Study
PLCO
(Learn more about this study)
Project ID
PLCO-482
Initial CDAS Request Approval
May 21, 2019
Title
Integration of angiogenesis gene-pathway and lifestyle factors in breast cancer susceptibility
Summary
Breast cancer (BC) remains cancer with the highest incidence, and it is the second leading cause of cancer deaths. Substantial epidemiological evidence supports the possible role of genetic and environmental factors in BC susceptibility. Evidence suggests that angiogenesis, a pathophysiological process of new blood vessel formation, plays an important role in cancer development. Angiogenesis is regulated by endogenous angiogenesis stimulators and angiogenesis inhibitors. However, the role of angiogenesis balance in BC incidence remains mostly unexplained. Furthermore, several lifestyle factors such as consumption of fruits and vegetables, red and processed meat, and alcohol, obesity, and smoking are related to angiogenesis as well as BC risk. Using the Nurses’s Health Study and Nurses’s Health Study II as the discovery dataset and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial as the validation dataset, the goal of this application is to conduct novel research to investigate the role of angiogenesis balance in BC incidence through the integration of genetic variants, metabolomics, and lifestyle factors. To examine the impact of angiogenesis balance on BC incidence, the associations of genetic variants in angiogenesis stimulator and inhibitor genes with BC risk will be evaluated, using a nested case-control study of BC cases and matched controls (Aim-1A). To measure the impact of metabolites related to angiogenesis balance on BC, plasma metabolites associated with angiogenesis stimulator and inhibitor-related genetic variants will be identified among women without BC, using an agonistic approach, and then we will examine the associations of identified metabolites with subsequent overall BC risk and estrogen receptor status among BC cases and matched controls, using a nested case-control approach (Aim-1B). To understand the role of genetic variants in angiogenesis stimulator and inhibitor genes and their related metabolites in the association of lifestyle factors with BC, we will perform a gene-environment interaction analysis to identify single nucleotide polymorphisms (SNPs) and genes as well as metabolites that modify the associations of fruit and vegetable intake, red and processed meat intake, alcohol consumption, obesity, and smoking with BC incidence, using a nested case-control study of BC cases and matched controls (Aim-2). To understand the role of genetic variants in angiogenesis stimulator and inhibitor genes in the associations of lifestyle factor-related metabolites with BC, we will perform a gene-metabolite interaction analysis to identify SNPs and genes that modify the association of metabolomic profile indicative of fruit and vegetable intake, red and processed meat intake, alcohol consumption, obesity, and smoking with BC incidence, using a nested case-control study of BC cases and matched controls (Aim-3). This study will enable us to advance understanding of the molecular mechanisms by which angiogenesis affect BC incidence and identify objective novel biomarkers. These biomarkers may be amenable to lifestyle or therapeutic interventions, with important clinical and public health implications for targeted prevention efforts. By performing gene-environment interactions, we can identify subgroups of women that may benefit most from dietary and lifestyle intervention. The clinical importance of our study will potentially open a new avenue in precision medicine for personalized lifestyle recommendations.
Aims
Aim 1. To understand the role of angiogenesis balance in BC incidence.
Aim 1A. We will evaluate the associations of genetic variants in angiogenesis stimulator and angiogenesis inhibitor genes with breast cancer risk. Aim 1B. We will evaluate the associations of metabolites related to the genetic variants in angiogenesis stimulator and angiogenesis inhibitor genes with breast cancer risk. We hypothesize that disturbed angiogenesis balance may increase the risk of breast cancer.
Aim 2. To understand the role of genetic variations in the associations of lifestyle factors with BC incidence
Aim 2A. We will perform a gene-environment interaction analysis between genetic variants in angiogenesis stimulator and angiogenesis inhibitor genes and five lifestyle factors including red and processed meat intake, fruit and vegetable intake, alcohol consumption, smoking, and obesity with BC incidence. Aim 2B. We will evaluate the effect modification of metabolites related to genetic variants in angiogenesis stimulator and angiogenesis inhibitor genes on associations of lifestyle factors with BC incidence. As a secondary objective, we will assess gene-environment interaction analysis with BC subgroups as defined by hormone receptor status. We hypothesize that genetic factors and their related metabolites may affect the associations of lifestyle factors with BC incidence.
Aim 3. To understand the role of genetic variants in angiogenesis stimulator and inhibitor genes in the associations of lifestyle factor-related metabolites with BC risk
a. We will identify the metabolites associated with obesity, smoking, and physical activity and their relationship with breast cancer risk.
b. We will perform a gene-metabolite interaction analysis to identify SNPs and genes that modify the associations of metabolites related to fruits and vegetables, red and processed meat, alcohol, obesity, physical activity, and smoking with subsequent BC risk. We hypothesize that genetic factors may affect the associations between metabolomic profile indicative of lifestyle factors and BC incidence.
Collaborators
Timothy Rebbeck, Harvard T.H. Chan School of Public Health and Dana-Farber Cancer Institute
Michelle Holmes, Harvard T.H. Chan School of Public Health and Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School
Liming Liang, Harvard T.H. Chan School of Public Health
