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Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 9/2007

01-09-2007 | Laboratory Research

Heterogenic Loss of the Wild-Type BRCA Allele in Human Breast Tumorigenesis

Authors: Tari A. King, MD, Weiwei Li, MD, PhD, Edi Brogi, MD, Cindy J. Yee, PhD, Mary L. Gemignani, MD, Narciso Olvera, MS, Douglas A. Levine, MD, Larry Norton, MD, Mark E. Robson, MD, Kenneth Offit, MD, Patrick I. Borgen, MD, Jeff Boyd, PhD

Published in: Annals of Surgical Oncology | Issue 9/2007

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Abstract

Background

For individuals genetically predisposed to breast and ovarian cancer through inheritance of a mutant BRCA allele, somatic loss of heterozygosity affecting the wild-type allele is considered obligatory for cancer initiation and/or progression. However, several lines of evidence suggest that phenotypic effects may result from BRCA haploinsufficiency.

Methods

Archival fixed and embedded tissue specimens from women with germ line deleterious mutations in BRCA1 or BRCA2 were identified. After pathologic review, focal areas of normal breast epithelium, atypical ductal hyperplasia, ductal carcinoma-in-situ, and invasive ductal carcinoma were identified from 14 BRCA1-linked and 9 BRCA2-linked breast cancers. Ten BRCA-linked prophylactic mastectomy specimens and 12 BRCA-linked invasive ovarian carcinomas were also studied. Laser catapult microdissection was used to isolate cells from the various pathologic lesions and corresponding normal tissues. After DNA isolation, real-time polymerase chain reaction assays were used to quantitate the proportion of wild-type to mutant BRCA alleles in each tissue sample.

Results

Quantitative allelotyping of microdissected cells revealed a high level of heterogeneity in loss of heterozygosity within and between preinvasive lesions and invasive cancers from BRCA1 and BRCA2 heterozygotes with breast cancer. In contrast, all BRCA-associated ovarian cancers displayed complete loss of the wild-type BRCA allele.

Conclusions

These data suggest that loss of the wild-type BRCA allele is not required for BRCA-linked breast tumorigenesis, which would have important implications for the genetic mechanism of BRCA tumor suppression and for the clinical management of this patient population.
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Metadata
Title
Heterogenic Loss of the Wild-Type BRCA Allele in Human Breast Tumorigenesis
Authors
Tari A. King, MD
Weiwei Li, MD, PhD
Edi Brogi, MD
Cindy J. Yee, PhD
Mary L. Gemignani, MD
Narciso Olvera, MS
Douglas A. Levine, MD
Larry Norton, MD
Mark E. Robson, MD
Kenneth Offit, MD
Patrick I. Borgen, MD
Jeff Boyd, PhD
Publication date
01-09-2007
Publisher
Springer-Verlag
Published in
Annals of Surgical Oncology / Issue 9/2007
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-007-9372-1

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