Noninvasive Assessment of Lactating Breasts Using Somatic Mutations and DNA Methylation as a Presymptomatic Test for BRCA Breast Cancer
Abstract
BRCA1 and BRCA2 are genes encoding proteins involved in repairing damaged DNA. Women with defective BRCA genes have a reduced ability to repair DNA mutations, which leads to greatly elevated lifetime risk of breast and ovarian cancer. If the defective BRCA genes were inherited as a germline mutation, then they can be passed down to children leading to hereditary breast and ovarian cancer (HBOC). Women with a germline BRCA mutation have a higher incidence of pregnancy-associated breast cancer (PABC), and an increased risk of developing breast cancer during their premenopausal years. An important reason for developing new screening methods for lactating BRCA mutation carriers is that the standard breast cancer screening methods do not work well for nursing mothers. The elevated cancer incidence in BRCA mutation carriers is caused in part by accumulation of DNA damage (somatic mutations) due to failure of the DNA repair system, which the intact BRCA genes support. A greater understanding of early onset breast cancer in women with BRCA mutations, as well as effective screening during lactation, is needed to reduce breast cancer incidence and associated mortalities. Abnormal DNA methylation and somatic mutations underlie the development of all breast cancers and are the most promising molecular biomarkers for both early detection and individual assessment of breast cancer risk. In an effort to develop strategies to reduce breast cancer risk, we study breast milk. Breast milk provides a unique opportunity to non-invasively examine the breast, through sloughed cells, secreted proteins, and lipophilic environmental contaminants. Breast milk from all women contains millions of epithelial cells from the target tissue providing assessment at the earliest stages of disease development. This is in contrast to assessment of cell-free DNA in blood, where the amount of DNA is extremely limited and likely indicative of advanced disease and metastasis. We propose, in this project, to recruit lactating women who have tested positive for a BRCA mutation associated with increased risk of developing cancer. Study participants from across the US will be asked to provide bilateral breast milk samples, a saliva sample, and a copy of their BRCA test results. Participants also will be asked to complete a health and reproductive history questionnaire, and agree to long-term, annual follow-up. The study also will include, as controls, a panel of women who lack reported BRCA mutations and don’t have multiple close relatives with breast cancer. The sloughed epithelial cells present in the milk samples will be examined for DNA methylation and somatic mutations to uncover profiles that may identify breasts at increased risk of breast disease, as well as to shed light on breast cancer development in women with defects of DNA repair. We are recruiting only BRCA1 carriers and not BRCA2 mutation carriers because there are some differences between the resulting tumors, which may confuse analysis. In addition, BRCA1 women are more likely to develop breast tumors in the reproductive years. Some of the participants in the study will develop breast cancer within the next 5 years, terribly soon but beyond the time of the funded project. We will therefore also attempt to recruit a small group of lactating BRCA1 carriers who already have breast cancer in order to understand what a positive signal looks like, building on very limited data on two women that we include in the application. There will be two aspects to what a positive signal looks like: the types of mutation we detect and the strength of the signal (the fraction of collected cells that are affected). The study design provides a unique opportunity to examine breast cells from non-symptomatic BRCA carriers of reproductive-age in a critical period of breast development. We hope to convert the findings into a screening test for BRCA-related pathology during lactation, a peri
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010034
Entities
People
- Kathleen Arcaro
Organizations
- United States Army
- University of Massachusetts Amherst