Women who carry inactivating mutations in the BRCAI and BRCA2 genes in their germline are at of significantly elevated risk of breast and ovarian cancer. Many mutation carriers are able to take advantage of surgical prevention options that dramatically reduce the risk of developing these cancers. However, many others are found to carry Variants of Uncertain Significance (VUS), which are predominantly missense mutations. Few of these VUS have been classified as cancer predisposing or neutral variants. Thus, many carriers of these VUS mutations do not know if they are at elevated risk of cancer. As a result many women carrying VUS that may be neutral unnecessarily undergo prophylactic surgery that is associated with significant long term side effects. Here we propose to determine the cancer relevance of VUS found throughout the BRCAI and BRCA2 genes by establishing genetic and laboratory assay based methods of VUS analysis. Specifically, in Aim 1 we will classify VUS using a series of studies focusing on family history of cancer of individuals with VUS and on breast tumor pathology of individuals with VUS. To facilitate this approach we have recently established the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA), a consortium aimed at classifying additional VUS through pooling of available family information from many research centers. Only through the data sharing proposed in ENIGMA will it be possible to classify a substantial number of additional mutations using genetic approaches.
In Aim 2 we will focus on establishing the sensitivity and specificity of BRCA2 functional assays for classification of BRCA2 VUS. We will not study BRCAI because many of the variants in that gene have already been characterized by functional studies. By establishing the sensitivity and specificity of the assays relative to the genetic data from Aim 1 it may be possible to classify many additional VUS with insufficient family data for direct classification by genetic methods.
In Aim 3, we will focus on developing methods for providing these results to providers and patients. This will involve evaluation of the current utilization of reclassification results, provision of results of reclassification efforts, provision of educational materials to improve this process, and evaluation of improvements in utilization of results.

Public Health Relevance

These efforts will result in determination of which carriers of VUS in BRCA1 and BRCA2 are at either high, low or even moderate risk of breast cancer. Because the study results will be provided to clinical care providers and education regrading the use of these data will be provided, the study is inherently translational. Overall, the study will ensure improved selection of VUS carriers who can benefit from various forms of intervention to prevent and/or treat breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA116201-09
Application #
8757101
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
9
Fiscal Year
2014
Total Cost
$397,132
Indirect Cost
$99,416
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
(2015) Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk. Hum Mol Genet 24:285-98
Yee, Douglas (2015) A tale of two receptors: insulin and insulin-like growth factor signaling in cancer. Clin Cancer Res 21:667-9
Ingle, James N; Kalari, Krishna R; Buzdar, Aman U et al. (2015) Estrogens and their precursors in postmenopausal women with early breast cancer receiving anastrozole. Steroids 99:32-8
Kiiski, Johanna I; Pelttari, Liisa M; Khan, Sofia et al. (2014) Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer. Proc Natl Acad Sci U S A 111:15172-7
Whiley, Phillip J; Parsons, Michael T; Leary, Jennifer et al. (2014) Multifactorial likelihood assessment of BRCA1 and BRCA2 missense variants confirms that BRCA1:c.122A>G(p.His41Arg) is a pathogenic mutation. PLoS One 9:e86836
Osorio, Ana; Milne, Roger L; Kuchenbaecker, Karoline et al. (2014) DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers. PLoS Genet 10:e1004256
D'Assoro, A B; Liu, T; Quatraro, C et al. (2014) The mitotic kinase Aurora--a promotes distant metastases by inducing epithelial-to-mesenchymal transition in ER*(+) breast cancer cells. Oncogene 33:599-610
Agarwal, D; Pineda, S; Michailidou, K et al. (2014) FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium. Br J Cancer 110:1088-100
Abdel-Aal, Abu-Baker M; Lakshminarayanan, Vani; Thompson, Pamela et al. (2014) Immune and anticancer responses elicited by fully synthetic aberrantly glycosylated MUC1 tripartite vaccines modified by a TLR2 or TLR9 agonist. Chembiochem 15:1508-13
Joshi, Poorval M; Sutor, Shari L; Huntoon, Catherine J et al. (2014) Ovarian cancer-associated mutations disable catalytic activity of CDK12, a kinase that promotes homologous recombination repair and resistance to cisplatin and poly(ADP-ribose) polymerase inhibitors. J Biol Chem 289:9247-53

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