Abstract
Squamous cell carcinoma (SCC) of the lung kills over 350,000 people annually worldwide, and is the main lung cancer histotype with no targeted treatments. High-coverage whole-genome sequencing of the other main subtypes, small-cell and adenocarcinoma, gave insights into carcinogenic mechanisms and disease etiology. The genomic complexity within the lung SCC subtype, as revealed by The Cancer Genome Atlas, means this subtype is likely to benefit from a more integrated approach in which the transcriptional consequences of somatic mutations are simultaneously inspected. Here we present such an approach: the integrated analysis of deep sequencing data from both the whole genome and whole transcriptome (coding and non-coding) of LUDLU-1, a SCC lung cell line. Our results show that LUDLU-1 lacks the mutational signature that has been previously associated with tobacco exposure in other lung cancer subtypes, and suggests that DNA-repair efficiency is adversely affected; LUDLU-1 contains somatic mutations in TP53 and BRCA2, allelic imbalance in the expression of two cancer-associated BRCA1 germline polymorphisms and reduced transcription of a potentially endogenous PARP2 inhibitor. Functional assays were performed and compared with a control lung cancer cell line. LUDLU-1 did not exhibit radiosensitisation or an increase in sensitivity to PARP inhibitors. However, LUDLU-1 did exhibit small but significant differences with respect to cisplatin sensitivity. Our research shows how integrated analyses of high-throughput data can generate hypotheses to be tested in the lab.
Highlights
Lung cancer kills more people than colorectal, prostate and breast cancer combined [1]
We have previously catalogued the transcriptional consequences of somatic structural variants in this cell line but here we focus on point mutations, aiming to see whether the mutational signature would give insight into disease etiology or carcinogenic mechanism, as it has for other cancer subtypes [6,9,10]
Tobacco smoke is the main risk factor associated with lung cancer, accounting for 70–75% of worldwide incidence [1]
Summary
Lung cancer kills more people than colorectal, prostate and breast cancer combined [1]. SCC remains the most common lung cancer histotype for which no genomically targeted therapy currently exists [5] The lack of such therapy prompted inclusion of the lung SCC subtype in The Cancer Genome Atlas (TCGA) project, an international collaboration aimed at cataloguing cancer-driving genetic variation within tumours using multiple high-throughput approaches. One such approach was Next-Generation Sequencing (NGS), which has been used to gain insights into disease development and progression in several types of cancer, including both lung adenocarcinoma and small-cell lung cancer (SCLC) [6,7]. This type of in-depth characterisation of a given tumour can result in new hypotheses that can be tested using functional assays
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