Molecular profiling of Ductal Carcinoma In Situ

Breast cancer develops through multiple stages from hyperplasia to invasive and finally metastatic disease. Ductal carcinoma in situ (DCIS) is an abnormal proliferation of epithelial cells within the milk ducts in the breast without invasion beyond the basement membrane. The incidence of DCIS accounts for about 20-25% of newly diagnosed breast cancer cases. Some in situ lesions are believed to rapidly transit to invasive ductal carcinoma (IDC), while others remain unchanged or disappear. Nowadays, women who would never experience invasive breast cancer are undergoing unnecessary and potentially harmful treatment. Studies have revealed that the invasive phenotype of breast cancer is determined at the preinvasive stages of the tumor. Molecular studies of DCIS are therefore important in order to identify those lesions that have a greater risk of developing into invasive disease. The objective of this thesis was to characterize in situ and invasive breast carcinomas by gene expression profiling. Differences in gene expression within DCIS and between DCIS and invasive breast carcinomas were examined to gain insights about molecular mechanisms underlying tumor progression and to identify potential progression markers. 58 tumor tissues from 37 pure DCIS and 21 pure invasive cancers were subjected to microarray gene expression analysis using Agilent One-Color Microarray 8times 60K. Hierarchical clustering proved that the samples related more to subtype than diagnosis. The most significant genes separating the invasive cancers from DCIS were found to be involved in functions related to the extracellular matrix and tumor-stromal interaction. A subgroup of eight DCIS tumors separated from the other DCIS by high expression of genes characteristic of the invasive tumors. These genes could be potential progression markers if validated in other studies. Heterogeneity was observed among the DCIS patients and two subgroups of in situ lesions were clearly differentiated based on upregulated immune response. Elevated levels of immune signaling were found in HER2+, basal-like, normal-like and luminal B subtypes, but were completely absent in luminal A tumors. The suppressing role of the immune system compared with the promoting role needs to be further investigated, and could potentially increase our knowledge concerning the progression of in situ lesions to invasive breast cancer

Molecular Features of Subtype-Specific Progression from Ductal Carcinoma In Situ to Invasive Breast Cancer

Breast cancer consists of at least five main molecular “intrinsic” subtypes that are reflected in both pre-invasive and invasive disease. Although previous studies have suggested that many of the molecular features of invasive breast cancer are established early, it is unclear what mechanisms drive progression and whether the mechanisms of progression are dependent or independent of subtype. We have generated mRNA, miRNA, and DNA copy-number profiles from a total of 59 in situ lesions and 85 invasive tumors in order to comprehensively identify those genes, signaling pathways, processes, and cell types that are involved in breast cancer progression. Our work provides evidence that there are molecular features associated with disease progression that are unique to the intrinsic subtypes. We additionally establish subtype-specific signatures that are able to identify a small proportion of pre-invasive tumors with expression profiles that resemble invasive carcinoma, indicating a higher likelihood of future disease progression

Biochemical and genetic characterization of an unusual mild PEX3-related Zellweger spectrum disorder

Patients with PEX3 mutations usually present with a severe form of Zellweger spectrum disorder with death in the first year of life. Whole exome sequencing in adult siblings with intellectual disability revealed a homozygous variant in PEX3 that abolishes the normal splice site. A cryptic acceptor splice site is activated and an in-frame transcript with a deletion is produced. This transcript translates into a protein with residual activity explaining the relatively mild peroxisomal abnormalities and clinical phenotype. (C) 2017 Elsevier Inc All rights reserve

Molecular Features of Subtype-Specific Progression from Ductal Carcinoma In Situ to Invasive Breast Cancer

Breast cancer consists of at least five main molecular “intrinsic” subtypes that are reflected in both pre-invasive and invasive disease. Although previous studies have suggested that many of the molecular features of invasive breast cancer are established early, it is unclear what mechanisms drive progression and whether the mechanisms of progression are dependent or independent of subtype. We have generated mRNA, miRNA, and DNA copy-number profiles from a total of 59 in situ lesions and 85 invasive tumors in order to comprehensively identify those genes, signaling pathways, processes, and cell types that are involved in breast cancer progression. Our work provides evidence that there are molecular features associated with disease progression that are unique to the intrinsic subtypes. We additionally establish subtype-specific signatures that are able to identify a small proportion of pre-invasive tumors with expression profiles that resemble invasive carcinoma, indicating a higher likelihood of future disease progression