Characterization of a new cytogenetic subtype of ductal breast carcinomas.

About 50% of ductal breast carcinomas do not yield analysable karyotypes after short-term culturing. Comparison of the cytogenetic subset to the whole data set of tumors revealed that slightly hyperdiploid tumors, that is, with DNA index between 1.05 and 1.3, were under-represented in tumors for which cytogenetic analysis was successful. The purpose of this study was to determine whether the pattern of chromosome imbalances in this subset differs from that generally reported. Comparative genomic hybridization (CGH) was used on 43 primary ductal breast carcinomas selected for slight hyperdiploidy. Microsatellite instability (MSI), TP53 mutation and expression were also investigated. All tumors were MSI negative. In all, 18 tumors (42%) presented mostly unbalanced chromosome rearrangements and DNA amplifications, with only few or no whole chromosome gains (WCG). This pattern of chromosome imbalances corresponds to that described in most breast tumors by previous cytogenetic and CGH analyses. It was associated with TP53 mutation in 17% of tumors. Another subset of 17 tumors (39%) displayed different and new features, characterized by recurrent gains of whole chromosomes 5, 7 and 8 with few chromosome rearrangements, rare DNA amplifications and no TP53 mutation. Eight tumors with as many rearrangements as WCG were left unclassified. We propose that, beside a major pathway characterized by multiple chromosome rearrangements, there is a minor pathway mainly characterized by WCG.

Ductal breast carcinomas with whole chromosome gains as a particular subset of near-diploid tumors with different metastasis free survival.

We recently proposed the existence of a subtype of slightly hyperdiploid ductal breast cancers with cytogenetic alterations differing from those usually observed in the majority of these tumors. We aimed to establish whether these tumors, which represent about 50% of those with a DNA index (DI) comprised between 1.1 and 1.3, correspond to a particular clinicopathological entity. A retrospective study of 1771 patients operated for ductal carcinomas was performed. Three classes of tumors constituted according to DI were compared for the usual clinicopathological factors and clinical outcome. About 690 tumors (39%) were diploid/hypodiploid (DI < 1.1), 134 (7.6%) were hyperdiploid (1.1 < or = DI < 1.3) and 947 (53.4%) were polyploid (DI > or = 1.3). Median follow-up time was 106 months (range 1-177). Polyploid tumors were significantly associated with large tumor size, advanced clinical stage, high histological grade and S-phase fraction (SPF), positive lymph nodes and loss of steroid receptors. Hyperdiploid and diploid/hypodiploid tumors were similar for all the variables except SPF which was significantly higher in hyperdiploid tumors (p < 0.001). Overall survival was similar in hyperdiploid and diploid/hypodiploid tumors in univariate and multivariate analysis, while hyperdiploid tumors were significantly related to a poorer metastasis free survival, both in univariate (p = 0.023) and multivariate analysis (p = 0.031). Despite very close initial clinicopathological and biological characteristics, hyperdiploid tumors differed from diploid/hypodiploid tumors by a higher risk of metastasis, possibly related to their increased SPF.

Ductal breast carcinoma develops through different patterns of chromosomal evolution.

In a previous study that used comparative genomic hybridization (CGH) to analyze 43 ductal breast carcinomas selected for hyperdiploidy, we proposed the existence of two distinct pathways of chromosomal evolution. In the present study, in which we reassessed our cytogenetic findings on 158 ductal breast carcinomas selected for having a modal number of chromosomes of fewer than 60, we confirmed the existence of two subtypes of tumors. Along with the great majority of tumors (142 of 158) that evolved through structural rearrangements with no or very few whole-chromosome gains, we found that a minor subset (16 of 158) evolved through progressive gains of whole chromosomes with no or only a few associated rearrangements. In this article, we describe the karyotypes of these 16 tumors together with data from CGH, which was performed for 10 of them. Chromosomes 5, 7, 8, and 20 were the most frequently gained. Our findings support the evidence of a new pathway of chromosomal evolution in a small subset of ductal breast carcinomas characterized by numerical chromosome aberrations.

Potential rapid assessment of breast cancer prognosis using induced chromosome condensation performed on cytological specimens.

We have previously shown that assessment of chromosome alteration rate by cytogenetics is well correlated with breast cancer prognosis factors. As karyotypes are usually difficult to obtain from solid tumors using conventional methods, a new approach is proposed. Metaphase-like chromosomes were directly obtained following chromosome condensation using calyculin A (okadaic acid) from cytologic specimens of breast cancers sampled by fine needle. Chromosome counts and rearrangement rates were established in a series of 45 tumors, as early as 24-48 h after sampling. A high rate of rearranged chromosomes was found to correlate with high histological grade, TNM stage and S-phase fraction, loss of estrogen receptor expression and DNA aneuploidy. The indication of genome alteration provided by this method constitutes a simple, potent and early potential prognostic factor in breast cancer directly applied on cytological specimens.