Affiliations of authors: T. Shen, F. A. Tavassoli, Department of Gynecologic and Breast Pathology, Armed Forces Institute of Pathology, Washington, DC; A. O. Vortmeyer, Z. Zhuang, Laboratory of Pathology, National Cancer Institute, Bethesda, MD.
Correspondence to: Ting Shen, M.D., Ph.D., Department of Gynecologic and Breast Pathology, Armed Forces Institute of Pathology, 14th St. & Alaska Ave., N.W., Washington, DC 20306-6000.
Pregnancy-associated breast carcinoma (PABC) accounts for 0.2%-3.8% of all breast cancers (1). Compared with sporadic breast carcinoma, PABC occurs in younger women, tends to be diagnosed at a more advanced stage, and has a worse overall survival rate at least in some studies (2). Morphologically, PABC occurs in the setting of physiologic proliferation and functional activation of acini and ductules in response to hormonal alterations of pregnancy. What triggers this abnormal, irreversible, cancerous proliferation in the setting of a reversible physiologic proliferation is unknown.
To better understand carcinomas developing in the unusual setting of pregnancy, we analyzed a series of 12 archival samples from PABC patients for loss of heterozygosity (LOH) at multiple chromosomal loci, including several frequently affected loci in sporadic breast cancer (INT2, TP53, ANK1, and D16S413), and two hereditary breast cancer gene loci, BRCA1 (D17S250, D17S776, D17S855, and D17S1322) and BRCA2 (D13S290, D13S283, D13S263, and D13S267). There was no history of familial breast cancers for the 12 cases. For comparison, samples from 15 women with sporadic cases of breast ductal carcinomas were also tested for BRCA2 markers.
Our study demonstrates LOH in 11%-22% of nine informative samples
evaluated at four gene loci (TP53, INT2, ANK1, and D16S413) frequently altered in sporadic
breast cancer and in 55% at the BRCA1 locus. Remarkably, eight (88%) of nine
informative samples in our PABC series showed allelic deletion at the BRCA2 locus (Table 1). In contrast, only three (20%) of 15 sporadic breast carcinomas
showed LOH at the BRCA2 locus. The rate of BRCA2 deletion has been reported in
30%40% of sporadic breast carcinomas (3,4). The high
frequency of LOH at the BRCA2 gene locus in PABC is a novel finding that suggests a role for
the inherited breast cancer susceptibility gene BRCA2, located at chromosome 13q12-13, in the
development and progression of PABC. The rate of LOH at the BRCA2 locus in sporadic breast
cancer does not correlate with a particular age group (3,4). Therefore, the
high frequency of LOH at the BRCA2 gene locus in PABC does not appear to be related to the
relatively young age of PABC patients. A study by Beckmann et al. (5)
has suggested that deletion of the BRCA2 locus correlates with higher grade tumors. In our
series, two of two well-differentiated and three of three poorly differentiated tumors had LOH at
BRCA2. In the moderately differentiated category, three of four cases showed LOH at BRCA2.
The single case with retained heterozygosity at BRCA2 was moderately differentiated.
Furthermore, we detected BRCA2 deletion in the ductal carcinoma in situ (DCIS)
component in three of four cases that contained both DCIS and invasive tumors. This result
suggests that BRCA2 loss may represent a relatively early genetic event in PABC development.
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NOTES
The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as representing the views of the Department of the Army or the Department of Defense.
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