Chromosomal copy number alterations are associated with tumor response to chemoradiation in locally advanced rectal cancer

Abstract

Rectal cancer response to chemoradiation (CRT) varies from no response to a pathologic complete response (pCR). Identifying predictive biomarkers of response would therefore be useful. We assessed whether chromosomal copy number alterations (CNAs) can assist in predicting pCR. Pretreatment tumor biopsies and paired normal surgical tissues from the proximal resection margin were collected from 95 rectal cancer patients treated with preoperative CRT and total mesorectal excision in a prospective Phase II study. Tumor and control DNA were extracted, and oligonucleotide array-based comparative genomic hybridization (aCGH) was used to identify CNAs, which were correlated with pCR. Ingenuity pathway analysis (IPA) was then used to identify functionally relevant genes in aberrant regions. Finally, a predictive model for pCR was built using support vector machine (SVM), and leave-one-out cross validation assessed the accuracy of aCGH. Chromosomal regions most commonly affected by gains were 20q11.21-q13.33, 13q11.32-23, 7p22.3-p22.2, and 8q23.3-q24.3, and losses were present at 18q11.32-q23, 17p13.3-q11.1, 10q23.1, and 4q32.1-q32.3. The 25 (26%) patients who achieved a pCR had significantly fewer high copy gains overall than non-pCR patients (P = 0.01). Loss of chromosomal region 15q11.1-q26.3 was significantly associated with non-pCR (P < 0.00002; Q-bound < 0.0391), while loss of 12p13.31 was significantly associated with pCR (P < 0.0003; Q-bound < 0.097). IPA identified eight genes in the imbalanced chromosomal regions that associated with tumor response. SVM identified 58 probes that predict pCR with 76% sensitivity, 97% specificity, and positive and negative predictive values of 91% and 92%. Our data indicate that chromosomal CNAs can help identify rectal cancer patients more likely to develop a pCR to CRT.

Trial registration: ClinicalTrials.gov NCT00335816.

Copyright © 2011 Wiley-Liss, Inc.

Figures

Figure 1

Overall frequency of copy number alterations (CNAs) detected by oligonucleotide array-based comparative genomic hybridization (aCGH) in 95 rectal cancer patients. The most common alterations were gains in chromosomes 20, 13, 8 and 7 and losses in chromosomes 18, 8, 17 and 4.

Figure 2

a: 58 probes were used to build a predictive model using Support Vector Machine (SVM) to predict pathologic complete response (pCR). Sample identification - Red: Loss; Green: Gain; Yellow: pCR; Blue: Non-pCR. b: Receiver-Operator Characteristics (ROC) curve using the true positive rate and false positive rate to evaluate the prediction ability of pathologic complete response (pCR) using 58 probes selected from significant discriminated genomic aberrant regions between pCR and non-pCR patients. The area under the curve (AUC) value for the performance of the prediction is 0.96.

Figure 2

a: 58 probes were used to build a predictive model using Support Vector Machine (SVM) to predict pathologic complete response (pCR). Sample identification - Red: Loss; Green: Gain; Yellow: pCR; Blue: Non-pCR. b: Receiver-Operator Characteristics (ROC) curve using the true positive rate and false positive rate to evaluate the prediction ability of pathologic complete response (pCR) using 58 probes selected from significant discriminated genomic aberrant regions between pCR and non-pCR patients. The area under the curve (AUC) value for the performance of the prediction is 0.96.