Mechanisms and clinical applications of chromosomal instability in lymphoid malignancy

Abstract

SummaryLymphocytes are unique among cells in that they undergo programmed DNA breaks and translocations, but that special property predisposes them to chromosomal instability (CIN), a cardinal feature of neoplastic lymphoid cells that manifests as whole chromosome-or translocation-based aneuploidy. In several lymphoid malignancies translocations may be the defining or diagnostic markers of the diseases. CIN is a cornerstone of the mutational architecture supporting lymphoid neoplasia, though it is perhaps one of the least understood components of malignant transformation in terms of its molecular mechanisms. CIN is associated with prognosis and response to treatment, making it a key area for impacting treatment outcomes and predicting prognoses. Here we will review the types and mechanisms of CIN found in Hodgkin lymphoma, non-Hodgkin lymphoma, multiple myeloma and the lymphoid leukaemias, with emphasis placed on pathogenic mutations affecting DNA recombination, replication and repair; telomere function; and mitotic regulation of spindle attachment, centrosome function, and chromosomal segregation. We will discuss the means by which chromosome-level genetic aberrations may give rise to multiple pathogenic mutations required for carcinogenesis and conclude with a discussion of the clinical applications of CIN and aneuploidy to diagnosis, prognosis and therapy.

DNA Damage/Repair Management in Cancers

“…DNA damage and misrepair can persist within normal bystander cells as well as cancer cells, leading to clonal evolution with more aggressive features. Such abnormalities include the formation of abnormal nuclear bodies called micronuclei [137].…”

Genomic studies of multiple myeloma reveal an association between X chromosome alterations and genomic profile complexity

“…Homologous recombination (HR) and nonhomologous end‐joining (NHEJ) are important pathways in the DSB repair system. Deregulation of genes involved in these pathways such as ATM , NBN , XRCC4‐6 , PRKDC , DCLREC1C , and LIG4 leads to a higher level of chromosomal breakage with partial losses or gains of genomic material (Krem et al, ). These chromosomal fragments could be translocated and submitted to other gene expression regulation processes, resulting in a more important impact on the phenotype and prognosis of partial X alteration as compared to complete X monosomy.…”

New Insights in the Cytogenetic Practice: Karyotypic Chaos, Non-Clonal Chromosomal Alterations and Chromosomal Instability in Human Cancer and Therapy Response

“…KSP is an ATP hydrolase whose function is related to the regulation of microtubule movement during mitosis and with centrosome separation. Inhibition of KSP leads to cell cycle arrest and cell death [136,137]. Preliminary trials of KSP inhibitors in lymphoid malignancy patients indicate efficacy in refractory Multiple Myeloma (MM) [138], ability to induce disease stabilization in refractory DLBCL and favorable toxicity profile [139], confirming that CIN may be a therapeutic target useful not only to improve the response to therapy but also to reduce side effects in lymphoid malignancies.…”