Evidence for microsatellite instability in bilateral breast carcinomas

Abstract

The molecular pathogenesis of various categories of breast cancer (BC) has been well described, but surprisingly few reports have appeared on analysis of somatic mutations in bilateral BC. We have performed a polymerase chain reaction (PCR)-driven investigation of chromosomal regions showing common loss of heterozygosity (LOH) in 23 cases (46 tumors) from patients diagnosed with bilateral BC. LOH was observed in 15/46 (33%) informative tumors for chromosome 1p, 5/32 (16%) for 5q, 12/44 (27%) for 11q, 15/40 (38%) for 13q and 4/24 (17%) for 17p. These values are within the range of interlaboratory variations reported for unilateral BC. There was no strong evidence for concordance of LOH within the same patient for any of the chromosomal loci tested. Atypical for breast carcinomas, 7/46 (15%) tumors accumulated a high frequency (ranging from 11 to 29%) of shortened dinucleotide CA repeats, implying microsatellite instability (MI). Further analysis with the highly informative BAT-26 marker allowed for the classification of two of these tumors as having a replication error positive (RER⁺/MSI-H) phenotype, whereas the remaining five carcinomas harbored so-called borderline MI. Thus an involvement of both RER⁺ and borderline MI appears to be a distinct feature of bilateral breast carcinomas compared to unilateral lesions.

Introduction

Breast cancer (BC) is a common disease affecting approximately one of ten women during their lifetime. The probability of BC development is likely to be influenced by a combination of various risk factors. Although many of these factors have been already identified, the frequency of their direct involvement and the mechanisms of their participation in BC pathogenesis remain largely uncertain [1]. It is generally believed that bilateral BC patients represent a special group of BC, since the extent of contribution of exogenous and/or endogenous triggers is significantly higher in this cohort compared with unilateral cases. This interpretation is based on the fact that actual occurrence of bilateral BC considerably prevails over that expected from random co-incidence [2], [3], [4]. Bilateral BC is usually recognized either as a synchronous (time interval <0.5–1 year) or metachronous lesion. Synchronous bilateral BC accumulate at 0.5–1% of the total breast cancer incidence, whereas metachronous neoplasms occur 5–10 times more often [2], [4]. Diagnosis of bilateral BC is complicated by the requirement to discriminate between independent primary tumors and metastasis to the other breast. Although there are well established morphological and clinical criteria developed for such discrimination, occasional misinterpretation remains possible [3]. Extensive clinical studies have focused on the search for specific bilateral BC features. Nonetheless, comparison of bilateral and unilateral BC failed to reveal essential differences concerning pre-disease records, tumor morphology, or prognosis. Although some investigators reported slight predominance of positive family history and/or lobular carcinomas in the bilateral BC group, these tendencies were not sufficient to explain the specificity of this BC category [4], [5], [6], [7], [8], [9]. Certain bilateral BC appear to be attributed to germ-line mutations in familial cancer predisposition genes (BRCA1, BRCA2 etc.) [10], but the critical event for the vast majority of bilateral cases remains unknown.

Over the last decade impressive progress has been achieved in unraveling the molecular pathogenesis of BC. Many somatic mutations such as ERBB2 oncogene amplification, TP53 suppressor gene inactivation, and deletion of genetic material on chromosomes 1p, 1q, 3p, 5q, 6q, 11p, 11q, 13q, 16q, 17p, 18q, 22q etc. have been repeatedly shown to be typical for breast carcinomas. It is noteworthy that a very high degree of population heterogeneity exists for the pattern of somatic mutations in BC [11]. It is not known yet, whether this heterogeneity is due to diversity of triggering events or reflects the promiscuity of the mechanisms of BC development. While a multitude of reports have been devoted to studies of mammary tumors, in general, very little has been accomplished in this respect for bilateral BC. The most intriguing question is whether concordance or discordance of somatic changes in bilateral breast tumors exists within the same patient. In other words, does the nature of an exogenous or endogenous trigger factor strictly determine the subsequent chain of genetic alterations, or does a high breast cancer risk manifest itself through random gain of various somatic mutations?