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Identification and Validation of a Blood-Based 18-Gene Expression Signature in Colorectal Cancer

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Identification and Validation of a Blood-Based 18-Gene Expression Signature in Colorectal Cancer Published OnlineFirst March 27, 2013; DOI: 10.1158/1078-0432.CCR-12-3851 Clinical Cancer Imaging, Diagnosis, Prognosis Research Identification and Validation of a Blood-Based 18-Gene Expression Signature in Colorectal Cancer Ye Xu1,4, Qinghua Xu1,6,7, Li Yang1,4, Xun Ye6,7, Fang Liu6,7, Fei Wu6,7, Shujuan Ni1,2,3,5, Cong Tan1,2,3,5, Guoxiang Cai1,4, Xia Meng6,7, Sanjun Cai1,4, and Xiang Du1,2,3,5 Abstract Purpose: The early detection of colorectal cancer (CRC) is crucial for successful treatment and patient survival. However, compliance with current screening methods remains poor. This study aimed to identify an accurate blood-based gene expression signature for CRC detection. Experimental Design: Gene expression in peripheral blood samples from 216 patients with CRC tumors and 187 controls was investigated in the study.Wefirstconductedamicroarrayanalysistoselect candidate genes that were significantly differentially expressed between patients with cancer and con- trols. A quantitative reverse transcription PCR assay was then used to evaluate the expression of selected genes. A gene expression signature was identified using a training set (n ¼ 200) and then validated using an independent test set (n ¼ 160). Results: We identified an 18-gene signature that discriminated the patients with CRC from controls with 92% accuracy, 91% sensitivity, and 92% specificity. The signature performance was further validated in the independent test set with 86% accuracy, 84% sensitivity, and 88% specificity. The area under the receiver operating characteristics curve was 0.94. The signature was shown to be enriched in genes related to immune functions. Conclusions: This study identified an 18-gene signature that accurately discriminated patients with CRC from controls in peripheral blood samples. Our results prompt the further development of blood- based gene expression biomarkers for the diagnosis and early detection of CRC. Clin Cancer Res; 1–11. Ó2013 AACR. Introduction (FOBT), stool DNA tests, flexible sigmoidoscopy, computed Colorectal cancer (CRC) is the third most common tomographic (CT) colonography, and colonoscopy. Differ- malignancy and the fourth most common cause of can- ent screening strategies are preferred in various countries. cer-related mortality worldwide (1). In 2008, more than 1 However, compliance with current CRC screening recom- million cases were newly diagnosed and more than 600,000 mendations remains poor. The most reliable screening tool, people died from the disease (2). Given its slow develop- colonoscopy, is invasive, costly, and conducted infrequent- ment from removable precancerous lesions and curable ly. In contrast, the currently most widely used noninvasive early stages, screening for CRC has the potential to reduce screening option, FOBT, has important limitations, includ- both the incidence and mortality of the disease (3). The ing inconvenience and low sensitivity. available screening tools include fecal occult blood testing The discovery of novel biomarkers based on the analysis of blood samples has become a focus of current research. A novel blood biomarker may offer several practical advan- Authors' Affiliations: 1Department of Oncology, Shanghai Medical Col- lege; 2Institute of Biomedical Sciences; 3Institute of Pathology, Fudan tages compared with the currently used screening University; Departments of 4Colorectal Surgery and 5Pathology, Fudan approaches. First, in vitro blood tests are safe and minimally 6 University Shanghai Cancer Center; Fudan University Shanghai Cancer invasive. Second, no dietary restriction, colon cleansing, or Center—Institut Merieux Laboratory; and 7bioMerieux (Shanghai) Co., Ltd., Shanghai, China sedation is required. Third, the sample collection and processing procedures may be easier and more convenient. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Furthermore, there is no microflora that could degrade the biomarker or hamper the analysis. Thus, a sensitive and Y. Xu and Q. Xu contributed equally to this work. specific in vitro blood test that detects CRC in the currently Corresponding Authors: Xiang Du, Fudan University Shanghai Cancer noncompliant patient population will improve participa- Center, 270 Dong'an Road, Shanghai 200032, China. Phone: 86-21- 64175590-8911; Fax: 86-21-64174774; E-mail: [email protected]; tion in screening, increase the accuracy of detection, and and Sanjun Cai. Phone: 86-21-6417590-1108; Fax: 86-21-64035387; therefore save lives. E-mail: [email protected] Several studies have shown that molecular biomarkers in doi: 10.1158/1078-0432.CCR-12-3851 the peripheral blood can be used to develop in vitro tests for Ó2013 American Association for Cancer Research. the detection of CRC. The DNA methylation biomarker www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst March 27, 2013; DOI: 10.1158/1078-0432.CCR-12-3851 Xu et al. toms of inflammatory bowel diseases, polyps, or CRC, Translational Relevance which had been confirmed by colonoscopy, were enrolled Colorectal cancer (CRC) is the leading cause of cancer- from a population-based screening program. Figure 1 related deaths worldwide. The early detection of CRC is depicts 3 different phases of the study design and Table crucial for successful treatment and patient survival. 1 summarizes the clinical characteristics of the samples in However, compliance with current screening methods the study. remains poor and there is a clear need for an accurate in In the discovery set, we analyzed the whole-blood gene vitro blood test to increase participation in CRC screen- expression profiles of 100 patients with CRC and 100 ing. This study shows that the gene expression profiles of controls using GeneChip U133plus2 microarrays (Affy- peripheral blood samples can be used to distinguish metrix). There were no significant differences in the between patients with CRC and controls. An 18-gene distribution of age or gender between the CRC and signature was identified and validated as highly sensitive control groups. The CRC group included 41 patients with and specific for detecting CRC in blood samples. These colon cancer and 59 with rectal cancer. Sixteen of the results open an avenue for the further development of patients with cancer were stage I, 36 were stage II, 24 were blood-based gene expression biomarkers for the diag- stageIII,and24werestageIV.Thesignificanceanalysisof nosis and early detection of CRC. microarray (SAM) method was used to identify genes that were differentially expressed between the CRC and con- trol groups (10). The list of genes was further refined by expression signal intensity, fold change, biologic anno- methylated Septin 9 (mSEPT9) previously showed a sensi- tation, and probe set grade. Finally, 52 unique genes were tivity of 70% and a specificity of 90% for discriminating selected for further testing by quantitative reverse tran- patients with CRC from controls (4, 5). Recently, the scription PCR (qRT-PCR). performance of mSEPT9 was determined in a prospective The training set consisted of 100 patients with CRC and study of 7,940 average-risk individuals undergoing colo- 100 controls, including 71 patients with CRC and 86 con- noscopy for CRC screening. The sensitivity in the 45 patients trols that were also used in the discovery set to assess the with CRC was 67%, with a specificity of 88% (6). DNA correspondence between the microarray and qRT-PCR mea- microarray technology can quantify the expression of sev- surements. The remaining 43 samples from the discovery set eral thousand genes simultaneously and may be able to were not applicable for qRT-PCR experiments due to low capture the complex biology that underlies colorectal RNA concentrations and, thus, were replaced these with tumorigenesis and progression better than single gene new samples. The distributions of age and gender were markers. A number of studies have been published, using balanced between the CRC and control groups. The CRC DNA microarray technology to identify blood-based gene group included 51 patients with colon cancer and 49 with expression signatures for CRC detection. Han and collea- rectal cancer. Eleven of the patients with cancer were stage I, gues reported a 5-gene signature with 88% sensitivity and 40 were stage II, 22 were stage III, and 27 were stage IV. These 64% specificity (7). Marshall and colleagues recently pub- samples were used as the training set to identify the gene lished a 7-gene signature with a sensitivity of 72% and a expression signature for differentiation between the CRC specificity of 70% (8). Rosenthal and colleagues also group and the control group. reported a panel of 202 genes with 90% sensitivity and In the test set, we used an independent cohort of 87 88% specificity (9). patients with CRC and 73 controls. The CRC group included In this study, we tested the hypothesis that gene expression 27 patients with colon cancer and 60 with rectal cancer. profiling of peripheral blood cells could yield diagnostic Eleven of the patients with cancer were stage I, 31 were stage information in a cohort of Chinese patients. An 18-gene II, 31 were stage III, and 13 were stage IV. The TNM variables signature was identified and validated as highly sensitive and of one patient were not available. The fully specified gene specific for detecting CRC in blood samples. expression signature from the training set was applied
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