Chromosome Imbalances in Cancer: Molecular Cytogenetics Meets Genomics

Abstract

Genomic instability is a hallmark of cancer, and it is well-known that in several cancers the karyotype is unstable and rapidly evolving. Molecular cytogenetics has contributed to the description and interpretation of cancer karyotypes, in particular through multicolor FISH approaches which can define even complex chromosome rearrangements. The introduction of genome-wide methods has made available a powerful set of tools with higher resolution than cytogenetics, thus appropriate to comprehend the huge variability of cancer cells. This review focuses on novel findings deriving from the combination of cytogenetic and genomic approaches in cancer research.

Common fragile site instability in normal cells: Lessons and perspectives

“…In contrast, after the discovery of CNVs, a normal component of the human genome consisting mainly in large‐scale deletions, duplications, and inversions of variable length, the relationship linking CFS instability to CNVs was directly investigated in tumors. In fact, de novo CNVs are rather frequent in cancer . Recently, the focus has moved backward in order to understand how CNVs and submicroscopic rearrangements occur at CFSs in normal cells, in the presence of properly regulated cell cycle and DNA damage repair pathways.…”

“…In perspective, the possible role that chromothripsis and other forms of highly localized complex chromosomal rearrangements (Table ) may play in generating CNVs, and submicroscopic rearrangements at CFSs should be evaluated thoroughly. Chromothripsis is the result of a one‐off intrachromosomal catastrophe occurring during a single‐cell division; it leads to massive rearrangements restricted to only one or few chromosomes, as the consequence of deep fragmentation and resealing . Traces of additional types of catastrophic events have been recorded in cancer genomes in recent years: among them, chromoanasynthesis is another distinct form of highly localized complex chromosomal rearrangement mediated by cycles of MM‐BIR and/or FoSTeS triggered by a DNA replication error .…”

“…In fact, de novo CNVs are rather frequent in cancer. 82,83 Recently, the focus has moved backward in order to understand how CNVs and submicroscopic rearrangements occur at CFSs in normal cells, in the presence of properly regulated cell cycle and DNA damage repair pathways. In this field, intense work has been performed by applying genomic approaches such as comparative genomic hybridization arrays and next generation sequencing (NGS).…”

“…In this field, intense work has been performed by applying genomic approaches such as comparative genomic hybridization arrays and next generation sequencing (NGS). 83 The first evidence that replication stress in nontransformed cells can lead to the formation of genomic deletions, closely resembling those found in tumors, was obtained studying FHIT/FRA3B in humanmouse somatic hybrid cells. Soon after, submicroscopic changes at CNVs were observed also in normal human fibroblasts and mouse embryonic stem (ES) cells cultured under replication stress (extensively reviewed by Glover et al 35 ).…”

“…-cell division; it leads to massive rearrangements restricted to only one or few chromosomes, as the consequence of deep fragmentation and resealing 83,92. Traces of additional types of catastrophic events have been recorded in cancer genomes in recent years: among them, chromoanasynthesis is another distinct form of highly localized complex chromosomal rearrangement mediated by cycles of MM-BIR and/or FoSTeS triggered by a DNA replication error 92.…”