Abstract 3810: Persistence of smoking signature 4 in the non-small cell lung cancer genome
Authors: Nicola Pantelis A. , Rafee Shereen , Burghel George , Wallace Andrew , Schlecht Helene , Baker Eleanor , Baker Katie , Priest Lynsey , Carter Mathew , Moghadam Sharzad , Rogan Jane , Bristow Robert G. , Newman William , Blackhall Fiona H. , Lindsay Colin 
Published: September 2020

Abstract
Introduction Lung cancer is the most common cause of cancer-related death. Carcinogenic and endogenous processes driving somatic mutation acquisition in cancer can be extracted and defined as mutational signatures using whole genome sequencing (WGS). Tobacco smoke is the main aetiological cause of lung cancer, with mutational signature 4 representing the characteristic C&gt;A transversions produced by smoking. Whilst smoking cessation has been shown to reduce lung cancer risk in epidemiological studies, there has been little exploration into the persistence of smoking 4 in NSCLC genomes after a patient has quit smoking. We investigated the extent and persistence of signature 4 in NSCLC genomes of current, ex- and never-smokers, correlating in particular with clinical history of smoking cessation.
Methods 132 NSCLC samples were resected from 131 patients in Greater Manchester. These samples were submitted to the 100,000 Genomes Project (Genomics England). WGS was performed on tumour specimens and matched blood samples. Data generated was processed by a standard pipeline devised by Genomics England. Tumour mutational burden (TMB), mutational signatures and copy number variation (CNV) were obtained. Clinical data collected included: smoking status, date of diagnosis, TNM stage, date of relapse and date of death (where relevant). Fisher's exact tests and Kruskal-Wallis tests were used for statistical comparisons, with Kaplan-Meier plots for survival.
Results Signature 4 was associated with a smoking history in 102/119 (85.7%) NSCLCs with a detailed smoking history available. In 17/119 (14.3%) patients with a smoking history but no signature 4 NSCLC, 15/17 (88.2%) patients quit smoking a median of 22 years ago (range 0.006 - 45 years). 6/7 (85.7%) never-smoker NSCLCs were non-signature 4 NSCLCs. 60/75 (80%) ex-smokers had sufficient smoking data to assess signature 4 persistence. Signature 4 endured in the lung tissue prior to tumour diagnosis for a median of 180 months (15 years) (range 1 - 600 months). There was no association between the time of smoking cessation and the time to NSCLC diagnosis (R2=0.0009, p=0.82). Non-signature 4 NSCLCs had a more diverse signature profile (signature 4: mean 4.36, 95% CI 4.13-4.58; non-signature 4: mean 5.52, 95% CI 4.95-6.09; p=&lt;0.0001) with a lower TMB (signature 4: median 9.76/Mb, 95% CI 9.8-12.7; non-signature 4: median 2.02/Mb, 95% CI 1.3-9.3; p=&lt;0.0001). There was no difference in relapse-free survival between signature 4 and non-signature 4 patients with early stage disease (signature 4: median 456 days, HR 0.999, 95% CI 0.419-2.385; non-signature 4: median 319 days, HR 1.001, 95% CI 0.417-2.399).
Conclusion The genomic alterations introduced by smoking persist for many years after smoking cessation. NSCLCs arising from smoking carry a distinctive identity compared to those from never-smokers, with higher TMBs driven primarily by signature 4. Whilst survival analysis is limited in this cohort, the pervasive contributions from smoking suggest that lung cancer screening programmes should include all patients with a smoking history.
Citation Format: Pantelis A. Nicola, Shereen Rafee, George Burghel, Andrew Wallace, Helene Schlecht, Eleanor Baker, Katie Baker, Lynsey Priest, Mathew Carter, Sharzad Moghadam, Jane Rogan, Robert G. Bristow, William Newman, Fiona H. Blackhall, Colin Lindsay. Persistence of smoking signature 4 in the non-small cell lung cancer genome [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3810.