Circulating cell-free DNA as a strong multimarker diagnostic, theranostic and prognostic tool for metastatic colorectal cancer patients management care


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Alain R Thierry1
1French Institute of Health and Medical Research (INSERM), Montpellier, France

Abstract

Circulating cell-free DNA (ccfDNA) analysis constitutes a hopeful approach to provide a non-invasive tumour molecular test for cancer patients. We studied tumour-derived ccfDNA by an original approach focusing on its size distribution. Our group was the first to demonstrate that tumour-derived ccfDNA was highly fragmented and mainly composed of <100 bp fragments by q-pcr and afm which is smaller than the observed size between 145 180 reported in literature. based upon this discovery, we designed intplex, an allele specific qpcr system targeting short sequences of dna specifically adapted for ccfdna analysis. with design our rigorous guidelines analysis, unprecedented results have been determined confirmed powerful biomedical potential analysis: validated detection KRAS/BRAF point mutation in 106 clinical samples from mCRC patients with 98% of specificity with tumour tissue analysis in a blinded multicenter clinical study. We showed the high diagnostic potential of ccfDNA concentration allowing discrimination between healthy subjects and cancer patients. Moreover, we revealed the prognostic significance of this analysis on a cohort of 106 mCRC patients. Intplex allows the determination of the mutation load which is the proportion of mutant ccfDNA in total ccfDNA reflecting the proportion of specific tumour ccfDNA in total ccfDNA. Finally, ccfDNA analysis made possible the detection of the emergence of RAS and BRAF mutations following anti-EGFR therapy in mCRC patients. The Intplex test can be adapted to all mutations, genes or cancers and enables rapid, highly sensitive, cost effective and repetitive analysis. Our technical approach offers the opportunity to detect quantitative and dynamic mutations and could constitute a non-invasive attractive tool potentially allowing diagnosis, prognosis, theranostics, therapeutic monitoring and follow-up of cancer patients expanding the scope of personalised cancer medicine.

Full authorship

Alain R Thierry1, Safia El Messaoudi1, Cynthia Sanchez1, Brice Pastor1, Caroline Mollevi2, Charles Theillet1, Scott Kopetz3, Muriel Mathonnet4, Denis Pezet5, and Marc Ychou2

1U896 INSERM, CRLC Montpellier IRCM-Institut Recherche en Cancérologie de Montpellier, 208 Rue des Apothicaires, 34298 Montpellier, France

 2Institut du Cancer de Montpellier, Department of Digestive Oncology, 208 Rue des Apothicaires, 34298 Montpellier, France

3Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas

 4Centre Hospitalier Universitaire, Department of Digestive Surgery, Clinical Investigational Center, CIC-P Inserm 0801, 2 Avenue Martin Luther-King, 87042 Limoges, France

5CHU Clermont Fd, Department of Digestive Surgery, 1 Place Lucie Aubrac 63003 Clermont Ferrand, France