With recent advances in DNA sequencing technology, profiling one's own genetic information is becoming a reality for many patients and their families. In fact, assaying for mutated genes known to increase the risk of breast cancer has become commonplace for individuals at high risk. Hereditary forms of breast cancer comprise approximately 20,000 cases annually in the United States. It is believed that the breast and ovarian cancer susceptibility genes, BRCA1 and BRCA2, account for the majority of germ-line mutations in families with a genetic predisposition for developing breast and/or ovarian cancers. Since their discovery in the mid 1990's, over a thousand different alleles have been associated with each gene and these DNA germline mutations have been catalogued in the Breast Cancer Database. Unfortunately, a large number of germline changes reported for either BRCA1 or BRCA2 are not definitively linked to disease. These genomic alterations have been termed variants of uncertain significance (VUS) and their role in breast carcinogenesis remains unclear. In addition, penetrance of known deleterious mutations varies widely among carriers and it is hypothesized this is due to both genetic and environmental modifiers. This variability creates important clinical challenges in assessing carrier risk, since many individuals elect for prophylactic procedures or chemopreventive measures that are expensive and associated with significant side effects. Using modern somatic cell gene targeting techniques, we are developing a novel model to assess relative risk for deleterious BRCA alleles. In addition, we will use this model to further categorize VUS as either benign or deleterious. By thoroughly characterizing BRCA alleles, we hope to provide additional knowledge for further risk stratification that could be incorporated with many current models. This will aid clinicians and families that harbor these mutations/VUS in making decisions when considering the risks and benefits of prophylactic surgeries and other primary prevention strategies.

Public Health Relevance

The goal of the proposed project is to assess relative risk of BRCA alleles for predisposing individuals to breast cancer. Ultimately, the thorough characterization BRCA alleles will afford carriers with the knowledge necessary to make appropriate decisions and arrange prophylactic actions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA168180-02
Application #
8548094
Study Section
Special Emphasis Panel (ZRG1-F09-D (08))
Program Officer
Bini, Alessandra M
Project Start
2012-08-30
Project End
2015-08-29
Budget Start
2013-08-30
Budget End
2014-08-29
Support Year
2
Fiscal Year
2013
Total Cost
$42,232
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Cidado, Justin; Wong, Hong Yuen; Rosen, D Marc et al. (2016) Ki-67 is required for maintenance of cancer stem cells but not cell proliferation. Oncotarget 7:6281-93
Chu, David; Paoletti, Costanza; Gersch, Christina et al. (2016) ESR1 Mutations in Circulating Plasma Tumor DNA from Metastatic Breast Cancer Patients. Clin Cancer Res 22:993-9
Forde, Patrick M; Cochran, Rory L; Boikos, Sosipatros A et al. (2016) Familial GI Stromal Tumor With Loss of Heterozygosity and Amplification of Mutant KIT. J Clin Oncol 34:e13-6
Blair, Brian G; Wu, Xinyan; Zahari, Muhammad Saddiq et al. (2015) A phosphoproteomic screen demonstrates differential dependence on HER3 for MAP kinase pathway activation by distinct PIK3CA mutations. Proteomics 15:318-26
Toro, Patricia Valda; Erlanger, Bracha; Beaver, Julia A et al. (2015) Comparison of cell stabilizing blood collection tubes for circulating plasma tumor DNA. Clin Biochem 48:993-8
Zabransky, Daniel J; Yankaskas, Christopher L; Cochran, Rory L et al. (2015) HER2 missense mutations have distinct effects on oncogenic signaling and migration. Proc Natl Acad Sci U S A 112:E6205-14
Croessmann, Sarah; Wong, Hong Yuen; Zabransky, Daniel J et al. (2015) NDRG1 links p53 with proliferation-mediated centrosome homeostasis and genome stability. Proc Natl Acad Sci U S A 112:11583-8
Wong, Hong Yuen; Wang, Grace M; Croessmann, Sarah et al. (2015) TMSB4Y is a candidate tumor suppressor on the Y chromosome and is deleted in male breast cancer. Oncotarget 6:44927-40
Cochran, Rory L; Cidado, Justin; Kim, Minsoo et al. (2015) Functional isogenic modeling of BRCA1 alleles reveals distinct carrier phenotypes. Oncotarget 6:25240-51
Cochran, Rory L; Cravero, Karen; Chu, David et al. (2014) Analysis of BRCA2 loss of heterozygosity in tumor tissue using droplet digital polymerase chain reaction. Hum Pathol 45:1546-50

Showing the most recent 10 out of 14 publications