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Characterization of Genomic Alterations in Colorectal Liver Metastasis and Their Prognostic Value.

ABSTRACT: Colorectal liver metastases (CRLMs) are clinically heterogeneous lesions with poor prognosis. Genetic alterations play a crucial role in their progression. The traditional Fong clinical risk score (Fong-CRS) is commonly used for risk stratification and prognosis prediction. By identifying the genomic alterations of CRLMs, we aimed to develop a mutation-based gene-signature-based clinical score (mut-CS) system to improve clinical prognostication. Tumour tissues from 144 patients with CRLMs were analysed with next-generation sequencing (NGS). A mut-CS scoring system considering the unique mutation-based gene signature, primary site, and Fong-CRS was developed and could identify CRLM patients with poor prognosis. The mean time-dependent receiver operating characteristic curve AUC value of the mut-CS system was greater than that of previously established scoring measures (the Fong-CRS, the e-clinical score, the presence of concomitant RAS and TP53 mutations, and other clinical traits). Taking together, we identified a mutant signature that exhibits a strong prognostic effect for CRLMs. Traditional clinical scoring system characteristics were incorporated into the new mut-CS scoring system to help determine the appropriate treatment for CRLMs.

SUBMITTER: Bao X

PROVIDER: S-EPMC9289210 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Characterization of Genomic Alterations in Colorectal Liver Metastasis and Their Prognostic Value.

Bao Xuanwen X Wang Kun K Liu Ming M Li Bin B Wang Hongwei H Jin Kemin K Yan Xiaoluan X Zhang Hangyu H Bao Quan Q Xu Da D Wang Lijun L Liu Wei W Wang Yanyan Y Li Juan J Liu Lijuan L Fang Weijia W Xing Baocai B

Frontiers in cell and developmental biology 20220704

Colorectal liver metastases (CRLMs) are clinically heterogeneous lesions with poor prognosis. Genetic alterations play a crucial role in their progression. The traditional Fong clinical risk score (Fong-CRS) is commonly used for risk stratification and prognosis prediction. By identifying the genomic alterations of CRLMs, we aimed to develop a mutation-based gene-signature-based clinical score (mut-CS) system to improve clinical prognostication. Tumour tissues from 144 patients with CRLMs were a ...[more]

PMID: 35860598

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Project description:Circulating tumor cells (CTCs) are critical in the development of distant organ tumor metastasis, and are associated with advanced cancer stage and poor patient outcome. Here, we present the first genome-wide nucleotide-level characterization of CTCs. Our single-nucleotide polymorphism (SNP) analysis in patients with melanoma involved: 1) global comparative genomic analysis of CTCs and matched regional metastases, 2) identification of key genomic aberrations in CTCs, 3) verification of these target genes in aggressive distant tumor metastases, and 4) evidence of selective expression and functional consequence of CTC-associated genes in melanomas. We report 131 aberrant loci in CTCs that are potentially pro-metastatic, and show that such expression of a 5-marker gene panel (CSMD2, CNTNAP5, FLJ14051, ADAM6, TRPM2) in melanomas confers prognostic utility. Successful treatment of melanoma requires understanding of the metastatic process and identification of patients with tumors most likely to develop aggressive metastatic disease. Melanomas are heterogeneous, and CTCs have long been recognized as vehicles for cancer spread, representing particularly aggressive tumor clones that can evolve into successful clinical metastases. Elucidation of genomic aberrations in CTCs will aid in the development of prognostic biomarkers and therapeutic strategies to target CTCs to prevent or control distant cancer spread. This study provides the first detailed genomic confirmation of the close relation between CTCs and tumor metastases, and illustrates how CTCs can be utilized as a novel approach and rational source for identification of pro-metastatic genes in cancer research. Three individual patient cohorts were utilized in the study. CNV and LOH loci were evaluated initially in metastatic melanoma patients (n=13) in a discovery cohort. SNP loci that harbored CNV/LOH in CTCs were then separately verified for: (a) presence in distant organ metastasis (AJCC Stage IV melanoma) (n=27), and (b) relevance to prognosis in regional melanoma metastasis (AJCC Stage III melanoma) (n=35). The first discovery patient cohort group was utilized for capture of CTCs, and consisted of peripheral blood mononuclear cell (PBMC) and tumor specimens from metastatic melanoma patients (n=13). CTC-related loci were verified in a second cohort of patients with Stage IV distant organ metastases (n=27), including 15 brain, 4 lung, and 8 gastrointestinal (bowel, liver) metastases. The third patient cohort consisted of early passage (<12) established melanoma cell lines derived from 35 regional melanoma metastases (Stage III) for evaluation of the prognostic utility of the CTC-associated aberrant loci.

Project description:UnlabelledIntegrins are cell surface adhesion molecules (CAM) that regulate via intercellular and cell-matrix signaling various cellular processes including wound healing, cell differentiation, division, growth, migration and metastatic dissemination. Although a correlation between carcinogenesis and changes in integrin expression, especially β1 integrin, has been reported, its role in colorectal liver metastases remains unclear. This study aimed to evaluate the expression of β1 integrin in colorectal liver metastases and to correlate the pattern of expression with clinicopathological features and to investigate the putative role of β1 integrin expression on survival of these patients.MethodsFormalin-fixed, paraffin-embedded (FFPE) tumor samples of 81 patients who were operated because of colorectal liver metastases without any neoadjuvant therapy were obtained and stained with hematoxylin and eosin (H & E). An immunohistochemical examination was performed using Dako, Peroxidase/DAB kit and a primary monoclonal β1 integrin (CD29, fibronectin receptor subunit beta; ab3167, Abcam plc). β1 integrin expression was evaluated according to the immunoreactive score of Remmele and Stegner and was related with clinicopathological features of prognostic significance and with disease-free and overall survival as well. Statistical analysis was performed using SPSS version 21.0.Resultsβ1 integrin was overexpressed in tumor cells in 37 (48%) patients and in stromal cell in 27 (33%) patients. The β1 expression was not statistically correlated with clinicopathological features of the primary tumors but it was statistically correlated (p=0.03) with the histological grading of liver metastases. Kaplan-Meier survival analysis showed that there is a tendency but no statistically significant correlation in disease-free and overall survival.ConclusionConsidering that expression of β1 integrin in colorectal liver metastases remains controversial, specially its relation with survival of patients, we showed that the β1 expression represents a reliable prognostic factor regarding the grading of liver metastases of CRC and our findings imply that β1 integrin expression profiles may have further potential in identifying the stage of colorectal liver metastases and being a marker of prognosis in these patients.

Dataset Information

Characterization of Genomic Alterations in Colorectal Liver Metastasis and Their Prognostic Value.

Publications

Characterization of Genomic Alterations in Colorectal Liver Metastasis and Their Prognostic Value.

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