Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell–like diffuse large B cell lymphoma

To elucidate the mechanisms underlying chromosomal translocations in diffuse large B cell lymphoma (DLBCL), we investigated the nature and extent of immunoglobulin class switch recombination (CSR) in these tumors. We used Southern blotting to detect legitimate and illegitimate CSR events in tumor samples of the activated B cell–like (ABC), germinal center B cell–like (GCB), and primary mediastinal B cell lymphoma (PMBL) subgroups of DLBCL. The frequency of legitimate CSR was lower in ABC DLBCL than in GCB DLBCL and PMBL. In contrast, ABC DLBCL had a higher frequency of internal deletions within the switch μ (Sμ) region compared with GCB DLBCL and PMBL. ABC DLBCLs also had frequent deletions within Sγ and other illegitimate switch recombinations. Sequence analysis revealed ongoing Sμ deletions within ABC DLBCL tumor clones, which were accompanied by ongoing duplications and activation-induced cytidine deaminase–dependent somatic mutations. Unexpectedly, short fragments derived from multiple chromosomes were interspersed within Sμ in one case. These findings suggest that ABC DLBCLs have abnormalities in the regulation of CSR that could predispose to chromosomal translocations. Accordingly, aberrant switch recombination was responsible for translocations in ABC DLBCLs involving BCL6, MYC, and a novel translocation partner, SPIB

Multi-layered cancer chromosomal instability phenotype

Whole chromosomal instability (W-CIN) – unequal chromosome distribution during cell division - is a characteristic feature of a majority of cancer cells distinguishing them from their normal counterparts. The precise molecular mechanisms that may cause missegregation of chromosomes in tumor cells just recently became more evident. The consequences of W-CIN are numerous and play a critical role in carcinogenesis. W-CIN mediates evolution of cancer cell population under selective pressure and can facilitate the accumulation of genetic changes that promote malignancy. It has both tumor-promoting and tumor-suppressive effects, and their balance could be beneficial or detrimental for carcinogenesis. The characterization of W-CIN as a complex multilayered adaptive phenotype highlights the intra- and extracellular adaptations to the consequences of genome reshuffling. It also provides a framework for targeting aggressive chromosomally unstable cancers

Stable Karyotypes in Epithelial Cancer Cell Lines Despite High Rates of Ongoing Structural and Numerical Chromosomal Instability

Most human tumors and tumor cell lines exhibit numerical and structural chromosomal abnormalities. The goal of this study was to determine the ongoing rates of structural and numerical instability in selected cancer cell lines and to investigate the consequences of these rates to karyotypic progression. We studied two colorectal. (20HCT-116 and HT-29) and two ovarian. (20SKOV-3 and OVCAR-8) cancer cell lines and their single cell subclones. We found that the signature karyotypes of all four cell lines were distinct and each aberrant. Whereas high rates of ongoing structural and/ or numerical chromosomal instability could be demonstrated in all cell lines, there was a relative stability of the consensus karyotype over many generations. No new clonal structural chromosomal reconfigurations emerged and the few numerical changes of karyotypes were restricted to abnormal chromosomes. This implies a kind of genomic optimization under the conditions of cell culture and suggests a link between genomic stabilization and cell propagation. We have been able to support this possibility by computer modeling. We did not observe a profound difference in the rates of numerical or structural instability in the cell lines with a replication error phenotype. (20RER+) versus the other cell lines

Chromosomal Instability Is Associated with Higher Expression of Genes Implicated in Epithelial-Mesenchymal Transition, Cancer Invasiveness, and Metastasis and with Lower Expression of Genes Involved in Cell Cycle Checkpoints, DNA Repair, and Chromatin Maintenance1

Chromosomal instability—a hallmark of epithelial cancers—is an ongoing process that results in aneuploidy and karyotypic heterogeneity of a cancer cell population. Previously, we stratified cancer cell lines in the NCI-60 drug discovery panel based on their karyotypic complexity and heterogeneity. Using this stratification in conjunction with drug response data for the cell lines allowed us to identify classes of chemical compounds whose growthinhibitory activity correlates with karyotypic complexity and chromosomal instability. In this article, we asked the question: What are the biological processes, pathways, or genes associated with chromosomal instability of cancer cells? We found that increased instability of the chromosomal content in a cancer cell population, particularly, persistent gains and losses of chromosomes, is associated with elevated expression of genes involved with aggressive cellular behavior, including invasion- and metastasis-associated changes in cell communication, adhesion, motility, and migration. These same karyotypic features are negatively correlated with the expression of genes involved in cell cycle checkpoints, DNA repair, and chromatin maintenance

Novel near-diploid ovarian cancer cell line derived from a highly aneuploid metastatic ovarian tumor

<div><p>A new ovarian near-diploid cell line, OVDM1, was derived from a highly aneuploid serous ovarian metastatic adenocarcinoma. A metastatic tumor was obtained from a 47-year-old Ashkenazi Jewish patient three years after the first surgery removed the primary tumor, both ovaries, and the remaining reproductive organs. OVDM1 was characterized by cell morphology, genotyping, tumorigenic assay, mycoplasma testing, spectral karyotyping (SKY), and molecular profiling of the whole genome by aCGH and gene expression microarray. Targeted sequencing of a panel of cancer-related genes was also performed. Hierarchical clustering of gene expression data clearly confirmed the ovarian origin of the cell line. OVDM1 has a near-diploid karyotype with a low-level aneuploidy, but samples of the original metastatic tumor were grossly aneuploid. A number of single nucleotide variations (SNVs)/mutations were detected in OVDM1 and the metastatic tumor samples. Some of them were cancer-related according to COSMIC and HGMD databases (no founder mutations in <i>BRCA1</i> and <i>BRCA2</i> have been found). A large number of focal copy number alterations (FCNAs) were detected, including homozygous deletions (HDs) targeting <i>WWOX</i> and <i>GATA4</i>. Progression of OVDM1 from early to late passages was accompanied by preservation of the near-diploid status, acquisition of only few additional large chromosomal rearrangements and more than 100 new small FCNAs. Most of newly acquired FCNAs seem to be related to localized but massive DNA fragmentation (chromothripsis-like rearrangements). Newly developed near-diploid OVDM1 cell line offers an opportunity to evaluate tumorigenesis pathways/events in a minor clone of metastatic ovarian adenocarcinoma as well as mechanisms of chromothripsis.</p></div

Whole chromosome gains and losses and number of FCNAs in tumor sample MT1 and OVDM1 cell line (early, intermediate, and late passages).

<p>Whole chromosome gains and losses and number of FCNAs in tumor sample MT1 and OVDM1 cell line (early, intermediate, and late passages).</p