AS538 - Genomic Analysis of Breast Cancer Genes in the WHI: Creation of a Public Genomics Resource

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Investigator Names and Contact Information

Mary-Claire King [mcking@u.washington.edu]

Introduction/Intent

Each year, 230,000 US women are diagnosed and 40,000 women die of breast cancer.  Family history is one of the most significant risk factors for breast cancer, yet most of that risk remains unexplained and even less is presently addressed in clinical practice.  Given the public health importance of breast cancer, it is not surprising that it was one of the first complex diseases to be evaluated by genomics approaches.

A major challenge for the translation of genomics to patient care is characterization of relevant variants of causal genes. This challenge is timely now for inherited predisposition to breast cancer, because multiple causal genes are known, specialized breast screening modalities are available, risk-reducing surgery is effective, and treatment of breast cancer can be tailored to the patient's genotype. Inherited predisposition to breast cancer has become a model for the translation of genomics to patient care.  ​

The single largest remaining gap in this translation is knowledge of the profiles of rare variants in breast cancer genes among cancer-free older women. Only by knowing variant profiles in women who have not developed breast cancer can the risk associated with any variant in any breast cancer gene in a young still-unaffected woman be properly understood.

The goal of this project is to create a database of allele frequencies of all variants in breast cancer genes among cancer-free older women. We will carry out targeted genomic sequencing of DNA from cancer-free participants in the WHI and create a public genomics database for the use of all investigators in the evaluation of inherited predisposition to breast cancer. 

Specifically, we propose to characterize the complete variant spectra of 24 genes known or suspected to be associated with inherited breast cancer, only two of which (BRCA1 and BRCA2) are presently included in standard clinical care. For all characterizations, we will use "BROCA," our recently developed approach for simultaneous capture and multiplexed sequencing of exons, introns, regulatory, and flanking intergenic regions of all known breast cancer genes. 

We propose to identify all genetic variants of all classes in these 24 genes in approximately 30,000 WHI participants who remained in follow-up and free of cancer until at least age 65. The WHI is ideally suited for this task because women's cancers were carefully documented and participants who remain unaffected have passed through the most high-risk years for carriers of actionable mutations in high-penetrance breast and ovarian cancer genes.

Materials/Methods

A major challenge for the translation of genomics to patient care is characterization of relevant variants of causal genes. This challenge is timely now for inherited predisposition to breast cancer, because multiple causal genes are known, specialized breast screening modalities are available, risk-reducing surgery is effective, and treatment of breast cancer is influenced by the patient's genotype. The goal of this project is to use inherited predisposition to breast cancer as a model for the translation of genomics to patient care. 

Specifically, we propose to characterize the complete variant spectra of 18 genes known to be associated with inherited breast cancer, only two of which (BRCA1 and BRCA2) are presently included in standard clinical care.  In parallel, we will evaluate in the same way 6 candidate genes that have emerged from our ongoing family studies. For all characterizations, we will use "BROCA," our recently developed approach for simultaneous capture and multiplexed sequencing of exons, introns, regulatory, and flanking intergenic regions of all known breast cancer genes. 

We propose to identify all genetic variants of all classes in these 24 genes in approximately 30,000 women from the WHI who remained in follow-up and free of cancer until at least age 65. Frequencies of all variants identified in these unaffected women will be provided on a publicly accessible database. We intend that this database be used by investigators nationwide and by individual providers and consumers, with the purpose of understanding the meaning of variants encountered in women at risk. The WHI is ideally suited for this task because women's cancers were carefully and completely documented and participants who remain unaffected are now at least 65 years old, so have passed through many of the most high risk years for carriers of actionable mutations in high-penetrance breast and ovarian cancer genes.

Aim 1: Determine the complete variant profiles of breast cancer genes in a cohort of 30,000 cancer-free WHI participants, age 65 or older, using BROCA, our custom targeted DNA capture and massively parallel sequencing approach. We will sequence 24 genes, including 18 documented breast cancer genes and for 6 candidate genes.

Aim 2. Develop and operationalize a publicly accessible database that includes allele frequencies for each variant in each class in each BROCA gene.