Ductal invasive G2 and G3 carcinomas of the breast are the end stages of at least two different lines of genetic evolution

Abstract

Ductal invasive grade (G) 2 and G3 carcinomas represent the majority of invasive breast cancers. Previous morphological and cytogenetic studies have provided evidence that ductal invasive G2 carcinoma may originate from at least two different genetic pathways. The aim of this study was to evaluate further the heterogeneity of G2 breast cancer in comparison with G3 cancers by cytogenetic and quantitative analysis. To this end, 35 cases of ductal invasive G2 and 42 cases of ductal invasive G3 carcinomas were investigated by means of comparative genomic hybridization (CGH) and these findings were correlated with DNA ploidy status, mitotic activity index (MAI), mean nuclear area (MNA), volume per lumen (VPL), and clinico-pathological parameters. The findings of this study demonstrate that ductal invasive G2 carcinomas, in contrast to ductal invasive G3 carcinomas, have to be interpreted as the morphological end stage resulting from two different cytogenetic and morphological pathways; the loss of 16q material is the cytogenetic key event in the evolution of a subgroup of this entity. By correlating genetic alterations with DNA ploidy status, an extended morphology-based cytogenetic progression model is presented, with early and late genetic alterations in the pathogenesis of breast cancer. The correlation with MAI gives rise to the hypothesis that these different genetic pathways significantly differ in their proliferation rate. Further studies will be required to elucidate which genes contribute to an altered proliferation rate in these subgroups and to the associated prognosis.

8p deletion is strongly linked to poor prognosis in breast cancer

“…58 In an analysis of all cancers as well as in the largest subgroup of carcinomas with NST, 8p deletions were strongly linked to features of unfavorable tumor phenotype, such as advanced tumor stage, high tumor grade, rapid high tumor cell proliferation rate and poor survival. These findings are in line with previous studies reporting associations between 8p loss/LOH with adverse tumor phenotype [25][26][27][28][29] and poor clinical outcome. 25,27,29,31 Studies that could find associations of 8p deletions with tumor progression had involved remarkably small cohorts of 40, 35 44, 36 46, 33 52,38 55, 39 60, 14 61, 32 76 34 and 105 37 patients.…”

“…8p deletion typically involves extended areas or even the entire 8p arm, with several putative tumor suppressor genes which are located in this region. [17][18][19][20][21][22][23][24] Some breast cancer studies found associations between 8p deletions and advanced tumor stage, [25][26][27] highgrade, 28 metastatic growth, 25,27,29 familial breast cancer risk, 30 and poor prognosis, 25,27,29,31 but these associations could not be confirmed by others. 14,[32][33][34][35][36][37][38][39] To better understand the clinical relevance of 8p deletions in breast cancer, including association to tumor grade, pathological tumor stage, patient survival, hormone receptor status, and amplifications of HER2, MYC and CCND1, we analyzed more than 2,100 breast cancers with clinical follow-up data.…”

Comparative genomic hybridization analysis on male breast cancer

“…However, 216q also correlated with lower grades of malignancy and lower proliferation rates. Similar observations were made by Buerger et al 26 who found 216q and a lower mitotic activity index to be more frequent in grade II than in grade III female breast cancers. These authors proposed a cytogenetic progression model in which tumors with 216q might define a cytogenetic pathway separating grade II from grade III tumors.…”

Simultaneous chromosome 1q gain and 16q loss is associated with steroid receptor presence and low proliferation in breast carcinoma

“…21 Altogether, these data supported the hypothesis that low/intermediate-and high-grade breast carcinoma develop according to distinct pathways: chromosome 16q loss was proposed as a marker of a distinct genetic pathway in breast carcinoma development. 3,7 In the present study, all but one samples were classified as G2 or G3 and only three samples were invasive lobular carcinoma. The percentage of samples showing chromosome 1q gain/16q loss was lower in G3 with respect to G2 samples.…”

“…2,5 Chromosome 1q gains and 16q losses are considered as early changes since they have been detected as the sole chromosome abnormalities in near-diploid breast carcinoma 1,6 and in well-differentiated samples with a few alterations. 3,7 These genetic changes and the resulting chromosome imbalances have been thought to play a pathogenic role in breast carcinoma development. As simultaneous chromosome 1q gains and 16q losses have often been detected, we hypothesized that they might be related with particular biopathologic characteristics.…”