Lung Cancer In Never-smokers Research Articles

P4.04D.02 Lung Cancer in Never Smokers and Individuals with a Family History of Lung Cancer: Missed Opportunities for Screening

P4.04D.02 Lung Cancer in Never Smokers and Individuals with a Family History of Lung Cancer: Missed Opportunities for Screening

P4.07E.03 Real-World Data on Early Lung Cancer in Never-Smokers and Light Smokers-Prevalence, Family History, and Molecular Alterations

P4.07E.03 Real-World Data on Early Lung Cancer in Never-Smokers and Light Smokers-Prevalence, Family History, and Molecular Alterations

MA13.08 PM2.5 Exposure Impact on Never-Smoking Lung Cancer Patients

MA13.08 PM2.5 Exposure Impact on Never-Smoking Lung Cancer Patients

P1.03D.09 Single Cell RNA Sequencing and Functional Monocyte Stimulation Reveals Phenotypic Predispositions to Developing Lung Cancer in Never Smokers

P1.03D.09 Single Cell RNA Sequencing and Functional Monocyte Stimulation Reveals Phenotypic Predispositions to Developing Lung Cancer in Never Smokers

P1.01B.02 The Genomic Landscape of Lung Cancer in Never-Smokers from the Women's Health Initiative

P1.01B.02 The Genomic Landscape of Lung Cancer in Never-Smokers from the Women's Health Initiative

Factors Mediating Lung Cancer in Never Smokers Identified from Epidemiologic Analysis

Lung Cancer in Never-Smokers (LCINS) is one of the leading causes of cancer patient deaths in the United States. Unlike lung cancer onset by cigarette smoking, LCINS is not as readily understood and research on the subject has been conflicting. Thus, early diagnosis and prevention are key in reducing mortality among LCINS patients. In this study, the Prostate, Lung, Colorectal, and Ovarian (PLCO) dataset contains more than 155,000 participants and over 36,000 never-smokers. Data from more than 5,000 patients with LCINS were analyzed using R and Excel software to determine risk factors of LCINS. The factors analyzed for predictive power in LCINS incidence were age, height, weight, body mass index, race, income, family history, and secondary smoke exposure. Multiple statistical methods, including t-tests, ANOVA tests, and logistic regression, were implemented to assess each factor. Through comparison and corroboration of results from these statistical methods, age and race were identified as the key factors that had statistically significant evidence as potential influences in LCINS incidence. This was indicated by strong positive correlation between age/race and the predicted probability of LCINS development with a statistically significant p value. Other physical characteristics did not appear to have a significant impact on the likelihood of developing LCINS. In addition, the statistical method that provided the most information regarding a factor’s power was logistical regression due to the binomial outcome of whether or not a patient has LCINS. It enables a deeper elucidation of how individual factors influence the probability of LCINS development. These results provide valuable insights into demographic risk factors for LCINS and lay the groundwork for future investigations, potentially including the application of advanced analytical techniques such as deep learning algorithms to explore additional predictive factors for LCINS and other lung cancer subtypes.

Squamous Cell Carcinoma in Never Smokers: An Insight into SMARCB1 Loss.

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) constituting 85% of cases. Among NSCLCs, squamous cell carcinoma (SqCC) is strongly associated with smoking. However, lung cancer in never smokers (LCINS) represents approximately 25% of lung cancer cases globally and shows increasing incidence, particularly in East Asia. LCINS-SqCC is less well-characterized, especially regarding its genomic alterations and their impact on clinical outcomes. We conducted a retrospective analysis over a 20-year period (July 2003-July 2023) at two major tertiary centers in the UK. The cohort included 59 patients with LCINS-SqCC who underwent radical surgical resection. Data collected included demographic information, comorbidities, histopathological details, and outcome metrics such as disease-free and overall survival. Molecular sequencing of tumor specimens was performed to identify genomic aberrations. The cohort had a median age of 71 years (IQR 62-77) and a median BMI of 25.4 (IQR 22.8-27.8), with a slight male predominance (53%). The majority of patients (93%) had a preoperative MRC of 1-2. Recurrent disease was observed in 23 patients (39%), and 32 patients (54%) had died at a median follow-up of 3 years. Median disease-free survival was 545 days (IQR 132-1496), and overall survival was 888 days (IQR 443-2071). Preoperative creatinine levels were higher in patients who experienced recurrence (p = 0.037). Molecular analysis identified biallelic SMARCB1 loss in two younger patients, associated with rapid disease progression despite R0 resection. These patients' tumors were PDL1-negative, TTF-1-negative, and positive for cytokeratin, CD56, and p40. SMARCB1-deficient SqCC in never smokers represents a highly aggressive variant with poor disease-free survival, highlighting the importance of integrating advanced molecular diagnostics in clinical practice. This study underscores the necessity for personalized treatment strategies, including targeted therapies such as EZH2 inhibitors and immune checkpoint blockade, to address the unique molecular pathways in SMARCB1-deficient cancers. Further clinical trials are essential to optimize therapeutic approaches for this challenging subgroup of lung cancer.

The genomic landscape of lung cancer in never-smokers from the Women's Health Initiative.

Over 200,000 individuals are diagnosed with lung cancer in the United States every year, with a growing proportion of cases, especially lung adenocarcinoma, occurring in individuals who have never smoked. Women over the age of 50 comprise the largest affected demographic. To understand the genomic drivers of lung adenocarcinoma and therapeutic response in this population, we performed whole genome and/or whole exome sequencing on 73 matched lung tumor/normal pairs from postmenopausal women who participated in the Women's Health Initiative. Somatic copy number alterations showed little variation by smoking status, suggesting that aneuploidy may be a general characteristic of lung cancer regardless of smoke exposure. Similarly, clock-like and APOBEC mutation signatures were prevalent but did not differ in tumors from smokers and never-smokers. However, mutations in both EGFR and KRAS showed unique allelic differences determined by smoking status that are known to alter tumor response to targeted therapy. Mutations in the MYC-network member MGA were more prevalent in tumors from smokers. Fusion events in ALK, RET, and ROS1 were absent, likely due to age-related differences in fusion prevalence. Our work underscores the profound effect of smoking status, age, and sex on the tumor mutational landscape and identifies areas of unmet medical need.

Lung cancer among patients with secondhand smoke exposure: A systematic review.

e22506 Background: Smoking tobacco is recognized as the leading cause of lung cancer. However, it is imperative to note that 10–15% of lung cancer patients have no history of smoking, and that lung cancer remains the leading cause of cancer deaths among non-smokers. Since passive smokers are exposed to many carcinogenic compounds in the exhaled smoke, it is naturally plausible that secondhand smoking (SHS) is a risk factor for lung cancer. However, current USPSTF screening guidelines for lung cancer with low dose CT (LDCT) do not include patients exposed to SHS. We performed a systematic review to highlight SHS as an etiology of lung cancer and insights for inclusion in cancer screening criteria. Methods: We utilized the PubMed, Medline, Science Direct, and ClinicalTrials.gov databases to search for relevant literature using keywords ('low Dose CT,' 'secondhand smoke,' 'lung cancer'). The search strategy was designed to ensure a comprehensive retrieval of pertinent literature, minimizing the possibility of omitting articles due to insignificant spelling and/or semantic variations. Eligible studies had to be published between 2010 and 2023 and focused on examining the effect of SHS in populations at risk of lung cancer or those undergoing lung cancer screening. Articles not available in English were excluded from this systematic review. In total, 239 relevant articles were retrieved from all databases, narrowing down to 14 articles after the initial screening and further reducing to 4 articles after the second round of screening. Results: Three of the four articles included in our systemic review were conducted in Asia. A study by He et al. showed a substantial increase in the relative risk of lung cancer among SHS (RR 2.00; 95% CI, 0.62-6.40), with significant dose-response relationships between cumulative SHS exposure at home and work and the increased risk of cause-specific and total mortality. Another observational study on the use of LDCT in Japan has interestingly shown a shifting landscape of lung cancer demographics, with 49.6% of patients identified as never-smokers and 70.0% of the never-smoker lung cancer patients having SHS exposure. Secondhand smoking has also been reported to increase the risk of pulmonary nodules (HR 1.17; 95% CI, 1.01-1.35) and pulmonary emphysema (OR 13.6; 95% CI, 1.70-106.1) in those with moderate-to-high SHS exposure, which was the population where lung cancer was more prevalent. Conclusions: Our findings suggest a critical gap in current healthcare recommendations, specifically addressing the absence of guidelines for LDCT screening in individuals with moderate-to-high SHS exposure despite established evidence linking SHS to a significant increase in the risk of lung cancer development. More studies are needed to formulate evidence-based guidelines for lung cancer screening and detection in this population, given the expected mortality reduction benefit.

Radon exposure in Colombian never smoker patients with non-small cell lung cancer: A pilot study.

e22521 Background: Lung cancer (LC) is the leading cause of cancer-related death globally, with 1.8 million deaths estimated in 2022. In Colombia, up to 74% of patients with LC are diagnosed with stage IV which negatively impacts survival, with 6,000 estimated deaths in 2022. The most critical strategy for reducing LC is the reduction of tobacco exposure; however, up to 38% of LC cases are not related to tobacco. Among other risk factors different from tobacco smoke; indoor radon, a radioactive gas found naturally in closed spaces, stands out and could be the most important one. In Latin America, information on the influence of radon on the incidence of LC is scarce. This study aims to establish the prevalence of Radon exposure in Colombian never-smoker LC patients. Methods: This is a Pilot study. Adult patients with de novo NSCLC diagnosis ( < 6 mo) were included. Past smokers (≥100 cigarettes in life or ≥1 cigarette daily for 6 mo) or patients with a change in place of living in the last 10 years were excluded. Sociodemographics, clinical, and molecular information were obtained and included in an eCRF using REDCap®, Radon measurement was done using a DTPA-type detector (Alfa-track). The detector was located in the patient's home, (60-140 cm from the floor at the point of least ventilation of the space to be measured), for 90 days, Subsequently an automated count quantification was carried out using the Radosys® system at a certified lab (Universidad Santiago de Compostella Radon Lab). The Radon levels were reported in Bq/m3, using the average value observed during the measurement period (The threshold was 20 Bq/m3). Results: Between February 2022 to May 2023, 30 patients were included in the study, 86.7% were women, 73% had stage IV disease at inclusion, 53% had a driver mutation, with EGFR being the most frequent (62,5%) followed by ALK (31.3%). The mean Radon levels were 25.6 Bq/m3 (5 – 48). No patient had Radon levels ≥100 Bq/m3. Conclusions: In this pilot study, we didn´t find high radon exposure among never-smoker NSCLC patients. 2 other studies on indoor Radon concentrations have been done in Colombia, with only one demonstrating high radon levels (≥100 Bq/m3) in Bogotá. These differences could be explained by the type of house, rainfall adjustment, or underlying rock composition in our study. It´s important to increase the sample size for a definitive conclusion and to explore other risk factors in non-smoker patients as the quality of air or occupation, among others. [Table: see text]

Race, age at diagnosis and histological characteristics of lung cancer in never-smokers (LCINS) and ever-smokers in low-dose computed tomography (LDCT) screening: a systematic review and meta-analysis

Race, age at diagnosis and histological characteristics of lung cancer in never-smokers (LCINS) and ever-smokers in low-dose computed tomography (LDCT) screening: a systematic review and meta-analysis

A nested case-control study of untargeted plasma metabolomics and lung cancer among never-smoking women within the prospective Shanghai Women's Health Study.

The etiology of lung cancer in never-smokers remains elusive, despite 15% of lung cancer cases in men and 53% in women worldwide being unrelated to smoking. Here, we aimed to enhance our understanding of lung cancer pathogenesis among never-smokers using untargeted metabolomics. This nested case-control study included 395 never-smoking women who developed lung cancer and 395 matched never-smoking cancer-free women from the prospective Shanghai Women's Health Study with 15,353 metabolic features quantified in pre-diagnostic plasma using liquid chromatography high-resolution mass spectrometry. Recognizing that metabolites often correlate and seldom act independently in biological processes, we utilized a weighted correlation network analysis to agnostically construct 28 network modules of correlated metabolites. Using conditional logistic regression models, we assessed the associations for both metabolic network modules and individual metabolic features with lung cancer, accounting for multiple testing using a false discovery rate (FDR) < 0.20. We identified a network module of 121 features inversely associated with all lung cancer (p = .001, FDR = 0.028) and lung adenocarcinoma (p = .002, FDR = 0.056), where lyso-glycerophospholipids played a key role driving these associations. Another module of 440 features was inversely associated with lung adenocarcinoma (p = .014, FDR = 0.196). Individual metabolites within these network modules were enriched in biological pathways linked to oxidative stress, and energy metabolism. These pathways have been implicated in previous metabolomics studies involving populations exposed to known lung cancer risk factors such as traffic-related air pollution and polycyclic aromatic hydrocarbons. Our results suggest that untargeted plasma metabolomics could provide novel insights into the etiology and risk factors of lung cancer among never-smokers.

Proteogenomic Characterization Reveals Estrogen Signaling as a Target for Never-Smoker Lung Adenocarcinoma Patients without EGFR or ALK Alterations.

The proteogenomic landscape in never-smoker lung cancer without known driver mutations reveals prognostic proteins and enhanced estrogen signaling that can be targeted as a potential therapeutic strategy to improve patient outcomes.

Abstract LB231: The mutagenic forces shaping the genomic landscape of lung cancer in never smokers

Abstract While most lung cancers are associated with tobacco smoking, prior studies have indicated that 15-20% of cases are found in never smokers. Lung cancer in never smokers (LCINS) shows demographic variations, being more common in females and Asian populations. Epidemiological studies have also identified environmental risk factors for LCINS, including exposure to secondhand tobacco smoke and air pollution. As part of the Sherlock-Lung project (current data freeze of 1217 samples), we generated deep WGS data from a large international cohort of 871 treatment-naïve LCINS recruited from 28 locations across four continents. Our cohort allowed mapping the genomic landscape operative in lung cancer histologies commonly found in never smokers, including adenocarcinomas (n=737) and carcinoids (n=61), as well as other histologies rarely attributed to never smokers (n=73). Information on passive smoking was collected for 458 patients, with 250 being exposed to secondhand smoke. We identified driver alterations and performed mutational signature analyses for single base substitutions (SBS), indels, doublet base substitutions (DBS), copy number alterations, and structural variants. We detected eighteen SBS signatures, with eight not previously linked to LCINS, including SBS4, associated with smoking but also observed in lifelong non-smokers exposed to different environmental mutagens, such as indoor pollution. Several additional signatures were detected in other variant types, including a novel indel signature. Notably, secondhand smoke exposure corresponded to increased SBS burden, although it was not associated with specific signatures. In contrast, we observed a signature-specific association of air pollution (measured as PM2.5 exposure) with SBS, indel, and DBS burden. SBS4 and correlated signatures ID3 and DBS2 were positively associated with PM2.5 exposure. Similarly, clock-like signature SBS5 was highly correlated with PM2.5, potentially acting as a readout of a promotion mechanism where lung cells undergo more cell divisions in individuals living in highly polluted areas. We also observed variability across histologies and ancestries for signatures and driver mutations, including enrichment of signatures SBS17b and SBS40a as well as KRAS mutations in adenocarcinomas from Europeans; aristolochic-acid associated signature SBS22a, and EGFR and TP53 mutations in adenocarcinomas from East Asians; and signature SBS8 and ARID1A mutations in carcinoids from Europeans. The unprecedented size of our cohort allowed us to refine the prevalence and intensity of the driver mutations and mutational signatures involved in LCINS, as well as their variability across ancestries, geographical locations, and histologies. Our results indicate that air pollution may act as both initiator and promoter of neoplastic expansion of LCINS. Citation Format: Marcos Diaz-Gay, Tongwu Zhang, Azhar Khandekar, Burçak Otlu, Shuvro Nandi, Christopher D. Steele, Nathaniel Rothman, Stephen J. Chanock, Qing Lan, Ludmil B. Alexandrov, Maria Teresa Landi. The mutagenic forces shaping the genomic landscape of lung cancer in never smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB231.

Abstract LB286: Extrachromosomal DNA in lung cancer from never smokers

Abstract Extrachromosomal DNA (ecDNA), circular DNA that resides outside of the linear chromosome, is a potent form of oncogene amplification in cancer. The structure and properties of ecDNA are markedly different from those of linear DNA, characterized by features like non-Mendelian inheritance and an altered epigenetic landscape. A prior pan-cancer analysis ​​indicated patients with cancers harboring ecDNA have statistically worse overall survival when compared to cancer patients with other types of focal amplification. Moreover, its unique characteristics also make it a promising target for therapy. Recently, efforts have intensified to profile ecDNA across many cancer types, yet comprehensive studies of ecDNA in lung cancer in never smokers (LCINS) is lacking. Given that LCINS is partially driven by somatic copy number alterations, we hypothesized that ecDNA-driven focal amplifications significantly influence LCINS tumor evolution. As part of the Sherlock-Lung project (current data freeze, 1217 samples), we comprehensively profiled 871 treatment-naive samples using a robust computational pipeline that refined copy number segmentation by accounting for tumor purity and ploidy. ecDNA was present in 151 (17.3%) of tumor samples, with a third of ecDNA-positive samples harboring more than one distinct ecDNA amplicon. Consistent with prior reports, no ecDNA was found in bulk sequenced blood or matched normal lung tissues. These ecDNA often included genes (84%), frequently overlapping with known oncogenes like MDM2, TERT, and MYC, which showed higher expression levels compared to non-amplified or other amplified genes. Notably, most MDM2 amplifications (36/45) were on ecDNA. ecDNA was significantly associated with whole genome doubling, tumor stage, and several endogenous mutational signatures, including APOBEC (SBS2 and SBS13), and clock-like signature (SBS1). Intriguingly, ecDNA-positive tumors were associated with significantly worse survival compared to tumors without any focal amplifications, though tumors with other amplification types (e.g. breakage-fusion-bridge, linear amplification, or complex events) had similar survival impacts. The unprecedented size of our cohort and the integration of clinical, epidemiologic, and multi-omics data allowed us to perform the first in-depth characterization of ecDNA in LCINS. We reconstructed the genomic regions involved in ecDNA and revealed the full spectrum of simple and complex ecDNAs across cancer histologies as well as the clinical and functional impact of ecDNA on LCINS. Citation Format: Azhar Khandekar, Tongwu Zhang, Marcos Diaz-Gay, Jens Luebeck, Ludmil Alexandrov, Maria Landi. Extrachromosomal DNA in lung cancer from never smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB286.

Abstract LB228: Evolutionary trajectories of lung cancer in never smokers

Abstract Purpose of the study Elucidating evolutionary trajectories of cancers allows us to understand the key events, and the order in which they occur, throughout their development. This can help us to find important associations with tumor progression and prognosis. Our aim was to perform de novo identification of the evolutionary trajectories within Sherlock-lung, with a dataset containing the largest collection of lung cancer in never smokers (LCINS) samples ever analyzed. Experimental procedures Our Plackett-Luce ordering model utilized copy number data from Battenberg and mutation cancer cell fraction (CCF) data from DPClust. Frequently-occurring copy number events and driver mutations are ordered within each sample using their copy number states and CCFs. An aggregate ordering is then calculated for a sample set. Mixture model analysis identifies subsets of samples displaying distinct orders of events, uncovering diverse evolutionary trajectories within a tumor set. Dataset The Sherlock-lung whole genome sequencing dataset (n=1217) was filtered to the samples that allowed us to identify subclonal expansions. Samples required at least 10 reads per chromosome copy and a minimum cellularity of 30%. This provided 458 LCINS samples of various histologies. 155 smoker samples were also analyzed for comparison. Results We identified two subsets of LCINS tumors following distinct evolutionary trajectories. The “loss-based” subset commonly saw whole genome duplication (WGD) combined with copy number losses occurring earlier, and at higher prevalence, than gains. Contrastingly, in the “gain-based” subset, WGD was relatively rare but ploidy increased via copy number gains, which were more prevalent than losses. Interestingly, these different trajectories converged on similar overall copy number states. The loss-based subset had a higher mutational burden and a higher proportion of the genome altered, and followed a more smoker-like trajectory than the gain-based subset. Considering these differences alongside the convergence in copy number states, it is intriguing that survival times were similar between the two subsets. Copy number events defined the difference between the two trajectories. However, driver mutations also played important roles in tumor evolution in LCINS. TP53 and EGFR mutations were associated with greater genomic instability. Conversely, KRAS mutations were associated with more stable genomes. Samples with early clonal mutations in TP53, ERBB2, and PIK3CA, as well as those with a copy number gain of ERBB2, exhibited shorter survival times. Conclusions Two distinct evolutionary trajectories of LCINS were identified by de novo Plackett-Luce event ordering analysis. The contrast between the subgroups was defined by different paths of copy number activity, but they ultimately converged on similar overall copy number states and outcomes. Key early driver mutations influenced genomic instability and survival times. Citation Format: Christopher Wirth, Tongwu Zhang, Wei Zhao, Phuc Hoang, Jian Sang, Nathaniel Rothman, Marcos Díaz-Gay, Ruxandra Teslo, Naser Ansari-Pour, Máire Ní Leathlobhair, Iliana Peneva, William Eagles, Lixing Yang, Ludmil Alexandrov, David C. Wedge, Maria Teresa Landi. Evolutionary trajectories of lung cancer in never smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB228.

EPR24-112: Lung Cancer in Never Smokers: The Role of Radon Exposure and Public Knowledge.

EPR24-112: Lung Cancer in Never Smokers: The Role of Radon Exposure and Public Knowledge.

Reproductive factors and risk of lung cancer among 300,000 Chinese female never-smokers: evidence from the China Kadoorie Biobank study

BackgroundLung cancer is the leading cause of cancer mortality among Chinese females despite the low smoking prevalence among this population. This study assessed the roles of reproductive factors in lung cancer development among Chinese female never-smokers.MethodsThe prospective China Kadoorie Biobank (CKB) recruited over 0.5 million Chinese adults (0.3 million females) from 10 geographical areas in China in 2004–2008 when information on socio-demographic/lifestyle/environmental factors, physical measurements, medical history, and reproductive history collected through interviewer-administered questionnaires. Cox proportional hazard regression was used to estimate adjusted hazard ratios (HRs) of lung cancer by reproductive factors. Subgroup analyses by menopausal status, birth year, and geographical region were performed.ResultsDuring a median follow-up of 11 years, 2,284 incident lung cancers occurred among 282,558 female never-smokers. Ever oral contraceptive use was associated with a higher risk of lung cancer (HR = 1.16, 95% CI: 1.02–1.33) with a significant increasing trend associated with longer duration of use (p-trend = 0.03). Longer average breastfeeding duration per child was associated with a decreased risk (0.86, 0.78–0.95) for > 12 months compared with those who breastfed for 7–12 months. No statistically significant association was detected between other reproductive factors and lung cancer risk.ConclusionOral contraceptive use was associated with an increased risk of lung cancer in Chinese female never-smokers. Further studies are needed to assess lung cancer risk related to different types of oral contraceptives in similar populations.

Abstract 6250: The RNA editing landscape of lung cancer in never smokers

Abstract Adenosine-to-Inosine (A-to-I) editing represents a crucial RNA modification mechanism, holding the potential to drive carcinogenesis. This sophisticated post-transcriptional process is catalyzed by a series of ADAR (adenosine deaminase acting on RNA) family members, which can profoundly reshape the cellular epitranscriptomic landscape. While previous explorations have illuminated the important role of A-to-I editing in lung cancer tumorigenesis and prognosis, most studies have focused on lung cancer from smokers. To investigate the contribution on RNA-editing in lung cancers in never smokers (LCINS) , we embarked on a rigorous dissection of A-to-I RNA editing events in 603 LCINS. Harnessing transcriptome and whole-genome sequencing technologies, we identified 15,880 A-to-I sites, of which 75% were positively linked to the enzymatic activity of ADAR1. 92.80% of detected editing sites were located at Alu repetitive regions, with the remainder in non_Alu repeat (4.1%) and non-repeat regions (3.1%). The global RNA editing levels, measured as Alu Editing Index (AEI), were found to be significantly associated with ADAR1 expression, Tumor Mutational Burden, and Neoantigens Burden. A subtle correlation between global RNA editing levels and tumor stage was also noted. Delving into cancer-associated editing events, we identified 5,539 differentially edited sites in tumors compared with normal tissues, which were located at 823 genes, including several key tumor suppressors and oncogenes, like MDM2, BRAF, TP53, BRCA2, ATM, and VHL. Subsequent pathway analysis identified TGF-beta, Notch Signaling, and DNA Damage Response as the key pathways for cancer progression. Using the characterized A-to-I editing profiles, we built a prognostic risk stratification model, with high risk scores significantly linked to poor survival outcomes, even after adjusting for other clinical factors. Our study provides a comprehensive A-to-I editing landscape of lung cancer in never smokers, highlighting the potential roles of RNA modifications in the pathogenesis of this lethal disease. Citation Format: Jian Sang, Wei Zhao, Tongwu Zhang, Maria Teresa Landi. The RNA editing landscape of lung cancer in never smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6250.

Abstract 877: Molecular and radiographic profiling of lung cancer in never-smokers

Abstract Gene expression changes in nasal and bronchial epithelium, and quantitative features from chest CT reflect the presence of lung cancer in current and former smokers and can serve as biomarkers. Between 10-20% of lung cancer cases are diagnosed in patients who have never smoked (&amp;lt;100 lifetime cigarettes) and biomarkers could assist the diagnosis of pulmonary nodules discovered incidentally in this population. We compared lung cancer-associated gene expression and radiomic features in never-smokers and ever-smokers. Nasal epithelial RNA was isolated and sequenced from brushings collected at UCLA from 73 patients presenting to interventional radiology for biopsy for suspected lung cancer. Limma was used to identify genes with lung cancer-associated expression in never-smokers by comparing 13 patients with benign nodules with 14 patients diagnosed with lung cancer. Similarities between cancer-associated genes in never-smokers and those previously identified in ever-smokers were assessed by gene set enrichment analysis (GSEA). Next, using all 73 samples, genes whose lung cancer-associated expression is modified by smoking status were identified via an interaction term. Radiomic features for 46 patients (31 ever-smokers, 15 never-smokers) were extracted using PyRadiomics, including features from the interior of the nodule and perinodular features generated 10, 15, and 20 mm away from the boundary of the nodule. A binomial model was used to identify features with a significant interaction effect between cancer and smoking status. We identified 74 genes decreased and 84 genes increased in cancer in never-smokers (p &amp;lt; 0.005), controlling for age and median TIN. Genes changed in ever-smoker lung cancer patients were significantly enriched among the genes most associated with lung cancer in never smokers (GSEA; p = 0.0059 and p = 4.38e-15). Next, there were 51 genes with a p-value &amp;lt; 0.01 for the cancer*smoking interaction term. Lastly, four radiomic features were associated with the perinodular term for cancer and smoking status (FDR&amp;lt; 0.2), including two nodular and two boundary features. These results suggest that lung cancer-associated gene expression differences in ever-smokers are preserved in never-smokers, suggesting the potential relevance of previously derived biomarkers for this population. There may also be never-smoker-specific gene expression patterns associated with lung cancer. Our radiomic findings suggest that both nodular and perinodular characteristics may be important predictors of malignancy. Citation Format: Minyi Lee, Anil Yadav, Gang Liu, Steven Dubinett, Jennifer Beane, William Hsu, Ashley Prosper, Denise Aberle, Marc Lenburg. Molecular and radiographic profiling of lung cancer in never-smokers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 877.