A molecular signature for the prediction of recurrence in colorectal cancer

Molecular Cancer, Feb 2015

Background Several clinical and pathological factors have an impact on the prognosis of colorectal cancer (CRC), but they are not yet adequate for risk assessment. We aimed to identify a molecular signature that can reliably identify CRC patients at high risk for recurrence. Results Two hundred eighty-one CRC samples (stage II/III) were included in this study. A two-step gene expression profiling study was conducted. First, gene expression measurements from 81 fresh frozen CRC samples were obtained using Affymetrix Human Genome U133 Plus 2.0 Arrays. Second, a focused gene expression assay, including prognostic genes and genes of interest from literature reviews, was performed using 200 fresh frozen samples and a Taqman low-density array (TLDA) analysis. An optimal 31-gene expression classifier for the prediction of recurrence among patients with stage II/III CRC was developed using logistic regression analysis. This gene expression signature classified 58.5% of patients as low-risk and 41.5% as high-risk (Pā€‰<ā€‰0.001). The signature was the strongest independent prognostic factor in the multivariate analysis. The five-year relapse-free survival (RFS) rates for the low-risk patients and the high-risk patients were 88.5% and 41.3% (Pā€‰<ā€‰0.001), respectively. Conclusion We identified a 31-gene expression signature that is closely associated with the clinical outcome of stage II/III CRC patients.

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A molecular signature for the prediction of recurrence in colorectal cancer

Lisha Wang 0 1 Xiaohan Shen 0 1 Zhimin Wang Xiuying Xiao Ping Wei 0 1 Qifeng Wang 0 1 Fei Ren 0 1 Yiqin Wang 0 1 Zebing Liu 0 1 Weiqi Sheng 0 1 Wei Huang Xiaoyan Zhou 0 1 Xiang Du 0 1 0 Department of Oncology, Shanghai Medical College, Fudan University , Shanghai 200032 , China 1 Department of Pathology, Fudan University Shanghai Cancer Center , Shanghai 200032 , China Background: Several clinical and pathological factors have an impact on the prognosis of colorectal cancer (CRC), but they are not yet adequate for risk assessment. We aimed to identify a molecular signature that can reliably identify CRC patients at high risk for recurrence. Results: Two hundred eighty-one CRC samples (stage II/III) were included in this study. A two-step gene expression profiling study was conducted. First, gene expression measurements from 81 fresh frozen CRC samples were obtained using Affymetrix Human Genome U133 Plus 2.0 Arrays. Second, a focused gene expression assay, including prognostic genes and genes of interest from literature reviews, was performed using 200 fresh frozen samples and a Taqman low-density array (TLDA) analysis. An optimal 31-gene expression classifier for the prediction of recurrence among patients with stage II/III CRC was developed using logistic regression analysis. This gene expression signature classified 58.5% of patients as low-risk and 41.5% as high-risk (P < 0.001). The signature was the strongest independent prognostic factor in the multivariate analysis. The five-year relapse-free survival (RFS) rates for the low-risk patients and the high-risk patients were 88.5% and 41.3% (P < 0.001), respectively. Conclusion: We identified a 31-gene expression signature that is closely associated with the clinical outcome of stage II/III CRC patients. - Introduction Colorectal cancer (CRC) is the third most common type of cancer, with a worldwide annual incidence of over 1.2 million cases and a mortality rate of approximately 50% [1,2]. The growing awareness that CRC is a heterogeneous disease with respect to clinical behavior and prognosis translates into an urgent need for robust molecular subclassifiers in addition to the current parameters. To date, some clinical and pathologic features, such as intestinal perforation/obstruction, adjacent organ involvement (T4), high tumor grade, lymphatic/vascular invasion and inadequate sampling of lymph nodes, can identify a minority of CRC patients who are at a high risk of recurrence [3,4]. However, these prognostic factors are all relatively weak. To address this issue, the prognostic potential of molecular markers, including chromosome and microsatellite instability (MSI) and the mutation status of the KRAS or BRAF genes, has been systematically investigated in CRC [5-8]. Thus far, only KRAS mutation analysis has been used in clinical practice as a predictive marker of the effect of EGFR antibodies in metastatic disease [5,9]. Analyses of other known critical CRC molecular markers are not currently recommended for screening or for prognostic prediction because they require further validation. With the recent advent of microarray technology, risk assessment for CRC has been improved by the use of gene expression profiling. DNA microarray technology can measure thousands of mRNA transcripts at once and may be able to describe the complex biology of a tumor more accurately than single markers [10,11]. In the current study, we used gene expression analysis data from recurrent and non-recurrent patients with CRC to identify differentially expressed probes. To further validate gene expression, we selected 48 genes that could be assayed using a TaqMan low-density array (TLDA), a real time quantitative PCR (RT-qPCR) based technology, using fresh frozen CRC tissues. Patients and methods Patients and tumor samples Samples were prospectively collected between 2007 and 2009 at Fudan University Shanghai Cancer Center. The inclusion criteria were as follows: primary sporadic colorectal adenocarcinoma (excluding familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC)), 18 to 75 years of age, no preoperative chemotherapy and radiotherapy, and similar postoperative chemotherapy regimens. The patients were staged according to the American Joint Committee on Cancer/ International Union against Cancer (AJCC/UICC) TNM staging system- seventh edition (2010). Histologic grading (differentiation) was based on the WHO classification of tumors of the digestive system-fourth edition (2010). This study was approved by the Ethical Committee of our Cancer Center, and written informed consent was obtained from each patient. Microarray gene expression profiling Tumor tissues were taken from 81 patients with CRC, rapidly frozen in RNAlater, and stored at 80C until processing. All samples were visually inspected by two pathologists, who confirmed the presence of tumor cells (70%) in all samples. RNA was isolated using Trizol (Life Technologies, Car (...truncated)


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Lisha Wang, Xiaohan Shen, Zhimin Wang, Xiuying Xiao, Ping Wei, Qifeng Wang, Fei Ren, Yiqin Wang, Zebing Liu, Weiqi Sheng, Wei Huang, Xiaoyan Zhou, Xiang Du. A molecular signature for the prediction of recurrence in colorectal cancer, Molecular Cancer, 2015, pp. 22, 14, DOI: 10.1186/s12943-015-0296-2