Numerical chromosomal instability mediates susceptibility to radiation treatment.

Samuel F Bakhoum,Lilian Kabeche,Gloria E Reynolds,Bassem I Zaki,Matthew D Wood,Raymond J Louie,Duane A Compton,Joanna Phillips,Christopher D Laucius,Claudia Petritsch,Ashley M Laughney,Denise A Chan,John P Murnane,Dian Qu

doi:10.1038/ncomms6990

Abstract

The exquisite sensitivity of mitotic cancer cells to ionizing radiation (IR) underlies an important rationale for the widely used fractionated radiation therapy. However, the mechanism for this cell cycle-dependent vulnerability is unknown. Here we show that treatment with IR leads to mitotic chromosome segregation errors in vivo and long-lasting aneuploidy in tumour-derived cell lines. These mitotic errors generate an abundance of micronuclei that predispose chromosomes to subsequent catastrophic pulverization thereby independently amplifying radiation-induced genome damage. Experimentally suppressing whole-chromosome missegregation reduces downstream chromosomal defects and significantly increases the viability of irradiated mitotic cells. Further, orthotopically transplanted human glioblastoma tumours in which chromosome missegregation rates have been reduced are rendered markedly more resistant to IR, exhibiting diminished markers of cell death in response to treatment. This work identifies a novel mitotic pathway for radiation-induced genome damage, which occurs outside of the primary nucleus and augments chromosomal breaks. This relationship between radiation treatment and whole-chromosome missegregation can be exploited to modulate therapeutic response in a clinically relevant manner.

Highlights

The exquisite sensitivity of mitotic cancer cells to ionizing radiation (IR) underlies an important rationale for the widely used fractionated radiation therapy
These lagging chromosomes can directly lead to chromosome missegregation and aneuploidy. w-CIN does not exist in isolation, as it was recently shown that lagging chromosomes can undergo severe structural damage by generating whole-chromosome-containing micronuclei[11]
We recently showed that IR exposure during mitosis directly induces chromosome segregation errors in a dose-dependent manner[17]

Summary

Introduction

The exquisite sensitivity of mitotic cancer cells to ionizing radiation (IR) underlies an important rationale for the widely used fractionated radiation therapy. We recently demonstrated that activation of the DNA damage response pathway during mitosis, using IR or Doxorubicin, directly leads to the formation of lagging chromosomes during anaphase[17] This suggests that IR has the potential to generate both w-CIN and s-CIN in a context-dependent manner. This is relevant given that mitosis has long been recognized as the most radiosensitive phase of the cell cycle[20,21], offering a potentially important therapeutic target Along these lines, we recently found that, in patients diagnosed with rectal adenocarcinoma, elevated pre-treatment rates of chromosome segregation errors forebode superior response to chemoradiation therapy[22].

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Conclusion