Recurrent Genomic Alterations With Impact on Survival in Colorectal Cancer Identified by Genome-Wide Array Comparative Genomic Hybridization

doi:10.1053/j.gastro.2006.10.021

Gastroenterology

Volume 131, Issue 6, December 2006, Pages 1913-1924

https://doi.org/10.1053/j.gastro.2006.10.021 Get rights and content

Background & Aims: Although genetic aspects of tumorigenesis in colorectal cancer (CRC) have been well studied, reliable biomarkers predicting prognosis are scarce. We aimed to identify recurrently altered genomic regions (RAR) in CRC with high resolution, to investigate their implications on survival and to explore novel cancer-related genes in prognosis-associated RARs. Methods: A 1-Mb resolution microarray-based comparative genomic hybridization (array CGH) was applied to 59 CRCs. RARs, defined as genomic alterations, detected in more than 10 cases were identified and analyzed for their association with survival. Expression levels of genes in prognosis-associated RARs were examined by real-time quantitative polymerase chain reaction. Results: Twenty-seven RARs were identified. Eleven high-level amplifications and 2 homozygous deletions also were detected, but they were not as common as RARs. Multivariate analysis revealed RAR-L1 (loss on 1p36; hazard ratio = 8.15, P = .002) and RAR-L20 (loss on 21q22; hazard ratio = 3.53, P = .034) are independent indicators of poor prognosis. Expression of CAMTA1, located in RAR-L1, was reduced frequently in CRCs, and low CAMTA1 expression was associated significantly with poor prognosis, which indicates that CAMTA1 may play a role as a tumor suppressor in CRC. Five pairs of RARs were correlated significantly to each other and 3 pairs share genes involved in the same biological functions, suggesting possible collaborative roles in tumorigenesis. Conclusions: We identified recurrent genomic changes in 59 CRCs. RARs could be more important in sporadic tumors where the effect of genomic changes on tumorigenesis is relatively smaller than in familial cancer. Our results and analysis strategy will be helpful to elucidate pathogenesis of CRCs or to develop biomarkers for predicting prognosis.

Section snippets

Study Materials

Surgical specimens from 59 CRC patients who underwent surgical resection from 1995 to 1997 at Dankook University Hospital in Cheonan, Korea, were examined in this study. This study was performed under the approval of the Institutional Review Boards of Kangnam St. Mary’s Hospital and The Catholic University of Korea. After surgical resection, tumor and adjacent normal tissues from each patient were collected separately and snap-frozen. Frozen sections were prepared of 10-μm thickness on a

General Characteristics of Study Subjects and Genomic Alterations in 59 CRCs

The clinicopathologic data of all 59 patients are summarized in Table 1. There were 39 men and 20 women and the mean patient age at the time of surgery was 58.7 years (range, 23–81 y). Among the 59 patients, 41 (69.5%) had rectosigmoid cancer. Thirty-six cancers (61.0%) were categorized as early stage tumors. At the end of the follow-up period, 23 patients were dead.

The overall genomic alterations detected in 59 colorectal cancers are illustrated in Figure 1A. The frequency plot of the

Discussion

CRC is one of the well-studied neoplastic diseases at the molecular level. A genetic model of colorectal tumorigenesis and related critical mutations such as APC, RAS, and p53 have been well postulated.⁴ However, clinically applicable biomarkers that reliably predict clinical outcome in individual CRC cases still are scarce. By using whole-genome array CGH in this study, we successfully identified novel chromosomal aberrations and a putative tumor-suppressor gene in a recurrently deleted

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The data presented here indicate that combining CMA and NGS yields more actionable information about relevant changes in the tumor genome and may better guide treatment decisions than either technology alone. The largest exome sequencing study of lung and colon tumor genomes to date was published by the Cancer Genome Atlas (36,37). Consistent with this and numerous other studies (38–40), most of the significantly recurrent actionable genomic alterations detected by both DNA sequencing and CMA in the colon cohort were observed at known cancer-related genes, such as APC, TP53, KRAS, PIK3CA, FBXW7, SMAD4, APC, SMARCB1, and PTEN.
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: Supported by the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (0405-BC02-0604-0004).

¹: M.-Y.K. and S.-H.Y. contributed equally to this paper.

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Microarray and other new technologyRecurrent Genomic Alterations With Impact on Survival in Colorectal Cancer Identified by Genome-Wide Array Comparative Genomic Hybridization

Section snippets

Study Materials

General Characteristics of Study Subjects and Genomic Alterations in 59 CRCs

Discussion

Semin Cancer Biol

Methods

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Hum Pathol

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Cancer Genet Cytogenet

Exp Mol Pathol

Blood

Clin Colorectal Cancer

Gastroenterology

Global cancer statistics, 2002

CA Cancer J Clin

Cause of death due to malignancy in 2004

Korean Statistical Information System

Nationwide Cancer Incidence in Korea, 1999-2001; first result using the National Cancer Incidence Database

Cancer Res Treat

Current status and future clinical applications of array based comparative genomic hybridization

Genomics Informatics

High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays

Nat Genet

DNA microarrays for comparative genomic hybridization based on DOP-PCR amplification of BAC and PAC clones

Genes Chromosomes Cancer

Genome-wide screening of genomic alterations and their clinicopathologic implications in non-small cell lung cancers

Clin Cancer Res

A whole-genome mouse BAC microarray with 1-Mb resolution for analysis of DNA copy number changes by array comparative genomic hybridization

Genome Res

ArrayCyGHt: a web application for analysis and visualization of array-CGH data

Bioinformatics

Reduced expression of CAMTA1 correlates with adverse outcome in neuroblastoma patients

Clin Cancer Res

Allelic losses at 1p36 and 19q13 in gliomas: correlation with histologic classification, definition of a 150-kb minimal deleted region on 1p36, and evaluation of CAMTA1 as a candidate tumor suppressor gene

Clin Cancer Res

Microarray and other new technology
Recurrent Genomic Alterations With Impact on Survival in Colorectal Cancer Identified by Genome-Wide Array Comparative Genomic Hybridization