Paradoxical relationship between chromosomal instability and survival outcome in cancer

Abstract

Chromosomal instability (CIN) is associated with poor prognosis in human cancer. However, in certain animal tumor models elevated CIN negatively impacts upon organism fitness, and is poorly tolerated by cancer cells. To better understand this seemingly contradictory relationship between CIN and cancer cell biological fitness and its relationship with clinical outcome, we applied the CIN70 expression signature, which correlates with DNA-based measures of structural chromosomal complexity and numerical CIN in vivo, to gene expression profiles of 2,125 breast tumors from 13 published cohorts. Tumors with extreme CIN, defined as the highest quartile CIN70 score, were predominantly of the estrogen receptor negative (ER(-)), basal-like phenotype and displayed the highest chromosomal structural complexity and chromosomal numerical instability. We found that the extreme CIN/ER(-) tumors were associated with improved prognosis relative to tumors with intermediate CIN70 scores in the third quartile. We also observed this paradoxical relationship between CIN and prognosis in ovarian, gastric, and non-small cell lung cancer, with poorest outcome in tumors with intermediate, rather than extreme, CIN70 scores. These results suggest a nonmonotonic relationship between gene signature expression and HR for survival outcome, which may explain the difficulties encountered in the identification of prognostic expression signatures in ER(-) breast cancer. Furthermore, the data are consistent with the intolerance of excessive CIN in carcinomas and provide a plausible strategy to define distinct prognostic patient cohorts with ER(-) breast cancer. Inclusion of a surrogate measurement of CIN may improve cancer risk stratification and future therapeutic approaches.

Fig. 1. CIN70 score and structural chromosomal complexity

(A) The structural chromosomal complexity score based on SNP array data is shown for each CIN70 quartile in 271 breast cancer samples. (B) Nuclear DNA content versus CIN70 quartile in 44 breast cancer samples. (C) Frequency of diploid, genomically stable (dGS); aneuploid, genomically stable (aGS); and aneuploid, genomically unstable (aGU) in each CIN70 quartile.

Fig. 2. Distribution of CIN70 scores across breast cancer subtypes

(A) Overall distribution of CIN70 scores across 2125 breast cancer patients stratified by ER and ERBB2 receptor subtype. Percentages on Y-axis denote quartile thresholds. (B) Distribution of each breast cancer subtype within each of the four CIN70 score quartiles.

Fig. 3. Survival of cancer patients stratified by CIN70 score quartile

Kaplan-Meier survival curves are presented for (A) 265 ER-/ERBB2- breast cancer patients with recurrence-free or distant metastasis-free survival, (B) 652 patients with ovarian cancer, (C) 183 patients with squamous NSCLC, (D) 197 patients with gastric cancer.

Fig. 4. Quartile hazard ratio

Forest plots showing the hazard ratio of the quartiles. The hazard ratio of each quartile is based on a summary estimate of ER-/ERBB2-breast tumours, ovarian tumours, squamous NSCLC and gastric tumours.