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Whole-Genome Sequencing of High-Risk Families to Identify New Mutational Mechanisms of Breast Cancer Predisposition

Principal Investigator: WALSH, TOMAS
Institution Receiving Award: WASHINGTON, UNIVERSITY OF
Program: BCRP
Proposal Number: BC123495
Award Number: W81XWH-13-1-0335
Funding Mechanism: Idea Expansion Award: Collaborative Option
Partnering Awards: BC123495P1
Award Amount: $663,639.00


The discoveries of BRCA1 and BRCA2 have changed breast cancer prevention and treatment in remarkable ways. It is now possible for women to learn if they carry cancer-predisposing mutations in BRCA1 and BRCA2, and if so, to take steps to prevent breast and ovarian cancer. For the many women whose mothers or sisters carried such mutations and died of breast cancer, but do not carry the mutation themselves, genetic knowledge brings tremendous relief.

The National Comprehensive Cancer Network published practice guidelines for care of women with BRCA1 or BRCA2 mutations. These include (1) to undertake annual mammogram and breast MRI screening from age 25, (2) to discuss the option of risk reducing mastectomy, (3) to recommend risk reducing salpingo-oophorectomy between age 35-40 or upon completion of child bearing, followed if necessary by possible short-term hormone replacement therapy (HRT), and (4) to consider chemoprevention options. In addition, women who have been diagnosed with breast cancer may consider different treatment options if they carry mutations in BRCA1 or BRCA2. We have a great deal of work still to do to provide women with non-invasive options for prevention, but meanwhile knowledge of genetics continues to save lives.

One of our greatest frustrations is to discover that a family severely affected with breast cancer carries no mutation in BRCA1, BRCA2, or any of the known breast cancer genes. In our studies of 2,000 extended families at high risk of breast cancer, including more than 8,000 relatives, we have confronted this frustration many times. This proposal is the result.

There are at least 18 genes with mutations responsible for inherited breast cancer. BRCA1 and BRCA2 are the best known, conferring extremely high risks of breast and ovarian cancer, and responsible for 5% of all breast cancer in the United States and 10% of breast cancer diagnosed before age 45. Inherited mutations in TP53, CDH1, PTEN, and STK11 are associated with very high risks of breast cancer in the contexts of rare syndromes. Inherited mutations in several genes in pathways critical to genomic integrity confer two- to fourfold increased risks of breast cancer,; that is lifetime risks of 20% to 50%. These genes include Abraxas, ATM, BARD1, BRIP1, CHEK2, PALB2, RAD50, RAD51C, RAD51D, MRE11A, NBN and XRCC2. In our preliminary data, we describe mutations in six additional genes (ATR, BAP1, CHEK1, GEN1, RAD51B, and TP53BP1). The formulation of recommendations for care of women with mutations in these genes is presently under study by consensus conferences. These recommendations are likely to include increased surveillance, including tools such as MRI (magnetic resonance imaging) that are not offered universally.

Both statistical modeling studies and our direct observation of more 1,000 severely affected families suggest that many mutations and genes for breast cancer predisposition remain to be found, particularly among families with multiple cases of female breast cancer but no ovarian cancer or male breast cancer. We estimate that 70% of such families remain unresolved. As described in our technical abstract, we propose a novel approach based on whole genome sequencing to reveal unknown mutations in the non-coding regions of the genome. On the basis of our preliminary studies, we believe the integration of these tools with the genetic material and information provided by our participating families provides the best opportunity in decades to identify novel mutations and new mechanisms for inherited breast cancer.

This proposal will identify new mutations from families severely affected with breast cancer, but with no mutations in BRCA1, BRCA2, or other known breast cancer genes. We propose to carry out whole genome sequencing to identify regulatory mutations in the DNA of these families. If successful, our results will allow preventive management strategies to be extended to many families for whom the genes causing breast cancer are currently unknown. This proposal has the potential to improve patient care in the next few years by yielding a more comprehensive genomic profile of breast cancer predisposition. The short-term goals are to better identify women at risk and to allow closer surveillance. The long-term goals are to contribute to the design of new prevention strategies and a better understanding of the biological pathways involved in breast cancer development.