The molecular genetics of breast cancer: The contribution of comparative genomic hybridization

Comparative genomic hybridization (CGH) has been the technique of choice over the last 10 years for mapping DNA copy number changes in human tumors. Here we review the literature to demonstrate how CGH has contributed to the comprehension of molecular aspects of breast tumorigenesis. At least two distinct molecular pathways of breast cancer have been characterized that show a strong correlation with histological grade. It seems that grade I invasive ductal carcinomas (IDCs) arise from well-differentiated ductal carcinoma in situ (DCIS), whereas grade III IDCs come from poorly differentiated DCIS. In addition, dedifferentiation from a low- to a high-grade breast cancer has proven an unlikely phenomenon. CGH has been instrumental in dissecting distinct molecular pathways toward breast malignancy and in establishing a direct relationship between genotype and clinical pathological features. (C) 2005 Elsevier GrnbH. All rights reserved.

Molecular genetics of sudden cardiac death in small animals - A review

Sudden cardiac death in small animals is uncommon but often occurs due to cardiac conduction defects or myocardial diseases. Primary cardiac conduction defects are mainly caused by mutations in genes involved in impulse conduction processes (e.g., gapjunction genes and transcription factors) or repolarisation processes (e.g., ion-channel genes), whereas primary cardiomyopathies are mainly caused by defective force generation or force transmission due to gene mutations in either sarcomeric or cytoskeleton proteins. Although over 50 genes have been identified in humans directly or indirectly related to sudden cardiac death, no genetic aetiologies have been identified in small animals. Sudden cardiac deaths have been also reported in German Shepherds and Boxers. A better understanding of molecular genetic aetiologies for sudden cardiac death will be required for future study toward unveiling actiology in sudden cardiac death in small animals. (c) 2005 Elsevier Ltd. All rights reserved.

Molecular phylogeny and biogeography of the dung beetle genus Temnoplectron Westwood (Scarabaeidae: Scarabaeinae) from Australia’s wet tropics

The landscape of the Australian Wet Tropics can be described as islands of montane rainforest Surrounded by warmer or more xeric habitats. Historical glaciation cycles have caused expansion and contraction of these rainforest islands leading to consistent patterns of genetic divergence within species of vertebrates. To explore whether this dynamic history has promoted speciation in endemic and diverse groups Of insects, we used a combination of mtDNA sequencing and morphological characters to estimate relationships and the tempo of divergence among Australian representatives of the dung beetle genus Temnoplectron. This phylogenetic hypothesis shares a number of well-supported clades with a previously published phylogenetic hypothesis based on morphological data. though statistical support for several nodes is weak. Sister species relationships well-supported in both tree topologies. and a tree obtained by combining the two data sets. suggest that speciation has mostly been allopatric. We identify a number of speciation barriers, which coincide with phylogeographic breaks found in vertebrate species. Large sequence divergences between species emphasize that speciation events are ancient (pre-Pleistocene). The flightless, rainforest species appear to have speciated rapidly. but also in the distant past. (C) 2003 Elsevier Inc. All rights reserved.

RNA regulation: a new genetics?

Do non-coding RNAs that are derived from the introns and exons of protein-coding and non-protein-coding genes represent a fundamental advance in the genetic operating system of higher organisms? Recent evidence from comparative genomics and molecular genetics indicates that this might be the case. If so, there will be profound consequences for our understanding of the genetics of these organisms, and in particular how the trajectories of differentiation and development and the differences among individuals and species are genomically programmed. But how might this hypothesis be tested?

Pleomorphic lobular carcinoma of the breast: role of comprehensive molecular pathology in characterization of an entity

Immunohistochemical analysis of E-cadherin has changed the way lobular neoplasia is perceived. It has helped to classify difficult cases of carcinoma in situ with indeterminate features and led to the identification of new variants of lobular carcinoma. Pleomorphic lobular carcinoma (PLC) and pleomorphic lobular carcinoma in situ (PLCIS), recently described variants of invasive and in situ classic lobular carcinoma, are reported to be associated with more aggressive clinical behaviour. Although PLC/PLCIS show morphological features of classic lobular neoplasia and lack E-cadherin expression, it is still unclear whether these lesions evolve through the same genetic pathway as lobular carcinomas or are high-grade ductal neoplasms that have lost E-cadherin. Here we have analysed a case of extensive PLCIS and invasive PLC associated with areas of E-cadherin-negative carcinoma in situ with indeterminate features, using immunohistochemistry, chromogenic in situ hybridization, high-resolution comparative genomic hybridization (CGH) and array-based CGH. We observed that all lesions lacked E-cadherin and beta-catenin and showed gain of 1q and loss of 16q, features that are typical of lobular carcinomas but are not seen in high-grade ductal lesions. In addition, amplifications of c-myc and HER2 were detected in the pleomorphic components, which may account for the high-grade features in this case and the reported aggressive clinical behaviour of these lesions. Taken together, these data suggest that at least some PLCs may evolve from the same precursor or through the same genetic pathway as classic lobular carcinomas. Copyright (c) 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.