Relationship of extreme chromosomal instability with long-term survival in a retrospective analysis of primary breast cancer

Rebecca Roylance, David Endesfelder, Patricia Gorman, Rebecca A Burrell, Jil Sander, Ian Tomlinson, Andrew M Hanby, Valerie Speirs, Andrea L Richardson, Nicolai J Birkbak, Aron C Eklund, Julian Downward, Maik Kschischo, Zoltan Szallasi, Charles Swanton

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Abstract

BACKGROUND: Chromosomal instability (CIN) is thought to be associated with poor prognosis in solid tumors; however, evidence from preclinical and mouse tumor models suggest that CIN may paradoxically enhance or impair cancer cell fitness. Breast cancer prognostic expression signature sets, which reflect tumor CIN status, efficiently delineate outcome in estrogen receptor ER-positive breast cancer in contrast to ER-negative breast cancer, suggesting that the relationship of CIN with prognosis differs in these two breast cancer subtypes.

METHODS: Direct assessment of CIN requires single-cell analysis methods, such as centromeric FISH, aimed at determining the variation around the modal number of two or more chromosomes within individual tumor nuclei. Here, we document the frequency of tumor CIN by dual centromeric FISH analysis in a retrospective primary breast cancer cohort of 246 patients with survival outcome.

RESULTS: There was increased CIN and clonal heterogeneity in ER-negative compared with ER-positive breast cancer. Consistent with a negative impact of CIN on cellular fitness, extreme CIN in ER-negative breast cancer was an independent variable associated with improved long-term survival in multivariate analysis. In contrast, a linear relationship of increasing CIN with poorer prognosis in ER-positive breast cancer was observed, using three independent measures of CIN.

CONCLUSIONS: The paradoxical relationship between extreme CIN and cancer outcome in the ER-negative cohorts may explain why prognostic expression signatures, reflecting tumor CIN status, fail to predict outcome in this subgroup.

IMPACT: Assessment of tumor CIN status may support risk stratification in ER-negative breast cancer and requires prospective validation.

Original languageEnglish
Pages (from-to)2183-2194
Number of pages12
JournalCancer Epidemiology, Biomarkers and Prevention
Volume20
Issue number10
Early online date22 Jul 2011
DOIs
Publication statusPublished - Oct 2011

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Chromosomal Instability
Breast Neoplasms
Survival
Neoplasms
Single-Cell Analysis
Estrogen Receptors

Keywords

  • Biomarkers, Tumor
  • Breast Neoplasms
  • Chromosomal Instability
  • Comparative Genomic Hybridization
  • Female
  • Follow-Up Studies
  • Gene Expression Profiling
  • Humans
  • In Situ Hybridization, Fluorescence
  • Middle Aged
  • Neoplasm Grading
  • Oligonucleotide Array Sequence Analysis
  • Polymorphism, Single Nucleotide
  • Prognosis
  • Receptors, Estrogen
  • Retrospective Studies
  • Survival Rate
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Cite this

Relationship of extreme chromosomal instability with long-term survival in a retrospective analysis of primary breast cancer. / Roylance, Rebecca; Endesfelder, David; Gorman, Patricia; Burrell, Rebecca A; Sander, Jil; Tomlinson, Ian; Hanby, Andrew M; Speirs, Valerie; Richardson, Andrea L; Birkbak, Nicolai J; Eklund, Aron C; Downward, Julian; Kschischo, Maik; Szallasi, Zoltan; Swanton, Charles.

In: Cancer Epidemiology, Biomarkers and Prevention, Vol. 20, No. 10, 10.2011, p. 2183-2194.

Research output: Contribution to journalArticle

Roylance, R, Endesfelder, D, Gorman, P, Burrell, RA, Sander, J, Tomlinson, I, Hanby, AM, Speirs, V, Richardson, AL, Birkbak, NJ, Eklund, AC, Downward, J, Kschischo, M, Szallasi, Z & Swanton, C 2011, 'Relationship of extreme chromosomal instability with long-term survival in a retrospective analysis of primary breast cancer', Cancer Epidemiology, Biomarkers and Prevention, vol. 20, no. 10, pp. 2183-2194. https://doi.org/10.1158/1055-9965.EPI-11-0343
Roylance, Rebecca ; Endesfelder, David ; Gorman, Patricia ; Burrell, Rebecca A ; Sander, Jil ; Tomlinson, Ian ; Hanby, Andrew M ; Speirs, Valerie ; Richardson, Andrea L ; Birkbak, Nicolai J ; Eklund, Aron C ; Downward, Julian ; Kschischo, Maik ; Szallasi, Zoltan ; Swanton, Charles. / Relationship of extreme chromosomal instability with long-term survival in a retrospective analysis of primary breast cancer. In: Cancer Epidemiology, Biomarkers and Prevention. 2011 ; Vol. 20, No. 10. pp. 2183-2194.
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AU - Roylance, Rebecca

AU - Endesfelder, David

AU - Gorman, Patricia

AU - Burrell, Rebecca A

AU - Sander, Jil

AU - Tomlinson, Ian

AU - Hanby, Andrew M

AU - Speirs, Valerie

AU - Richardson, Andrea L

AU - Birkbak, Nicolai J

AU - Eklund, Aron C

AU - Downward, Julian

AU - Kschischo, Maik

AU - Szallasi, Zoltan

AU - Swanton, Charles

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N2 - BACKGROUND: Chromosomal instability (CIN) is thought to be associated with poor prognosis in solid tumors; however, evidence from preclinical and mouse tumor models suggest that CIN may paradoxically enhance or impair cancer cell fitness. Breast cancer prognostic expression signature sets, which reflect tumor CIN status, efficiently delineate outcome in estrogen receptor ER-positive breast cancer in contrast to ER-negative breast cancer, suggesting that the relationship of CIN with prognosis differs in these two breast cancer subtypes.METHODS: Direct assessment of CIN requires single-cell analysis methods, such as centromeric FISH, aimed at determining the variation around the modal number of two or more chromosomes within individual tumor nuclei. Here, we document the frequency of tumor CIN by dual centromeric FISH analysis in a retrospective primary breast cancer cohort of 246 patients with survival outcome.RESULTS: There was increased CIN and clonal heterogeneity in ER-negative compared with ER-positive breast cancer. Consistent with a negative impact of CIN on cellular fitness, extreme CIN in ER-negative breast cancer was an independent variable associated with improved long-term survival in multivariate analysis. In contrast, a linear relationship of increasing CIN with poorer prognosis in ER-positive breast cancer was observed, using three independent measures of CIN.CONCLUSIONS: The paradoxical relationship between extreme CIN and cancer outcome in the ER-negative cohorts may explain why prognostic expression signatures, reflecting tumor CIN status, fail to predict outcome in this subgroup.IMPACT: Assessment of tumor CIN status may support risk stratification in ER-negative breast cancer and requires prospective validation.

AB - BACKGROUND: Chromosomal instability (CIN) is thought to be associated with poor prognosis in solid tumors; however, evidence from preclinical and mouse tumor models suggest that CIN may paradoxically enhance or impair cancer cell fitness. Breast cancer prognostic expression signature sets, which reflect tumor CIN status, efficiently delineate outcome in estrogen receptor ER-positive breast cancer in contrast to ER-negative breast cancer, suggesting that the relationship of CIN with prognosis differs in these two breast cancer subtypes.METHODS: Direct assessment of CIN requires single-cell analysis methods, such as centromeric FISH, aimed at determining the variation around the modal number of two or more chromosomes within individual tumor nuclei. Here, we document the frequency of tumor CIN by dual centromeric FISH analysis in a retrospective primary breast cancer cohort of 246 patients with survival outcome.RESULTS: There was increased CIN and clonal heterogeneity in ER-negative compared with ER-positive breast cancer. Consistent with a negative impact of CIN on cellular fitness, extreme CIN in ER-negative breast cancer was an independent variable associated with improved long-term survival in multivariate analysis. In contrast, a linear relationship of increasing CIN with poorer prognosis in ER-positive breast cancer was observed, using three independent measures of CIN.CONCLUSIONS: The paradoxical relationship between extreme CIN and cancer outcome in the ER-negative cohorts may explain why prognostic expression signatures, reflecting tumor CIN status, fail to predict outcome in this subgroup.IMPACT: Assessment of tumor CIN status may support risk stratification in ER-negative breast cancer and requires prospective validation.

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KW - Comparative Genomic Hybridization

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KW - Follow-Up Studies

KW - Gene Expression Profiling

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KW - In Situ Hybridization, Fluorescence

KW - Middle Aged

KW - Neoplasm Grading

KW - Oligonucleotide Array Sequence Analysis

KW - Polymorphism, Single Nucleotide

KW - Prognosis

KW - Receptors, Estrogen

KW - Retrospective Studies

KW - Survival Rate

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, Non-U.S. Gov't

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VL - 20

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EP - 2194

JO - Cancer Epidemiology, Biomarkers and Prevention

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SN - 1055-9965

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