Chromosomal instability portends superior response of rectal adenocarcinoma to chemoradiation therapy

Authors

  • Bassem I. Zaki MD,

    1. Section of Radiation Oncology, Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
    2. Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth College, Lebanon, New Hampshire
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  • Arief A. Suriawinata MD,

    1. Department of Pathology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
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  • Alan R. Eastman PhD,

    1. Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth College, Lebanon, New Hampshire
    2. Department of Pharmacology and Toxicology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
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  • Kristen M. Garner PhD,

    1. Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth College, Lebanon, New Hampshire
    2. Department of Pharmacology and Toxicology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire
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  • Samuel F. Bakhoum MD, PhD

    Corresponding author
    1. Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth College, Lebanon, New Hampshire
    2. Department of Internal Medicine, Mount Auburn Hospital, Harvard Medical School, Cambridge, Massachusetts
    • Corresponding author: Samuel F. Bakhoum, MD, PhD, Department of Internal Medicine, Mount Auburn Hospital, Harvard Medical School, 330 Mount Auburn St, Cambridge, MA, 02138; Fax: (888) 419-2656; samuel.f.bakhoum.dm@dartmouth.edu

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  • We sincerely thank Duane A. Compton, PhD, Lilan Kabeche, PhD, and Mathieu Bakhoum, PhD, for critical feedback and Rand Swenson, MD, PhD, of the Dartmouth Medical School for providing the Nikon microscope.

Abstract

BACKGROUND

Persistent chromosome segregation errors represent a conspicuous feature of human neoplasms. It is widely accepted that this chromosomal instability is associated with poor prognosis; however, its effect on therapeutic response is a matter of conjecture.

METHODS

Here, the role of chromosome segregation errors in the response of patients with rectal adenocarcinoma to chemoradiation therapy (CRT) was examined. Pretreatment samples from 62 patients were surveyed for evidence of chromosome mis-segregation and mis-segregation frequency was correlated to the pathological response to CRT as determined by the tumor regression grade after surgical resection of irradiated tumors.

RESULTS

Surprisingly, it was found that errors in chromosome segregation predicted enhanced pathological response of rectal adenocarcinoma to CRT (odds ratio, 3.9; P = .02). Furthermore, tumor response inversely correlated with the frequency of cells that exhibited segregation errors during anaphase (correlation coefficient, 0.94; P < .05). Strikingly, elevated chromosome mis-segregation combined with decreased levels of the DNA damage repair protein Mre11 portended a markedly enhanced response (odds ratio, 54.0; P = .008).

CONCLUSIONS

The results of the current study demonstrate that chromosomal instability is a favorable predictor of response to CRT in patients with locally invasive rectal adenocarcinoma. Therefore, the authors propose that downstream structural damage to chromosomes resulting from segregation errors potentiates the effect of DNA-damaging therapies and synergizes with deficiencies in the DNA repair machinery. This work identifies a novel mechanistic marker that foretells treatment response to CRT and suggests that concomitant targeting of whole-chromosome segregation and DNA repair may constitute an effective therapeutic strategy. Cancer 2014;120:1733–1742. © 2014 American Cancer Society.

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