title: Mutation patterns in small cell and non-small cell lung cancer patients suggest a different level of heterogeneity between primary and metastatic tumors.
abstract: Several studies have shown heterogeneity in lung cancer, with parallel existence of multiple subclones characterized by their own specific mutational landscape. The extent to which minor clones become dominant in distinct metastasis is not clear. The aim of our study was to gain insight in the evolution pattern of lung cancer by investigating genomic heterogeneity between primary tumor and its distant metastases. Whole exome sequencing (WES) was performed on 24 tumor and five normal samples of two small cell lung carcinoma (SCLC) and three non-SCLC (NSCLC) patients. Validation of somatic variants in these 24 and screening of 33 additional samples was done by single primer enrichment technology. For each of the three NSCLC patients, about half of the mutations were shared between all tumor samples, whereas for SCLC patients, this percentage was around 95. Independent validation of the non-ubiquitous mutations confirmed the WES data for the vast majority of the variants. Phylogenetic trees indicated more distance between the tumor samples of the NSCLC patients as compared to the SCLC patients. Analysis of 30 independent DNA samples of 16 biopsies used for WES revealed a low degree of intra-tumor heterogeneity of the selected sets of mutations. In the primary tumors of all five patients, variable percentages (19-67%) of the seemingly metastases-specific mutations were present albeit at low read frequencies. Patients with advanced NSCLC have a high percentage of non-ubiquitous mutations indicative of branched evolution. In contrast, the low degree of heterogeneity in SCLC suggests a parallel and linear model of evolution.
authors.affiliation: Department of Pathology and Medical Biology.
authors.forename: Ali
authors.initials: A
authors.lastname: Saber
authors.affiliation: Department of Pulmonary Diseases and.
authors.forename: T Jeroen N
authors.initials: TJN
authors.lastname: Hiltermann
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, 9700 RB Groningen, The Netherlands.
authors.forename: Klaas
authors.initials: K
authors.lastname: Kok
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, 9700 RB Groningen, The Netherlands.
authors.forename: M Martijn
authors.initials: MM
authors.lastname: Terpstra
authors.affiliation: Department of Genetics, University of Groningen, University Medical Centre Groningen, 9700 RB Groningen, The Netherlands.
authors.forename: Kim
authors.initials: K
authors.lastname: de Lange
authors.affiliation: Department of Pathology and Medical Biology.
authors.forename: Wim
authors.initials: W
authors.lastname: Timens
authors.affiliation: Department of Pulmonary Diseases and.
authors.forename: Harry J M
authors.initials: HJM
authors.lastname: Groen
authors.affiliation: Department of Pathology and Medical Biology.
authors.forename: Anke
authors.initials: A
authors.lastname: van den Berg
mesh_terms: D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D019143:Evolution, Molecular; D059472:Exome / Q000235:genetics; D005260:Female; D018740:Genetic Heterogeneity; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D009367:Neoplasm Staging; D010802:Phylogeny; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000473:pathology