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Publications (89)
The use of publicly available sequencing datasets as controls (hereafter, "public controls") in studies of rare variant disease associations has great promise but can increase the risk of false-positive discovery. The specific factors that could contribute to inflated distribution of test statistics have not been systematically examined. Here, we l...
Background
Breast cancer incidence rates have not declined despite an improvement in risk prediction and the identification of modifiable risk factors, suggesting the need to identify novel risk factors and etiological pathways involved in this cancer. Metabolomics has emerged as a promising tool to find circulating metabolites associated with brea...
PURPOSE
Pancreatic ductal adenocarcinoma (PDAC) is a component of familial melanoma due to germline pathogenic variants (GPVs) in CDKN2A. However, it is unclear what role this gene or other genes play in its etiology.
MATERIALS AND METHODS
We analyzed 189 cancer predisposition genes using parametric rare-variant association (RVA) tests and nonpara...
Patients with severe aplastic anemia (SAA) can have an unrecognized inherited bone marrow failure syndrome (IBMFS) due to phenotypic heterogeneity. We curated germline genetic variants in 104 IBMFS-associated genes from exome sequencing performed on 732 patients who underwent HCT between 1989-2015 for acquired SAA. Patients with pathogenic/likely p...
Importance:
Screening mammography and magnetic resonance imaging (MRI) are recommended for women with ATM, CHEK2, and PALB2 pathogenic variants. However, there are few data to guide screening regimens for these women.
Objective:
To estimate the benefits and harms of breast cancer screening strategies using mammography and MRI at various start ag...
Background: It is important to identify inherited bone marrow failure syndromes (IBMFS) in patients with aplastic anemia in order to provide appropriate therapy. IBMFS are diagnosed through genetic or other diagnostic testing but can also go unrecognized, particularly in adults who may lack classic IBMFS features. This is particularly critical in l...
PURPOSE
Previous studies have shown an approximately two-fold elevation in the relative risk of urinary bladder cancer (UBC) among people with a family history that could not be entirely explained by shared environmental exposures, thus suggesting a genetic component in its predisposition. Multiple genome-wide association studies and recent gene pa...
Background:
Cannabis use is increasing, including among smokers, an at-risk population for cancer. Research is equivocal on whether using cannabis inhibits quitting cigarettes. The current longitudinal study investigated associations between smoking cannabis and subsequently quitting cigarettes.
Methods:
Participants were 4,535 adult cigarette s...
Purpose:
The prevalence of germline pathogenic variants (PVs) in established breast cancer predisposition genes in women in the general population over age 65 years is not well-defined. However, testing guidelines suggest that women diagnosed with breast cancer over age 65 years might have < 2.5% likelihood of a PV in a high-penetrance gene. This...
Purpose
Ataxia–Telangiectasia Mutated ( ATM ) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear.
Methods
F...
Background:
Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains larg...
A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4
A Correction to this paper has been published: https://doi.org/10.1038/s41588-021-00786-2.
Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have...
Breast cancer is the most common cancer in women, but its incidence can only be partially explained through established risk factors. Our aim was to use metabolomics to identify novel risk factors for breast cancer and to validate recently reported metabolite-breast cancer findings. We measured levels of 1275 metabolites in prediagnostic serum in a...
Background
Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants.
Methods
In a population-based case–control study, we performed sequencing using a custom multigene ampli...
Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringi...
Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringi...
Background:
Ewing sarcoma (EwS) is a rare, aggressive solid tumor of childhood, adolescence and young adulthood associated with pathognomonic EWSR1-ETS fusion oncoproteins altering transcriptional regulation. Genome-wide association studies (GWAS) have identified 6 common germline susceptibility loci but have not investigated low-frequency inherit...
Purpose
Evidence supports a role of whole grains in colorectal cancer (CRC) prevention, but the association between gluten intake and CRC risk in healthy populations is unclear. We examined the association of grain and gluten intake with risk of CRC overall and by subsite among Cancer Prevention Study-II Nutrition Cohort participants.
Methods
In 1...
We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72,284 cases and 80,354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression, and a newly developed case-only method, fo...
Importance
Osteosarcoma, the most common malignant bone tumor in children and adolescents, occurs in a high number of cancer predisposition syndromes that are defined by highly penetrant germline mutations. The germline genetic susceptibility to osteosarcoma outside of familial cancer syndromes remains unclear.
Objective
To investigate the germlin...
Previous transcriptome‐wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome‐wide association studies (GWAS), but analyses of breast cancer subtype‐specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and s...
Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible caus...
Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26...
PURPOSE
Risk-stratified breast cancer prevention requires accurate identification of women at sufficiently different levels of risk. We conducted a comprehensive evaluation of a model integrating classical risk factors and a recently developed 313-variant polygenic risk score (PRS) to predict breast cancer risk.
METHODS
Fifteen prospective cohorts...
Objective:
This study was undertaken to identify metabolites associated with BMI and waist circumference (WC) in women and to determine whether these metabolites are associated with biomarkers of metabolic health.
Methods:
Untargeted metabolomic analysis was done on serum from 1,534 women. Metabolites associated with BMI and WC were identified u...
Background Previous gene-environment interaction studies of breast cancer risk have provided sparse evidence of interactions. Using the largest available dataset to date, we performed a comprehensive assessment of potential effect modification of 205 common susceptibility variants by 13 established breast cancer risk factors, including replication...
Background
Little is known about the underlying molecular mechanisms of prostate cancer, especially advanced and fatal prostate cancer.
Objective
To examine associations of prediagnostic plasma metabolomic profiles with advanced and fatal prostate cancer.
Design, setting, and participants
In a case-cohort study of the Cancer Prevention Study-II N...
Background: rospective validation of breast cancer risk models integrating classical risk factors and genetic variants is required for risk-stratified prevention and screening strategies. The objective of this study was to validate a breast cancer risk model integrating classical risk factors and a 313-variant polygenic risk score (RS) in multiple...
Background: rospective validation of breast cancer risk models integrating classical risk factors and genetic variants is required for risk-stratified prevention and screening strategies. The objective of this study was to validate a breast cancer risk model integrating classical risk factors and a 313-variant polygenic risk score (RS) in multiple...
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Background In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. Methods We co...
Background:
Healthy diet patterns are associated with lower risk of cancer and other chronic diseases. Metabolomics has the potential to expand dietary biomarker development to include dietary patterns, which may provide a complement or alternative to self-reported diet.
Objective:
This study examined the correlation of serum untargeted metabolo...
Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26...
There is insufficient evidence linking excess body weight to risk of myeloid malignancies. We investigated this association using data from the Cancer Prevention Study‐II (CPS‐II), and a meta‐analysis of published cohort studies. Among 152 090 CPS‐II participants, 387 acute myeloid leukaemias (AML), 100 chronic myeloid leukaemias (CML) and 170 MDS...
In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.
Background:
We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.
Methods:
Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific...
Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible caus...
Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in...
Introduction
Processing delays after blood collection is a common pre-analytical condition in large epidemiologic studies. It is critical to evaluate the suitability of blood samples with processing delays for metabolomics analysis as it is a potential source of variation that could attenuate associations between metabolites and disease outcomes....
Over-the-counter analgesic use is common and is typically assessed through self-report; therefore, it is subject to misclassification. Detection of drug metabolites in biofluids offers a viable tool for validating self-reported analgesic use. Thus, the aim of this study was to determine the utility of a metabolomics approach for the validation of a...
Various subtypes of breast cancer defined by estrogen receptor (ER), progesterone receptor (PR), and HER2 exhibit etiologic differences in reproductive factors, but associations with other risk factors are inconsistent. To clarify etiologic heterogeneity, we pooled data from nine cohort studies. Multivariable, joint Cox proportional hazards regress...
Introduction
Postmenopausal hormone use is linked to several health outcomes and the risk associated with some may differ depending on whether estrogen is used alone or in combination with progestin.
Objective
Metabolomic analyses of postmenopausal hormone use and differences between hormone regimes was done to identify metabolites associated with...
Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of Eur...
The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of geneti...
Breast cancer risk variants identified in genome-wide association studies explain only a small fraction of familial relative risk, and genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predic...
Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-a...
Prostate cancer is a polygenic disease with a large heritable component. A number of common, low penetrance prostate cancer risk loci have been identified through GWAS. Here, we apply the Bayesian multivariate variable selection algorithm JAM to finemap 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-a...
Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of Eur...
Background:
Recent studies suggest that untargeted metabolomics is a promising tool to identify novel biomarkers of individual foods. However, few large cross-sectional studies with comprehensive data on habitual diet and circulating metabolites have been conducted.
Objective:
We aimed to identify potential food biomarkers and evaluate their pre...
Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of Eur...
Physical activity has been associated with lower lung cancer risk in numerous studies with estimates ranging from 20 to 50% lower risk in the most versus the least active study participants. Underweight and obesity have also been associated with lower lung cancer risk, with a nonlinear, inverted U-shaped relationship. However, associations of physi...
Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease1. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We i...
Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of Europea...
Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of Europea...
Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We id...
We thank all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. Genotyping of the OncoArray was principally funded from three sources: the PERSPECTIVE project, funded by the Government of Canada through Genome Canada and the Canadian...
Etiological differences between molecular subtypes of breast cancer, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), have been examined in previous studies but results are inconsistent, most likely due to small numbers of rarer subtypes. In a recent systematic review of these studi...
There is growing evidence that factors associated with circadian rhythm disruption may be associated with prostate cancer risk. In a previous analysis focusing on shift-work in the Cancer Prevention Study (CPS)-II that included only employed men, we observed an association between short sleep duration and higher risk of prostate cancer death that w...
Background: Physical activity has been associated with lower lung cancer risk in numerous studies with estimates ranging from 20-50% lower risk in the most versus the least active study participants. Underweight and obesity have also been associated with lower lung cancer risk, with a nonlinear, inverted U-shaped relationship. The associations betw...
Until the mid-twentieth century, opposition to Tobacco use was based primarily on moral and social issues rather than specific health effects or strategies to control the problem. Since then, a comprehensive approach has been developed to counter the activities of the Tobacco industry. National and international agencies work to protect non-smokers...
Background:
The 2014 US Surgeon General's report noted research gaps necessary to determine a causal relationship between active cigarette smoking and invasive breast cancer risk, including the role of alcohol consumption, timing of exposure, modification by menopausal status and heterogeneity by oestrogen receptor (ER) status.
Methods:
To addre...
Objective:
To evaluate the association of parity, number of live births, and age at first birth with mortality using multivariable-adjusted Cox proportional hazards regression models.
Design:
Observational cohort.
Setting:
Not applicable.
Patient(s):
A total of 424,797 women.
Intervention(s):
None.
Main outcome measure(s):
All-cause and...
Background
Numerous studies have sought to identify genes that influence the ability to quit smoking but none found any that are consistently associated with smoking cessation.
Methods
We developed a novel difficulty of quitting smoking phenotype based on the extremes of the number of quit attempts needed to achieve successful abstinence: easy qui...
Background:
Overweight and obesity are increasing worldwide. To help assess their relevance to mortality in different populations we conducted individual-participant data meta-analyses of prospective studies of body-mass index (BMI), limiting confounding and reverse causality by restricting analyses to never-smokers and excluding pre-existing dise...
Background Mortality among current smokers is 2 to 3 times as high as that among persons who never smoked. Most of this excess mortality is believed to be explained by 21 common diseases that have been formally established as caused by cigarette smoking and are included in official estimates of smoking-attributable mortality in the United States. H...
Mortality among current smokers is 2 to 3 times as high as that among persons who never smoked. Most of this excess mortality is believed to be explained by 21 common diseases that have been formally established as caused by cigarette smoking and are included in official estimates of smoking-attributable mortality in the United States. However, if...