Chromosomal Instability Selects Gene Copy-Number Variants Encoding Core Regulators of Proliferation in ER+ Breast Cancer

TY - JOUR

T1 - Chromosomal Instability Selects Gene Copy-Number Variants Encoding Core Regulators of Proliferation in ER+ Breast Cancer

AU - Endesfelder, David

AU - Burrell, Rebecca A.

AU - Kanu, Nnennaya

AU - McGranahan, Nicholas

AU - Howell, Mike

AU - Parker, Peter J.

AU - Downward, Julian

AU - Swanton, Charles

AU - Kschischo, Maik

PY - 2014/9/1

Y1 - 2014/9/1

N2 - Chromosomal instability (CIN) is associated with poor outcome in epithelial malignancies, including breast carcinomas. Evidence suggests that prognostic signatures in estrogen receptor-positive (ER+) breast cancer define tumors with CIN and high proliferative potential. Intriguingly, CIN induction in lower eukaryotic cells and human cells is context dependent, typically resulting in a proliferation disadvantage but conferring a fitness benefit under strong selection pressures. We hypothesized that CIN permits accelerated genomic evolution through the generation of diverse DNA copy-number events that may be selected during disease development. In support of this hypothesis, we found evidence for selection of gene amplification of core regulators of proliferation in CIN-associated cancer genomes. Stable DNA copy-number amplifications of the core regulators TPX2 and UBE2C were associated with expression of a gene module involved in proliferation. The module genes were enriched within prognostic signature gene sets for ER+ breast cancer, providing a logical connection between CIN and prognostic signature expression. Our results provide a framework to decipher the impact of intratumor heterogeneity on key cancer phenotypes, and they suggest that CIN provides a permissive landscape for selection of copy-number alterations that drive cancer proliferation.

AB - Chromosomal instability (CIN) is associated with poor outcome in epithelial malignancies, including breast carcinomas. Evidence suggests that prognostic signatures in estrogen receptor-positive (ER+) breast cancer define tumors with CIN and high proliferative potential. Intriguingly, CIN induction in lower eukaryotic cells and human cells is context dependent, typically resulting in a proliferation disadvantage but conferring a fitness benefit under strong selection pressures. We hypothesized that CIN permits accelerated genomic evolution through the generation of diverse DNA copy-number events that may be selected during disease development. In support of this hypothesis, we found evidence for selection of gene amplification of core regulators of proliferation in CIN-associated cancer genomes. Stable DNA copy-number amplifications of the core regulators TPX2 and UBE2C were associated with expression of a gene module involved in proliferation. The module genes were enriched within prognostic signature gene sets for ER+ breast cancer, providing a logical connection between CIN and prognostic signature expression. Our results provide a framework to decipher the impact of intratumor heterogeneity on key cancer phenotypes, and they suggest that CIN provides a permissive landscape for selection of copy-number alterations that drive cancer proliferation.

KW - EXPRESSION PROFILES

KW - COLORECTAL-CANCER

KW - ANEUPLOIDY

KW - PROGNOSIS

KW - SURVIVAL

KW - CELLS

KW - METAANALYSIS

KW - SUBTYPES

KW - BIOLOGY

KW - GENOME

U2 - 10.1158/0008-5472.CAN-13-2664

DO - 10.1158/0008-5472.CAN-13-2664

M3 - Article

SN - 0008-5472

VL - 74

SP - 4853

EP - 4863

JO - Cancer Research

JF - Cancer Research

IS - 17

ER -