K-ras gene mutational analysis supports a monoclonal origin of biphasic pleomorphic carcinoma of the lung

• DOI: 10.1038/modpathol.3800058
• Publication Date: 2004-02-27T18:08:03Z
• Authors: Giuseppe Pelosi; Aldo Scarpa; Michela Manzotti; Giulia Veronesi; Lorenzo Spaggiari; Filippo Fraggetta; Oscar Nappi; Elvira Benini; Felice Pasini; Davide Antonello; Antonio Iannucci; Patrick Maisonneuve; Giuseppe Viale
• Keywords: Adult; Male; Lung Neoplasms; DNA Mutational Analysis; Mutation, Missense; Adenocarcinoma; Polymerase Chain Reaction; 03 medical and health sciences; Clone Cells; DNA Mutational Analysis; Humans; Aged; Mutation, Missense; Vimentin; Polymorphism, Single-Stranded Conformational; DNA, Neoplasm; Genes, ras; Smoking; Polymerase Chain Reaction; Keratins; Lung Neoplasms; Adult; Carcinoma, Large Cell; Middle Aged; Adenocarcinoma; Carcinoma, Squamous Cell; Immunohistochemistry; Mutation; Carcinoma, Non-Small-Cell Lung; Male; Female; Survival Analysis; 0302 clinical medicine; Carcinoma, Non-Small-Cell Lung; Humans; Aged; DNA, Neoplasm; Middle Aged; Immunohistochemistry; Clone Cells; 3. Good health; Genes, ras; Mutation; Carcinoma, Squamous Cell; Carcinoma, Large Cell; Keratins; Female

We investigated 27 pleomorphic carcinomas of the lung for exon 1 K-ras gene mutations using polymerase chain reaction-single-strand conformation polymophism analysis and direct sequencing. All pleomorphic carcinomas were biphasic, that is, composed of an adeno-, squamous- or large-cell-carcinomatous component associated with a spindle- and/or giant-cell component. Of 27 cases, six (22%) showed K-ras codon 12 mutations, which is a figure higher than that previously reported on in pure sarcoma-like pleomorphic carcinomas. Five tumors displayed the same mutation in both the epithelial and the sarcomatoid components, whereas in one tumor the mutation was restricted to the epithelial component. All mutations occurred in smokers, and were transversions, including GGT (glycine) to TGT (cysteine) change in two cases, to GCT (alanine) in two and to GTT (valine) in two. No significant relationships were found between the occurrence and type of mutations and patients' survival or any other clinicopathological variable, suggesting that K-ras mutations are early events in the development of these tumors. Our results indicate that most, though not all, biphasic pleomorphic carcinomas of the lung are monoclonal in origin, and that cigarette smoking may have a causative role in the development of K-ras alterations in these tumors, as all mutations are transversions.