CORRESPONDENCE

High Frequency of Allelic Loss of BRCA2 Gene in Pregnancy-Associated Breast Carcinoma

Ting Shen, Alexander Oliver Vortmeyer, Zhengping Zhuang, Fattaneh A. Tavassoli

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)Go. 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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Table 1. Frequency of loss of heterozygosity (LOH) with four microsatellite markers at the BRCA2 locus in pregnancy-associated breast carcinoma*

 
LOH was also observed in lactational hyperplasia in four of nine informative cases (patients 1, 2, 7, and 8). All of the four patients showed LOH with BRCA2 markers. The pattern of the allelic loss associated with lactational change was the same pattern identified in tumor cells within the same specimen. Although the cells of lactational change show vacuolated cytoplasm and activated nuclei with small round nucleoli, significant atypia is not evident. In previous studies, LOH was detected in ordinary intraductal hyperplasia (6) and even in morphologically normal breast ducts adjacent to the carcinoma (7). Our results suggest that, although lactational change is a physiologic phenomenon in general, it may bear the genetic alterations long before frank carcinoma develops in some of those PABCs. LOH associated with lactational change in all four cases was observed at the BRCA2 locus. This result further supports that BRCA2 deletion is an early genetic event in the development of PABC.

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.

REFERENCES

1 Petrek JA. Breast cancer during pregnancy. Cancer 1994;74(1 Suppl):518-27.[Medline]

2 Guinee VF, Olsson H, Moller T, Hess KR, Taylor SH, Fahey T, et al. Effect of pregnancy on prognosis for young women with breast cancer. Lancet1994 ;343:1587-9.[Medline]

3 Lo YL, Yu JC, Huang CS, Tseng SL, Chang TM, Chang KJ, et al. Alleic loss of the BRCA1 and BRCA2 genes and other regions on 17q and 13q in breast cancer among women from Taiwan (area of low incidence but early onset). Int J Cancer 1998;79:580-7.[Medline]

4 Cleton-Jansen AM, Collins N, Lakhani SR, Weissenbach J, Devilee P, Cornelisse CJ, et al. Loss of heterozygosity in sporadic breast tumours at the BRCA2 locus on chromosome 13q12-q13. Br J Cancer 1995;72:1241-4.[Medline]

5 Beckmann MW, Picard F, An HX, van Roeyen CR, Dominik SI, Mosny DS, et al. Clinical impact of detection of loss of heterozygosity of BRCA1 and BRCA2 markers in sporadic breast cancer. Br J Cancer 1996;73:1220-6.[Medline]

6 O'Connell P, Pekkel V, Fuqua SA, Osborne CK, Clark GM, Allred DC. Analysis of loss of heterozygosity in 399 premalignant breast lesions at 15 genetic loci. J Natl Cancer Inst 1998;90:697-703.[Abstract/Free Full Text]

7 Deng G, Lu Y, Zlotnikov G, Thor AD, Smith HS. Loss of heterozygosity in normal tissue adjacent to breast carcinomas. Science 1996;274:2057-9.[Abstract/Free Full Text]


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