study, we estimated the association of SNPs with BCIS using two different comparison groups: healthy controls and invasive BC subjects to investigate whether BCIS and BC share a common genetic profile. Results: We found that five SNPs (CDKN2BAS-rs1011970, FGFR2-rs3750817, FGFR2-rs2981582, TNRC9-rs3803662, 5p12-rs10941679) were significantly associated with BCIS risk (P value adjusted for multiple comparisons <0.0016). Comparing invasive BC and BCIS, the largest difference was for CDKN2BAS-rs1011970, which showed a positive association with BCIS (OR = 1.24, 95 % CI: 1.11-1.38, P = 1.27 x 10 −4) and no association with invasive BC (OR = 1.03, 95 % CI: 0.99-1.07, P = 0.06), with a P value for case-case comparison of 0.006. Subgroup analyses investigating associations with ductal carcinoma in situ (DCIS) found similar associations, albeit less significant (OR = 1.25, 95 % CI: 1.09-1.42, P = 1.07 x 10 −3). Additional risk analyses showed significant associations with invasive disease at the 0.05 level for 28 of the alleles and the OR estimates were consistent with those reported by other studies. Conclusions: Our study adds to the knowledge that several of the known BC susceptibility loci are risk factors for both BCIS and invasive BC, with the possible exception of rs1011970, a putatively functional SNP situated in the CDKN2BAS gene that may be a specific BCIS susceptibility locus.

Cancer Research, 2014

Background: In contrast to the well-established role of estrogens in breast cancer risk and survi... more Background: In contrast to the well-established role of estrogens in breast cancer risk and survival, the role of androgens in breast carcinogenesis is unclear. Previous studies have shown that, in postmenopausal women, higher body mass index (BMI) and being less physically active are associated with an increased risk of invasive breast cancer, and the associations generally are stronger for estrogen receptor (ER) and/or progesterone receptor (PR) positive tumors. Although the androgen pathway also may play a mechanistic role with these breast cancer risk factors, no prior studies have specifically evaluated these associations by tumor androgen receptor (AR) status. Observing differential associations by AR status would provide etiologic insights into the contribution of the androgen pathway in breast carcinogenesis. Methods: We evaluated the associations of adult body size and physical activity with risk of incident invasive breast cancer by AR status in the Nurses’ Health Study. We used validated questionnaires to assess height, weight, and physical activity. AR status was determined using immunohistochemistry on sections from tumor tissue microarrays (TMAs); ER and PR status were determined using TMAs or medical record pathology reports. We applied a constrained competing risk survival model to evaluate these associations by AR status while controlling for ER/PR status and established breast cancer risk factors. Results: A total of 2,198 cases (1,701 AR+; 497 AR- tumors) were documented during 26 years of follow-up of 96,966 eligible women. After adjusting for ER/PR status and other breast cancer risk factors, higher BMI was associated with an increased risk of both AR+ and AR- tumors. The multivariable hazard ratios (MV HRs) and 95% confidence intervals (95%CIs) for every 5 kg/m2 increase in BMI were 1.05 (0.99, 1.10) for AR+ and 1.10 (1.00, 1.22) for AR- tumors (p-value for heterogeneity=0.46). Further, women engaged in higher amounts of total physical activity including brisk walking were at a lower risk of developing breast cancer. The MV HRs (95%CIs) per approximately 5 hours of brisk walking per week were 0.87 (0.72, 1.05) for AR+ and 0.69 (0.46, 1.04) for AR- tumors (p-value for heterogeneity=0.32). We further examined these associations by the combinations of ER/PR/AR status and observed that only BMI associations differed significantly across these subtypes (p-value for heterogeneity=0.03). The MV HRs (95%CIs) for 5 kg/m2 increase in BMI were 1.15 (1.08, 1.23) for ER+PR+AR+, 1.23 (1.04, 1.45) for ER+PR+AR-, 0.88 (0.75, 1.03) for ER+PR-AR+, 1.08 (0.92, 1.28) for ER-PR-AR+, 1.19 (1.01, 1.39) for ER-PR-AR-, 0.92 (0.70,1.22) for ER+PR-AR-. Conclusion: In postmenopausal women, higher adult body size was associated with an increased risk of both AR+ and AR- tumors while physical activity, including brisk walking, was associated with a reduced risk of both subtypes. The strongest associations observed with the ER+PR+AR- and ER+PR+AR+ tumors (i.e., subtypes with the most active estrogen signaling) supports the important role of estrogen signaling in the postmenopausal BMI/breast cancer relationship. Further, the positive association observed between BMI and ER-PR-AR- tumors suggests pathways other than sex steroids (e.g., the insulin pathway) also might play an etiologic role and more studies are warranted to confirm and extend these findings. Citation Format: Xuehong Zhang, A. Heather Eliassen, Rulla Tamimi, Aditi Hazra, Andrew H. Beck, Myles Brown, Laura C. Collins, Bernard Rosner, Susan E. Hankinson. Adult body size and physical activity in relation to risk of breast cancer defined by tumor androgen receptor status. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-275. doi:10.1158/1538-7445.AM2014-LB-275

Cancer research, Jan 10, 2015

Mammographic density measures adjusted for age and body mass index (BMI) are heritable predictors... more Mammographic density measures adjusted for age and body mass index (BMI) are heritable predictors of breast cancer risk but few mammographic density-associated genetic variants have been identified. Using data for 10,727 women from two international consortia, we estimated associations between 77 common breast cancer susceptibility variants and absolute dense area, percent dense area and absolute non-dense area adjusted for study, age and BMI using mixed linear modeling. We found strong support for established associations between rs10995190 (in the region of ZNF365), rs2046210 (ESR1) and rs3817198 (LSP1) and adjusted absolute and percent dense areas (all p…