Originally published as JCO Early Release 10.1200/JCO.2008.17.8228 on September 29 2008

This Article Full Text Full Text (PDF) Erratum (v27,p2415) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Spearman, A. D. Articles by Toland, A. E. Search for Related Content PubMed PubMed Citation Articles by Spearman, A. D. Articles by Toland, A. E. Social Bookmarking                            What's this?

Clinically Applicable Models to Characterize BRCA1 and BRCA2 Variants of Uncertain Significance

Andrew D. Spearman, Kevin Sweet, Xiao-Ping Zhou, Jane McLennan, Fergus J. Couch, Amanda Ewart Toland

From the Departments of Biology and Pathology; Clinical Cancer Genetics Program, Comprehensive Cancer Center; Division of Human Genetics, Department of Internal Medicine; and Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH; University of California, San Francisco Cancer Risk Program, San Francisco, CA; and the Departments of Oncology and Laboratory Medicine and Pathology, Mayo Clinic School of Medicine, Rochester, MN

Corresponding author: Amanda Ewart Toland, PhD, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Division of Human Cancer Genetics, 998 Biomedical Research Tower, 460 W 12th Ave, Columbus, OH 43210; e-mail: Amanda.toland{at}osumc.edu

Purpose Twenty percent of individuals with a strong family and/or personal history of breast and ovarian cancer carry a deleterious mutation in BRCA1 or BRCA2. Identification of mutations in these genes is extremely beneficial for patients pursuing risk reduction strategies. Approximately 7% of individuals who have genetic testing of BRCA1 and BRCA2 carry a variant of uncertain significance (VUS), making clinical management less certain. The majority of identified VUS occur only in one to two individuals; these variants are not able to be classified using current classification models with segregation analysis components.

Methods To develop a clinically applicable method that can predict the pathogenicity of VUS that does not require familial information or segregation analysis, we identified characteristics of breast or ovarian tumors that distinguished sporadic tumors from tumors with BRCA1 or BRCA2 mutations. Study participants included individuals with known deleterious mutations in BRCA1 or BRCA2 and individuals with classified or unclassified BRCA variants.

Results We applied the models to 57 tumors with 43 different deleterious BRCA mutations and 57 tumors with 54 unique classified and unclassified BRCA variants. Of the 33 previously unclassified VUS studied, we found evidence of neutrality for 21.

Conclusion Our models showed 98% sensitivity and 76% specificity for predicting classified DNA changes. We classified 64% of unknown variants as neutral. Classification of VUS as neutral will have immediate benefit for those individuals and their family members. These models are adaptable for the clinic and will be useful for individuals with limited available family history.

published online ahead of print at www.jco.org on September 29, 2008

Supported by the National Institutes of Health, National Cancer Institute, Bay Area Breast Spore Career Development Award No. P50 CA582017 [GenBank] (A.E.T.), Mayers Summer fellowships (A.D.S.), and internal funds from the Ohio State University Comprehensive Cancer Center (A.E.T.).

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?