👤 Sabina Barresi

Chronic lymphocytic leukemia (CLL) is divided into unmutated (UM-CLL) and mutated (M-CLL) subtypes depending on somatic hypermutation (SHM) frequency in their immunoglobulin heavy chain V (IGHV) region. We previously demonstrated that CD27bright memory B cells (MBCs) are germinal center (GC)-dependent with higher mutation rate, whereas CD27dull MBCs accumulate fewer mutations and originate independently from the GC. We conducted a meta-transcriptomic analysis on bulk RNA data from 116 individuals combining four CLL cohorts and healthy B cell subsets (naïve, CD27dull and CD27bright MBCs) to decipher the transcriptional and mechanistic functions of CLL subtypes. CD27bright MBCs showed more transcriptional similarity to M-CLL rather than UM-CLL. Functional enrichment analysis revealed that LPL, ZNF667 and ZNF667-AS1 are potential informative biomarkers for stratification of CLL subtypes. They are part of the mechanistic regulatory pathways of CLL pathology through cholesterol and Epithelial Mesenchymal Transition (EMT) regulation. We applied markers for the GC B-cell substages to map in silico the CLL cohorts to their potential GC B cell counterpart. UM-CLL represented transcriptional mimicry to an early intermediary GC substage whereas M-CLL mimicked later substages in the GC. This could potentially explain the IGHV mutational status of M-CLL as well as hypothesize that CLL subtypes could derive from a GC-dependent pathway. Show less

Derivative chromosome der(1;16), isochromosome 1q, and deleted 16q-producing arm-level 1q-gain and/or 16q-loss-are recurrent cytogenetic abnormalities in breast cancer, but their exact role in determining the malignant phenotype is still largely unknown. We exploited The Cancer Genome Atlas (TCGA) data to generate and analyze groups of breast invasive carcinomas, called 1,16-chromogroups, that are characterized by a pattern of arm-level somatic copy number aberrations congruent with known cytogenetic aberrations of chromosome 1 and 16. Substantial differences were found among 1,16-chromogroups in terms of other chromosomal aberrations, aneuploidy scores, transcriptomic data, single-point mutations, histotypes, and molecular subtypes. Breast cancers with a co-occurrence of 1q-gain and 16q-loss can be distinguished in a "low aneuploidy score" group, congruent to der(1;16), and a "high aneuploidy score" group, congruent to the co-occurrence of isochromosome 1q and deleted 16q. Another three groups are formed by cancers showing separately 1q-gain or 16q-loss or no aberrations of 1q and 16q. Transcriptome comparisons among the 1,16-chromogroups, integrated with functional pathway analysis, suggested the cooperation of overexpressed 1q genes and underexpressed 16q genes in the genesis of both ductal and lobular carcinomas, thus highlighting the putative role of genes encoding gamma-secretase subunits (APH1A, PSEN2, and NCSTN) and Wnt enhanceosome components (BCL9 and PYGO2) in 1q, and the glycoprotein E-cadherin (CDH1), the E3 ubiquitin-protein ligase WWP2, the deubiquitinating enzyme CYLD, and the transcription factor CBFB in 16q. The analysis of 1,16-chromogroups is a strategy with far-reaching implications for the selection of cancer cell models and novel experimental therapies. Show less

Multiple osteochondromas (MO) is an autosomal-dominant skeletal disorder caused by mutations in the exostosin-1 (EXT1) or exostosin-2 (EXT2) genes. In this study, we report the analysis of the mutational status of the EXT2 gene in tumor samples derived from a patient affected by hereditary MO, documenting the somatic loss of the germline mutation in a giant chondrosarcoma and in a rapidly growing osteochondroma. The sequencing of all exons and exon-intron junctions of the EXT1 and EXT2 genes from blood DNA of the proband did not reveal any mutation in the EXT1 gene but did demonstrate the presence of the transition point mutation c.67C > T in the EXT2 gene, determining the introduction of a stop codon in the coding sequence (p.Arg23*). A mutational analysis of other members of the family and the presence of osteochondromas in the metaphysis of long bones confirmed the diagnosis of hereditary multiple osteochondromas. Direct sequencing from DNA extracted from different sites of two tumor samples (a small rapidly growing osteochondroma and a giant peripheral secondary chondrosarcoma, each located at different chondrocostal junctions) revealed the loss of the germline EXT2 mutation. Analysis of microsatellite polymorphic markers in the 11p region harboring the EXT2 gene did not reveal any loss of heterozygosity. This observation supports a recent model of sarcomagenesis in which osteochondroma cells bear EXT homozygous inactivation, whereas chondrosarcoma-initiating cells are EXT-expressing cells. Show less