Nonrandom distribution of oncogene amplifications in bilateral breast carcinomas: Possible role of host factors and survival bias

Abstract

Amplification of HER2, C-MYC and CCND1 oncogenes is a hallmark of breast cancer (BC); however, its involvement in the bilateral form of this disease has not been investigated yet. In this study, 50 bilateral BC (biBC) pairs (100 tumors) and 72 control unilateral BC were examined using real-time PCR analysis of microdissected archival tissues. In biBC, the frequency of >3-fold oncogene amplification was 6/100 (6%) for HER2, 6/100 (6%) for C-MYC and 7/100 (7%) for CCND1. Altogether, 18/100 (18%) biBC tumors had increased gene dosage of at least one oncogene. Tumors forming synchronous biBC pairs had amplification in 11/46 cases (24%). In 3 of 8 patients with amplification-positive carcinomas, the amplification was detected in both neoplasms: 2 biBC had concordant activation of the same oncogene (HER2 and CCND1, respectively), and in the remaining case distinct oncogenes were affected (HER2 and C-MYC). In contrast, amplifications in metachronous biBC were strongly discordant: none of 27 first carcinomas carried this abnormality, while the frequency of amplification in second tumors (7/27; 26%) was similar to the one observed in unilateral BC (20/72; 28%). The trend toward concordance of oncogene amplification status in synchronous but not in metachronous biBC pairs can be explained by the nearly identical natural history of the disease in simultaneously arising tumors. The skewed pattern of amplifications in metachronous biBC might be attributed to their association with adverse BC prognosis; it appears that only patients with amplification-negative first BC have sufficient chances to survive until the development of the contralateral carcinoma. ' 2006 Wiley-Liss, Inc.

High level of miR-21, miR-10b, and miR-31 expression in bilateral vs. unilateral breast carcinomas

“…One of the explanations of phenotypic concordance of the tumors within biBC pairs includes possible metastatic nature of a subset of contralateral BC. However, virtually all available evidence suggest that a misdiagnosis between true double primary and BC metastasis to the opposite breast is exceptionally rare [1,5,9]. Given that synchronous biBC arise in nearly identical circumstances, i.e., age of the patient, hormonal or metabolic milieu, and history of exposure to various hazards, it is logical to expect that these tumor pairs are likely to share central events of tumor pathogenesis, including changes in the microRNA expression levels.…”

“…Perhaps, development of BC in these highly predisposed subjects involves somewhat distinct repertoire of molecular events. Unfortunately, only a few prior investigations reported a direct comparison of somatic events in bilateral vs. unilateral breast carcinomas [9,11,12]. Sequencing of TP53 gene detected similar frequency of mutations in biBC and [48], are designated by asterisks.…”

“…A subset of contralateral neoplasms from metachronous biBC, but not other categories of breast tumors, were shown to have the so-called microsatellite instability phenotype (MSI-H); this observation was linked to the mutagenic effect of the adjuvant therapy applied for the treatment of the first malignancy [11]. Furthermore, first tumors from the metachronous biBC pairs demonstrated lower frequency of oncogene amplifications than second cancers from the same patients, synchronous biBC or unilateral BC; this difference was explained by the adverse prognostic role of oncogene extra copies, i.e., by reduced chances of amplification-positive BC patients to survive until the development of new malignancy [9]. While TP53 mutations, MSI-H status, and gene amplifications showed non-random distribution only within specific categories of biBC tumors, elevated levels of miR-21, miR-10b, and miR-31 (Fig.…”

“…Age interval may contribute to dissimilarity of metachronous biBC, especially if the disease onsets are separated by menopause [5,7,8]. There is also a survival bias, which selects for metachronous contralateral BC only those patients whose first cancer behaved favorably, and thus provided sufficient time interval to develop the second disease [9]. In addition, adjuvant treatment of hormone-sensitive BC by tamoxifen or aromatase inhibitors prevents the progression of the estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive preneoplastic clones in the remaining breast, thus skewing the distribution of subsequent malignancies toward the receptor-negative variants [10].…”

“…biBC molecular characteristics have already been described with respect to genomic abnormalities, p53 mutations, oncogene amplifications, and expression of the subtype-specific markers [5,6,8,9,12]. The last decade brought into attention a novel class of molecules with a broad role in cancer development, i.e., microRNAs (miRs).…”