Analysis of Circulating Tumor DNA in Synchronous Metastatic Colorectal Cancer at Diagnosis Predicts Overall Patient Survival

Author:

Sayagués José María12ORCID,Montero Juan Carlos12ORCID,Jiménez-Pérez Andrea12,del Carmen Sofía3,Rodríguez Marta12ORCID,Vidal Tocino Rosario4ORCID,Montero Enrique5,Sanz Julia6,Abad Mar12

Affiliation:

1. Department of Pathology and IBSAL, University Hospital of Salamanca, University of Salamanca, 37007 Salamanca, Spain

2. Biomedical Research Networking Centers-Oncology (CIBERONC), 28029 Madrid, Spain

3. Department of Pathology, University Hospital of Marqués de Valdecilla, 39008 Santander, Spain

4. Department of Oncology and IBSAL, University Hospital of Salamanca, 37007 Salamanca, Spain

5. Department of Pathology, University Hospital of Zamora, 49071 Zamora, Spain

6. Department of Pathology, Puerto Real University Hospital, 11510 Cadiz, Spain

Abstract

Sporadic colorectal cancer (sCRC) initially presents as metastatic tumors in 25–30% of patients. The 5-year overall survival (OS) in patients with metastatic sCRC is 50%, falling to 10% in patients presenting with synchronous metastatic disease (stage IV). In this study, we systematically analyzed the mutations of RAS, PIK3CA and BRAF genes in circulating tumor DNA (ctDNA) and tumoral tissue DNA (ttDNA) from 51 synchronous metastatic colorectal carcinoma (SMCC) patients by real-time PCR, and their relationship with the clinical, biological and histological features of disease at diagnosis. The highest frequency of mutations detected was in the KRAS gene, in tumor biopsies and plasma samples, followed by mutations of the PIK3CA, NRAS and BRAF genes. Overall, plasma systematically contained those genetic abnormalities observed in the tumor biopsy sample from the same subject, the largest discrepancies detected between the tumor biopsy and plasma from the same patient being for mutations in the KRAS and PIK3CA genes, with concordances of genotyping results between ttDNA and ctDNA at diagnosis of 75% and 84%, respectively. Of the 51 SMCC patients in the study, 25 (49%) showed mutations in at least 1 of the 4 genes analyzed in patient plasma. From the prognostic point of view, the presence and number of the most common mutations in the RAS, PIK3CA and BRAF genes in plasma from SMCC patients are independent prognostic factors for OS. Determination of the mutational status of ctDNA in SMCC could be a key tool for the clinical management of patients.

Funder

Gerencia Regional de Salud de Castilla y León, Valladolid, Spain

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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