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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.

SUBMITTER: Chen Z

PROVIDER: S-EPMC3134546 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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

Chen Zhenbin Z Liu Zheng Z Li Wenyan W Qu Kun K Deng Xutao X Varma Madhulika G MG Fichera Alessandro A Pigazzi Alessio A Garcia-Aguilar Julio J

Genes, chromosomes & cancer 20110516 9

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 P ...[more]

PMID: 21584903

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Project description:Lymph node metastasis is an important indicator of oncologic outcome for patients with rectal cancer. Identifying predictive biomarkers of lymph node metastasis could therefore be clinically useful.The aim of this study was to assess whether chromosomal copy number alterations can assist in predicting persistent lymph node metastasis in patients with locally advanced rectal cancer treated with preoperative chemoradiation therapy.This is a nonrandomized, prospective phase II study.This study took place in a multi-institutional setting.Ninety-five patients with stage II (cT3-4, cN0) or stage III (any cT, cN1-2) rectal cancer were included.Patients were treated with preoperative chemoradiation therapy followed by total mesorectal excision. Pretreatment biopsy tumor DNA and surgical margin control DNA were extracted and analyzed by oligonucleotide array-based comparative genomic hybridization. Chromosomal copy number alterations were correlated with persistent lymph node metastasis. Finally, a model for predicting persistent lymph node metastasis was built.The primary outcomes assessed were whether chromosomal copy number alterations are associated with persistent lymph node metastasis in patients with rectal cancer and the accuracy of oligonucleotide array-based comparative genomic hybridization for predicting lymph node metastasis.Twenty-five of 95 (26%) patients had lymph node metastasis after chemoradiation. Losses of 28 chromosomal regions, most notably in chromosome 4, were significantly associated with lymph node metastasis. Our predictive model contained 65 probes and predicted persistent lymph node metastasis with 68% sensitivity, 93% specificity, and positive and negative predictive values of 77% and 89%. The use of this model accurately predicted lymph node status (positive or negative) after chemoradiation therapy in 82 of 95 patients (86%).The patient cohort was not completely homogeneous, which may have influenced their clinical outcome. In addition, although we performed rigorous, statistically sound internal validation, external validation will be important to further corroborate our findings.Copy number alterations can help identify patients with rectal cancer who are at risk of lymph node metastasis after chemoradiation.

Dataset Information

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

Publications

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

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