Replication stress links structural and numerical cancer chromosomal instability

Abstract

Cancer chromosomal instability (CIN) results in an elevated rate of change of chromosome number and structure and generates intratumour heterogeneity1,2. CIN is observed in the majority of solid tumours and is associated with both poor prognosis and drug resistance3,4. Therefore, understanding a mechanistic basis for CIN is paramount. Here we find evidence for impaired replication fork progression and elevated DNA replication stress in CIN+ colorectal cancer (CRC) cells relative to CIN− CRC cells, with structural chromosome abnormalities precipitating chromosome missegregation in mitosis. We identify three novel CIN-suppressor genes (PIGN (MCD4), RKHD2 (MEX3C) and ZNF516 (KIAA0222)) encoded on chromosome 18q, which is subject to frequent copy number loss in CIN+ CRC. 18q loss was temporally associated with aneuploidy onset at the adenoma-carcinoma transition. CIN-suppressor gene silencing leads to DNA replication stress, structural chromosome abnormalities and chromosome missegregation. Supplementing cells with nucleosides, to alleviate replication-associated damage5, reduces the frequency of chromosome segregation errors following CIN-suppressor gene silencing and attenuates segregation errors and DNA damage in CIN+ cells. These data implicate a central role for replication stress in the generation of structural and numerical CIN, which may inform new therapeutic approaches to limit intratumour heterogeneity.

Replication stress and cancer: It takes two to tango

“…Consistently, the analysis of CIN+ versus CIN-colon adenocarcinoma cells revealed the presence of RS only in CIN+ cells, along with corresponding chromosome segregation defects [38]. This study identified a number of genes commonly deleted in CIN+ cell lines.…”

“…Reduction of any of these genes in CIN-cells results in RS and alterations in chromosomes similar to those observed in CIN+ cells due to aberrant segregation during mitosis. Further proving the causal role of RS in the generation of CIN, the addition of nucleosides limited the segregation defects that arise upon deletion of CIN-suppressor genes [38]. At the molecular level, the link between RS and CIN might be intimately related to the observation that RS can promote the formation of anaphase bridges (see below).…”

Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response

“…In contrast to germline mutations in DNA repair pathways in rare inherited syndromes (such as the mismatch repair gene variants that cause Lynch syndrome), the acquisition of genomic instability in sporadic cancers has largely been believed to be a mid‐stage to late‐stage event during carcinogenesis 19. For example, in sporadic colorectal cancer – a tumour type in which the molecular progression of precancers (adenomas) to invasive carcinomas has been well characterized – mismatch repair deficiency (MMR‐D) or chromosomal instability occur after initiating (epi)mutations in APC , BRAF , or KRAS , or other events such as whole genome doubling or loss of chromosome 18q 19, 20, 21, 22, 23, 24. Thus, in addition to its clinical relevance, the demonstration that the POLE mutator phenotype operates from the first stages of tumour initiation would also reveal a novel pathway of sporadic tumourigenesis.…”

Instabilité chromosomique et cancer, enfin des CIN révélateurs

“…Reste que la distinction, parmi les mécanismes moléculaires responsables de la CIN, entre défauts prémitotiques ou mitotiques, méritait d'être abordée de manière systé-matique ; c'est ce qui a été entrepris par le groupe britannique dont les résultats ont été récemment publiés dans la revue Nature [3].…”