Dataset Information

High Intra- and Inter-Tumoral Heterogeneity of RAS Mutations in Colorectal Cancer.

ABSTRACT: Approximately 30% of patients with wild type RAS metastatic colorectal cancer are non-responders to anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs), possibly due to undetected tumoral subclones harboring RAS mutations. The aim of this study was to analyze the distribution of RAS mutations in different areas of the primary tumor, metastatic lymph nodes and distant metastasis. A retrospective cohort of 18 patients with a colorectal cancer (CRC) was included in the study. Multiregion analysis was performed in 60 spatially separated tumor areas according to the pathological tumor node metastasis (pTNM) staging and KRAS, NRAS and BRAF mutations were tested using pyrosequencing. In primary tumors, intra-tumoral heterogeneity for RAS mutation was found in 33% of cases. Inter-tumoral heterogeneity for RAS mutation between primary tumors and metastatic lymph nodes or distant metastasis was found in 36% of cases. Moreover, 28% of tumors had multiple RAS mutated subclones in the same tumor. A high proportion of CRCs presented intra- and/or inter-tumoral heterogeneity, which has relevant clinical implications for anti-EGFR mAbs prescription. These results suggest the need for multiple RAS testing in different parts of the same tumor and/or more sensitive techniques.

SUBMITTER: Jeantet M

PROVIDER: S-EPMC5187815 | biostudies-other | 2016 Dec

REPOSITORIES: biostudies-other

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High Intra- and Inter-Tumoral Heterogeneity of RAS Mutations in Colorectal Cancer.

Jeantet Marion M Tougeron David D Tachon Gaelle G Cortes Ulrich U Archambaut Céline C Fromont Gaelle G Karayan-Tapon Lucie L

International journal of molecular sciences 20161201 12

Approximately 30% of patients with wild type RAS metastatic colorectal cancer are non-responders to anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs), possibly due to undetected tumoral subclones harboring RAS mutations. The aim of this study was to analyze the distribution of RAS mutations in different areas of the primary tumor, metastatic lymph nodes and distant metastasis. A retrospective cohort of 18 patients with a colorectal cancer (CRC) was ...[more]

PMID: 27916952

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Project description:Colorectal cancer (CRC) is one of the major causes of cancer-related death worldwide, for which diagnosis and prognosis are still inadequate mainly due to local recurrence and metastasis, although medical and surgical treatment in cancer therapy advanced. Diagnosis is frequently late, the high capacity of CRC to infiltrate and develop metastasis has the consequence that 40% of patients with CRC have metastasis in liver already at the time of diagnosis. The prognosis of CRC is closely related to the stage, but classification of patients is affected by a great variability in response to therapy and clinical outcome. The localization of the tumor determines a huge inter-tumoral heterogeneity and the intra-tumoral heterogeneity connected to the tumor microenvironment increases the complexity. The heterogeneity typical of CRC is also associated to the several oncogenic signaling pathways, among them the glucose-related pathways, indeed, the glucose metabolic reprogramming of cancer cells appears to be implicated in the malignant progression of CRC. This metabolic alteration seems to be associated to the epithelial-mesenchymal transition (EMT), which is considered the main event promoting the invasion and migration of CRC cells. However, the comprehensive understanding of the molecular mechanisms associated to EMT in CRC is still a challenge and despite decades of research, the process of tumor dissemination is insufficiently understood. Therefore, it is necessary to identify novel biomarkers associated with the prevention, diagnosis and treatment of CRC, as well as potential therapeutic targets. In this context, we performed a large-scale shotgun proteomic investigation on CRC with the aim of discover novel potential protein hallmarks able to distinguish with high specificity and sensitivity tumoral tissue from the health one, and to classify the superficial and the internal deep tumoral tissues. The EMT process is driven by the deep tumoral cells in CRC, therefore, to find significant differences at proteomic levels with respect to the peripheric tumoral tissue and to the healthy mucosa, and to identify specific classifying factors can be useful to individuate potential biomarkers of CRC invasiveness and potential therapy targets. Moreover, the functional enrichment analysis of proteomic data can provide information on biological processes implicated and associated to the variations of the protein profiles, and thus, help to understand the molecular mechanism associated to the CRC progression and malignance. Our approaches coupling high-throughput proteomic strategy with highly accurate statistical and enrichments analysis highlighted not only confirmation on potential biomarkers already proposed in other studies but also novel biomarkers able to distinguish with high sensitivity and specificity the deep tumor from the superficial one and to the healthy mucosa. Our investigation suggested a strong contribution of proteins implicated in metabolic pathways as catalytic and regulatory activities, some of them with high classifying power and potentially useful as biomarker and therapeutic target.

Dataset Information

High Intra- and Inter-Tumoral Heterogeneity of RAS Mutations in Colorectal Cancer.

Publications

High Intra- and Inter-Tumoral Heterogeneity of RAS Mutations in Colorectal Cancer.

Similar Datasets

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