title: The transcriptional consequences of somatic amplifications, deletions, and rearrangements in a human lung squamous cell carcinoma.
abstract: Lung cancer causes more deaths, worldwide, than any other cancer. Several histologic subtypes exist. Currently, there is a dearth of targeted therapies for treating one of the main subtypes: squamous cell carcinoma (SCC). As for many cancers, lung SCC karyotypes are often highly anomalous owing to large somatic structural variants, some of which are seen repeatedly in lung SCC, indicating a potential causal association for genes therein. We chose to characterize a lung SCC genome to unprecedented detail and integrate our findings with the concurrently characterized transcriptome. We aimed to ascertain how somatic structural changes affected gene expression within the cell in ways that could confer a pathogenic phenotype. We sequenced the genomes of a lung SCC cell line (LUDLU-1) and its matched lymphocyte cell line (AGLCL) to more than 50x coverage. We also sequenced the transcriptomes of LUDLU-1 and a normal bronchial epithelium cell line (LIMM-NBE1), resulting in more than 600 million aligned reads per sample, including both coding and non-coding RNA (ncRNA), in a strand-directional manner. We also captured small RNA (<30 bp). We discovered significant, but weak, correlations between copy number and expression for protein-coding genes, antisense transcripts, long intergenic ncRNA, and microRNA (miRNA). We found that miRNA undergo the largest change in overall expression pattern between the normal bronchial epithelium and the tumor cell line. We found evidence of transcription across the novel genomic sequence created from six somatic structural variants. For each part of our integrated analysis, we highlight candidate genes that have undergone the largest expression changes.
authors.affiliation: Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom.
authors.forename: Lucy F
authors.initials: LF
authors.lastname: Stead
authors.forename: Stefano
authors.initials: S
authors.lastname: Berri
authors.forename: Henry M
authors.initials: HM
authors.lastname: Wood
authors.forename: Philip
authors.initials: P
authors.lastname: Egan
authors.forename: Caroline
authors.initials: C
authors.lastname: Conway
authors.forename: Catherine
authors.initials: C
authors.lastname: Daly
authors.forename: Kostas
authors.initials: K
authors.lastname: Papagiannopoulos
authors.forename: Pamela
authors.initials: P
authors.lastname: Rabbitts
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations; D005784:Gene Amplification; D017353:Gene Deletion; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D055106:Genome-Wide Association Study; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D011003:Ploidies; D014158:Transcription, Genetic