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Showing content from https://www.ncbi.nlm.nih.gov/pubmed/16551709 below:

Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer

. 2006 Mar 22;295(12):1379-88. doi: 10.1001/jama.295.12.1379. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer Silvia Casadei, Kathryn Hale Coats, Elizabeth Swisher, Sunday M Stray, Jake Higgins, Kevin C Roach, Jessica Mandell, Ming K Lee, Sona Ciernikova, Lenka Foretova, Pavel Soucek, Mary-Claire King

Affiliations

Affiliation

¹ Department of Medicine and Genome Sciences, University of Washington, Seattle, WA 98195-7720, USA.

PMID: 16551709
DOI: 10.1001/jama.295.12.1379

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Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer

Tom Walsh et al. JAMA. 2006.

. 2006 Mar 22;295(12):1379-88. doi: 10.1001/jama.295.12.1379. Authors Tom Walsh¹, Silvia Casadei, Kathryn Hale Coats, Elizabeth Swisher, Sunday M Stray, Jake Higgins, Kevin C Roach, Jessica Mandell, Ming K Lee, Sona Ciernikova, Lenka Foretova, Pavel Soucek, Mary-Claire King Affiliation

¹ Department of Medicine and Genome Sciences, University of Washington, Seattle, WA 98195-7720, USA.

PMID: 16551709
DOI: 10.1001/jama.295.12.1379

Item in Clipboard

Abstract

Context: Genetic testing for inherited mutations in BRCA1 and BRCA2 has become integral to the care of women with a severe family history of breast or ovarian cancer, but an unknown number of patients receive negative (ie, wild-type) results when they actually carry a pathogenic BRCA1 or BRCA2 mutation. Furthermore, other breast cancer genes generally are not evaluated.

Objective: To determine the frequency and types of undetected cancer-predisposing mutations in BRCA1, BRCA2, CHEK2, TP53, and PTEN among patients with breast cancer from high-risk families with negative (wild-type) genetic test results for BRCA1 and BRCA2.

Design, setting, and participants: Between 2002-2005, probands from 300 US families with 4 or more cases of breast or ovarian cancer but with negative (wild-type) commercial genetic test results for BRCA1 and BRCA2 were screened by multiple DNA-based and RNA-based methods to detect genomic rearrangements in BRCA1 and BRCA2 and germline mutations of all classes in CHEK2, TP53, and PTEN.

Main outcome measures: Previously undetected germline mutations in BRCA1, BRCA2, CHEK2, TP53, and PTEN that predispose to breast cancer; frequencies of these mutations among families with negative genetic test results.

Results: Of the 300 probands, 52 (17%) carried previously undetected mutations, including 35 (12%) with genomic rearrangements of BRCA1 or BRCA2, 14 (5%) with CHEK2 mutations, and 3 (1%) with TP53 mutations. At BRCA1 and BRCA2, 22 different genomic rearrangements were found, of sizes less than 1 kb to greater than 170 kb; of these, 14 were not previously described and all were individually rare. At CHEK2, a novel 5.6-kb genomic deletion was discovered in 2 families of Czechoslovakian ancestry. This deletion was found in 8 of 631 (1.3%) patients with breast cancer and in none of 367 healthy controls in the Czech and Slovak Republics. For all rearrangements, exact genomic breakpoints were determined and diagnostic primers validated. The 3 families with TP53 mutations included cases of childhood sarcoma or brain tumors in addition to multiple cases of breast cancer.

Conclusions: The mutational spectra of BRCA1 and BRCA2 include many high-penetrance, individually rare genomic rearrangements. Among patients with breast cancer and severe family histories of cancer who test negative (wild type) for BRCA1 and BRCA2, approximately 12% can be expected to carry a large genomic deletion or duplication in one of these genes, and approximately 5% can be expected to carry a mutation in CHEK2 or TP53. Effective methods for identifying these mutations should be made available to women at high risk.

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