title: High Intra- and Inter-Tumoral Heterogeneity of RAS Mutations in Colorectal Cancer.
abstract: Approximately 30% of patients with wild typeRASmetastatic colorectal cancer are non-responders to anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs), possibly due to undetected tumoral subclones harboringRASmutations. The aim of this study was to analyze the distribution ofRASmutations 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 andKRAS,NRASandBRAFmutations were tested using pyrosequencing. In primary tumors, intra-tumoral heterogeneity forRASmutation was found in 33% of cases. Inter-tumoral heterogeneity forRASmutation between primary tumors and metastatic lymph nodes or distant metastasis was found in 36% of cases. Moreover, 28% of tumors had multipleRASmutated 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 multipleRAStesting in different parts of the same tumor and/or more sensitive techniques.
authors.affiliation: Faculté de Médecine Pharmacie, Université de Poitiers, 86021 Poitiers, France. marion_doc@hotmail.fr.|Département de Cancérologie Biologique, Centre Hospitalo-Universitaire de Poitiers, 86021 Poitiers, France. marion_doc@hotmail.fr.|Département d'anatomopathologie, Centre Hospitalo-Universitaire de Poitiers, 86021 Poitiers, France. marion_doc@hotmail.fr.
authors.forename: Marion
authors.initials: M
authors.lastname: Jeantet
authors.affiliation: Faculté de Médecine Pharmacie, Université de Poitiers, 86021 Poitiers, France. david.tougeron@chu-poitiers.fr.|Département de Gastroentérologie, Centre Hospitalo-Universitaire de Poitiers, 86021 Poitiers, France. david.tougeron@chu-poitiers.fr.|Laboratoire Inflammation, Tissus Epithéliaux et Cytokines, EA 4331, Université de Poitiers, 86021 Poitiers, France. david.tougeron@chu-poitiers.fr.
authors.forename: David
authors.initials: D
authors.lastname: Tougeron
authors.affiliation: Faculté de Médecine Pharmacie, Université de Poitiers, 86021 Poitiers, France. gaelle.tachon@chu-poitiers.fr.|Département de Cancérologie Biologique, Centre Hospitalo-Universitaire de Poitiers, 86021 Poitiers, France. gaelle.tachon@chu-poitiers.fr.
authors.forename: Gaelle
authors.initials: G
authors.lastname: Tachon
authors.affiliation: Faculté de Médecine Pharmacie, Université de Poitiers, 86021 Poitiers, France. ulrich.cortes@chu-poitiers.fr.|Département de Cancérologie Biologique, Centre Hospitalo-Universitaire de Poitiers, 86021 Poitiers, France. ulrich.cortes@chu-poitiers.fr.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Cortes
authors.affiliation: Faculté de Médecine Pharmacie, Université de Poitiers, 86021 Poitiers, France. labonco@gmail.com.|Département de Cancérologie Biologique, Centre Hospitalo-Universitaire de Poitiers, 86021 Poitiers, France. labonco@gmail.com.
authors.forename: Céline
authors.initials: C
authors.lastname: Archambaut
authors.affiliation: Département d'anatomopathologie, Centre Hospitalo-Universitaire de Poitiers, 86021 Poitiers, France. Gaelle.fromont-hancard@univ-tours.fr.
authors.forename: Gaelle
authors.initials: G
authors.lastname: Fromont
authors.affiliation: Faculté de Médecine Pharmacie, Université de Poitiers, 86021 Poitiers, France. l.karayan-tapon@chu-poitiers.fr.|Département de Cancérologie Biologique, Centre Hospitalo-Universitaire de Poitiers, 86021 Poitiers, France. l.karayan-tapon@chu-poitiers.fr.|INSERM1084, Laboratoire de Neurosciences Expérimentales et Cliniques, Université de Poitiers, 86021 Poitiers, France. l.karayan-tapon@chu-poitiers.fr.
authors.forename: Lucie
authors.initials: L
authors.lastname: Karayan-Tapon
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000068818:Cetuximab / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D018740:Genetic Heterogeneity; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; C117307:KRAS protein, human; D008565:Membrane Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab
keywords: RAS mutation; colorectal cancer; inter-tumoral heterogeneity; intra-tumoral heterogeneity