title: Analysis of KRAS and BRAF genes mutation in the central nervous system metastases of non-small cell lung cancer.
abstract: KRAS mutations are associated with tumor resistance to EGFR TKIs (erlotinib, gefitinib) and to monoclonal antibody against EGFR (cetuximab). Targeted treatment of mutated RAS patients is still considered as a challenge. Inhibitors of c-Met (onartuzumab or tiwantinib) and MEK (selumetinib-a dual inhibitor of MEK1 and MEK2) signaling pathways showed activity in patients with mutations in KRAS that can became an effective approach in carriers of such disorders. BRAF mutation is very rare in patients with NSCLC, and its presence is associated with sensitivity of tumor cells to BRAF inhibitors (vemurafenib, dabrafenib). In the present study, the frequency and type of KRAS and BRAF mutation were assessed in 145 FFPE tissue samples from CNS metastases of NSCLC. In 30 patients, material from the primary tumor was simultaneously available. Real-time PCR technique with allele-specific molecular probe (KRAS/BRAF Mutation Analysis Kit, Entrogen, USA) was used for molecular tests. KRAS mutations were detected in 21.4 % of CNS metastatic lesions and in 23.3 % of corresponding primary tumors. Five mutations were identified both in primary and in metastatic lesions, while one mutation only in primary tumor and one mutation only in the metastatic tumor. Most of mutations were observed in codon 12 of KRAS; however, an individual patient had diagnosed a rare G13D and Q61R substitutions. KRAS mutations were significantly more frequent in adenocarcinoma patients and smokers. Additional analysis indicated one patient with rare coexistence of KRAS and DDR2 mutations. BRAF mutation was not detected in the examined materials. KRAS frequency appears to be similar in primary and CNS.
authors.affiliation: Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Jaczewskiego 8, 20-954, Lublin, Poland. marcin_nicos@interia.pl.|Postgraduate School of Molecular Medicine, Medical University of Warsaw, 02-091, Warsaw, Poland. marcin_nicos@interia.pl.
authors.forename: Marcin
authors.initials: M
authors.lastname: Nicoś
authors.affiliation: Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Jaczewskiego 8, 20-954, Lublin, Poland.
authors.forename: Paweł
authors.initials: P
authors.lastname: Krawczyk
authors.affiliation: Pathological Laboratory, Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, 20-954, Lublin, Poland.
authors.forename: Bożena
authors.initials: B
authors.lastname: Jarosz
authors.affiliation: Department of Thoracic Surgery, Medical University of Lublin, 20-954, Lublin, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Sawicki
authors.affiliation: Department of Pathomorphology, Medical University of Lublin, 20-954, Lublin, Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Szumiłło
authors.affiliation: Pathological Laboratory, Department of Neurosurgery and Pediatric Neurosurgery, Medical University of Lublin, 20-954, Lublin, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Trojanowski
authors.affiliation: Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, Jaczewskiego 8, 20-954, Lublin, Poland.
authors.forename: Janusz
authors.initials: J
authors.lastname: Milanowski
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000556:secondary*; D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000556:secondary*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D009362:Neoplasm Metastasis / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C117307:KRAS protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras)
keywords: BRAF mutations; Central nervous system metastases; KRAS mutations; NSCLC