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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Special Emphasis Panel (ZCA1-RPRB-7 (M1))
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Mayo Clinic, Rochester
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Abubakar, Mustapha; Orr, Nick; Daley, Frances et al. (2016) Prognostic value of automated KI67 scoring in breast cancer: a centralised evaluation of 8088 patients from 10 study groups. Breast Cancer Res 18:104
Cichon, Magdalena A; Moruzzi, Megan E; Shqau, Tiziana A et al. (2016) MYC Is a Crucial Mediator of TGFβ-Induced Invasion in Basal Breast Cancer. Cancer Res 76:3520-30
de la Hoya, Miguel; Soukarieh, Omar; López-Perolio, Irene et al. (2016) Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms. Hum Mol Genet 25:2256-2268
Durand, Nisha; Bastea, Ligia I; Long, Jason et al. (2016) Protein Kinase D1 regulates focal adhesion dynamics and cell adhesion through Phosphatidylinositol-4-phosphate 5-kinase type-l γ. Sci Rep 6:35963
Shi, Jiajun; Zhang, Yanfeng; Zheng, Wei et al. (2016) Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer. Int J Cancer 139:1303-17
Lei, Jieping; Rudolph, Anja; Moysich, Kirsten B et al. (2016) Genetic variation in the immunosuppression pathway genes and breast cancer susceptibility: a pooled analysis of 42,510 cases and 40,577 controls from the Breast Cancer Association Consortium. Hum Genet 135:137-54
(2016) Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. Nat Commun 7:12675
Li, Xu; Wang, Wenqi; Xi, Yuanxin et al. (2016) FOXR2 Interacts with MYC to Promote Its Transcriptional Activities and Tumorigenesis. Cell Rep 16:487-97
Schmidt, Marjanka K; Hogervorst, Frans; van Hien, Richard et al. (2016) Age- and Tumor Subtype-Specific Breast Cancer Risk Estimates for CHEK2*1100delC Carriers. J Clin Oncol 34:2750-60
Chiba, Akiko; Hoskin, Tanya L; Hallberg, Emily J et al. (2016) Impact that Timing of Genetic Mutation Diagnosis has on Surgical Decision Making and Outcome for BRCA1/BRCA2 Mutation Carriers with Breast Cancer. Ann Surg Oncol 23:3232-8

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