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PubMed2026

Breathing carcinogens: PM2.5 air pollution and lung cancer in never-smokers, a narrative review.

BACKGROUND AND OBJECTIVE: Lung cancer in never-smokers (LCINS) disproportionately affects women and younger individuals, and its incidence has increased over recent decades. Environmental respiratory hazards, such as particulate matter ≤2.5 µm (PM2.5), are associated with lung cancer incidence and mortality, but the mechanisms by which PM2.5 increases lung cancer susceptibility remain incompletely understood. This review summarizes the current evidence linking PM2.5 exposure to LCINS and identifies priorities for future research. METHODS: A narrative review was conducted using PubMed/MEDLINE to identify English-language studies published from 2000 through May 2026 using combinations of the terms "PM2.5", "fine particulate matter", "air pollution", "lung cancer", "never-smokers", "environmental respiratory hazards", "genomic alterations", and "tumor microenvironment". Additional relevant studies were identified through manual review of the reference lists of included articles. Studies were selected based on their relevance to the epidemiology, biological mechanisms, genomic and immune landscape, and clinical implications of PM2.5-associated LCINS, with emphasis on original investigations, high-quality reviews, and landmark publications. KEY CONTENT AND FINDINGS: PM2.5 exposure promotes inflammatory signaling, metabolic reprogramming, and tumor progression. Emerging evidence suggests that PM2.5 functions primarily as a tumor promoter rather than a direct mutagen and is associated with genomic and epigenetic alterations, more advanced disease, and worse survival following lung cancer diagnosis and surgical resection. LCINS also exhibits distinct molecular and immunologic characteristics with important implications for screening, molecular profiling, and targeted therapies. CONCLUSIONS: PM2.5 is an increasingly recognized contributor to lung carcinogenesis in never-smokers. Improved understanding of the biologic mechanisms linking environmental respiratory hazards to LCINS may inform future screening strategies, precision oncology approaches, and novel therapeutic targets for this growing and understudied patient population.

Fine particulate matter ≤2.5 µm in dia↗

PubMed2025

Stratifying Lung Adenocarcinoma Risk with Multi-ancestry Polygenic Risk Scores in East Asian Never-Smokers.

BACKGROUND: Lung adenocarcinoma (LUAD) in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve LUAD risk prediction. METHODS: PRSs were developed using genome-wide association study summary statistics from East Asian (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. Single-ancestry models included PRS-25, PRS-CT, and LDpred2; multi-ancestry models included LDpred2+PRS-EUR128, PRS-CSx, and CT-SLEB. Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium (FLCCA) and externally validated in the Nanjing Lung Cancer Cohort (NJLCC). We assessed predictive accuracy via AUC, with 10-year and (age 30-80) absolute risks estimates. RESULTS: The best multi-ancestry PRS, using East Asian and European data via CT-SLEB (clumping and thresholding, super learning, empirical Bayes), outperformed the best East Asian-only PRS (LDpred2; AUC=0.629, 95% CI:0.618,0.641), achieving an AUC of 0.640 (95% CI:0.629,0.653) and odds ratio of 1.71 (95% CI:1.61,1.82) per SD increase. NJLCC Validation confirmed robust performance (AUC =0.649, 95% CI: 0.623, 0.676). The top 20% PRS group had a 3.92-fold higher LUAD risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year LUAD risk at age 50 (0.42%) by age 41, nine years earlier. CONCLUSIONS: Multi-ancestry PRS approaches enhance LUAD risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

East Asian never smokers↗

PubMed2025

Immune landscape and novel therapeutic targets of epidermal growth factor receptor and anaplastic lymphoma kinase wild type never-smoker lung adenocarcinoma.

BACKGROUND: Never-smoker lung adenocarcinoma (NSLA) exhibits distinct immunosuppressive profiles and a lower tumor mutation burden compared with lung adenocarcinoma in smokers. These correlate with poor responses to immune checkpoint inhibitors. In this study, we aimed to elucidate the tumor-immune microenvironment of NSLA without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alterations and identify novel therapeutic targets. METHODS: We analyzed genome, transcriptome, and proteomic data from 102 NSLA tumor samples and 16 normal adjacent tissues. We classified tumors into distinct immune clusters (IC) based on gene signatures by profiling the tumor-infiltrating immune cells. RESULTS: The tumors were stratified into three ICs: hot, intermediate, and cold. Notably, only 21 (20.6%) patients exhibited hot IC enriched in cytotoxic T cells, natural killer cells, and B-cell signatures, which correlated with improved recurrence-free survival. Cold ICs (37.3%) exhibited higher myeloid-derived suppressor cell (MDSC) levels and M2 macrophage signatures, with poor immune cell infiltration and relatively low stimulatory cytokines and chemokines expression. CEACAM1, and NECTIN2 were upregulated in intermediate and cold ICs and correlated with MDSC and M2 macrophage infiltration. High expression of these genes was associated with poor survival outcomes. Protein-protein network analysis of 20 upregulated molecules associated with cancer- and driver-related proteins in cold IC identified XPO 1 as a key component. CONCLUSION: Our proteogenomic analysis highlighted the immunosuppressive properties of NSLA without EGFR and ALK alterations and identified novel therapeutic targets. These findings may provide novel treatment strategies that could improve the clinical outcomes of patients with NSLA.

Humans↗

PubMed2026

Detection of House Dust Mite-derived DNA in Human Lung Tumors by Whole-Genome Sequencing.

Lung cancer in never-smokers (LCINS) accounts for an increasing proportion of lung cancer cases, yet its risk factors remain poorly understood. House dust mites (HDM) are common aeroallergens that induce airway inflammation, but their potential contribution to lung cancer is unknown. We analyzed unmapped whole-genome sequencing reads from 783 lung cancers from the Sherlock-Lung (n = 621 never-smokers) and EAGLE (n = 162 smokers) cohorts, including 328 matched adjacent normal lung tissues. After removal of human sequences, reads were aligned to reference genomes from the two major HDM species and confirmed by BLAST. Samples with top BLAST matches were classified as HDM-detected. Associations between HDM detection and genomic, microbiome, and bulk RNA-seq-derived immune features were evaluated. HDM-derived DNA was detected at low abundance in a subset of tumors and adjacent normal tissues, with higher detection frequencies in tumors than matched normal tissues and in smokers than never-smokers. In LCINS tumors, HDM detection was not associated with tumor mutational burden or recurrent driver alterations but was associated with modest differences in immune cell composition and a limited but reproducible bacterial co-detection pattern. These findings provide a foundation for investigating aeroallergen-derived DNA signatures and their potential relationship to the lung tumor microenvironment.

Environmental exposure↗

PubMed2024

Design of the SPIROMICS Study of Early COPD Progression: SOURCE Study.

BACKGROUND: The biological mechanisms leading some tobacco-exposed individuals to develop early-stage chronic obstructive pulmonary disease (COPD) are poorly understood. This knowledge gap hampers development of disease-modifying agents for this prevalent condition. OBJECTIVES: Accordingly, with National Heart, Lung and Blood Institute support, we initiated the SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) Study of Early COPD Progression (SOURCE), a multicenter observational cohort study of younger individuals with a history of cigarette smoking and thus at-risk for, or with, early-stage COPD. Our overall objectives are to identify those who will develop COPD earlier in life, characterize them thoroughly, and by contrasting them to those not developing COPD, define mechanisms of disease progression. METHODS/DISCUSSION: SOURCE utilizes the established SPIROMICS clinical network. Its goal is to enroll n=649 participants, ages 30-55 years, all races/ethnicities, with ≥10 pack-years cigarette smoking, in either Global initiative for chronic Obstructive Lung Disease (GOLD) groups 0-2 or with preserved ratio-impaired spirometry; and an additional n=40 never-smoker controls. Participants undergo baseline and 3-year follow-up visits, each including high-resolution computed tomography, respiratory oscillometry and spirometry (pre- and postbronchodilator administration), exhaled breath condensate (baseline only), and extensive biospecimen collection, including sputum induction. Symptoms, interim health care utilization, and exacerbations are captured every 6 months via follow-up phone calls. An embedded bronchoscopy substudy involving n=100 participants (including all never-smokers) will allow collection of lower airway samples for genetic, epigenetic, genomic, immunological, microbiome, mucin analyses, and basal cell culture. CONCLUSION: SOURCE should provide novel insights into the natural history of lung disease in younger individuals with a smoking history, and its biological basis.

SPIROMICS↗

PubMed2026

Targeting EGFR-Mutant Non-Small Cell Lung Cancer in Asia: An Update on Monotherapy and Combination Therapy With EGFR Inhibitors.

EGFR-mutant lung cancer represents a major subtype of non-small cell lung cancer in Asia, with particularly high prevalence in never-smokers, women, and patients with adenocarcinoma histology. Although this clinicopathologic enrichment has been recognized for more than two decades, the mechanisms underlying the excess frequency of EGFR-mutant disease in Asian populations remain only partially understood. Accumulating evidence suggests a multifactorial basis involving host genetic susceptibility and diversity, endogenous mutational processes and exogenous exposures such as ambient particulate matter. In particular, recent genomic and experimental studies support a tumour-promotion framework in which inflammatory microenvironmental cues may facilitate the outgrowth of pre-existing oncogenic clones, while mutational signatures provide genomic footprints of these processes. In parallel, the treatment landscape for EGFR-mutant non-small cell lung cancer has evolved substantially with successive generations of EGFR tyrosine kinase inhibitors (EGFR-TKIs), leading to marked improvements in survival. However, acquired resistance remains inevitable in most patients with advanced disease and is driven by both genetic and non-genetic mechanisms, including secondary EGFR alterations, bypass pathway activation, TP53-associated genomic instability, adaptive mutagenesis, and drug-tolerant persister states. These insights have provided a strong rationale for combination strategies beyond EGFR-TKI monotherapy. In this review, we summarize current understanding of the epidemiology and biological basis of EGFR-mutant lung cancer in Asia and discuss the preclinical rationale and emerging clinical evidence supporting combination approaches with chemotherapy, anti-angiogenic agents, and EGFR/MET-directed therapies.

EGFR mutations↗

PubMed2026

EGFR-Mutant Non-Small Cell Lung Cancer With Small Cell Transformation: Clinicopathological Features, Treatment Landscape, and Biomarker Profiles.

INTRODUCTION: Transformed small-cell lung cancer (tSCLC) is a clinically important resistance mechanism to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer. This study characterizes clinical features, treatment outcomes, and biomarker profiles in patients with tSCLC. METHODS: Data from 45 patients with EGFR-mutant NSCLC who developed tSCLC between 2014 and 2023 were analyzed. Demographic characteristics, treatment histories, and delta-like ligand 3 (DLL3) and B7-H3 expression were collected. Objective response rate, progression-free survival (PFS), and posttransformation survival (PTS) were assessed. Spatial transcriptomic profiling was performed in selected cases. RESULTS: Most patients were women (60%) and never-smokers (75.6%). Exon 19 deletion was the predominant EGFR mutation (57.8%). Median PFS and PTS were 3.3 and 9.2 months, respectively. Etoposide plus platinum (EP) was the predominant first-line regimen (69.8%), with 23.2% of the patients receiving EP plus immune checkpoint or tyrosine kinase inhibitors. EP-based combination regimens yielded a numerically higher objective response rate and a significantly longer PFS than EP alone (7.5 versus 2.8 months, p = 0.002). PTS was longer with EP-based regimens than with other regimens (10.4 versus 6.4 months, p = 0.035). DLL3 and B7-H3 were expressed in 87.5% and 66.7% of tumors, respectively, without prognostic significance. Multivariable analysis identified brain metastasis and liver progression at transformation as adverse prognostic factors. Spatial transcriptomic analysis revealed neuroendocrine lineage reprogramming, stromal depletion, and immune exclusion. CONCLUSIONS: tSCLC remains an aggressive resistance phenotype with poor outcomes. EP-based combination strategies may provide clinical benefit, whereas frequent DLL3 expression supports further evaluation of targeted therapies.

Delta-like ligand 3↗

PubMed2025

Efficacy of EGFR tyrosine kinase inhibitors in patients with non-small cell lung cancer with EGFR exon 19 insertions: clinical-genomic, preclinical analysis through LC-SCRUM-Asia (multi-institutional genomic screening registry).

BACKGROUND: EGFR exon 19 insertions (EGFRex19ins) are rare EGFR mutations. Their clinical-genomic characteristics and outcomes with EGFR-tyrosine kinase inhibitors (TKIs) remain uncertain. METHODS: We evaluated the clinical-genomic characteristics and outcomes of EGFR-TKIs for EGFRex19ins in the multi-institutional prospective lung cancer genomic screening project (LC-SCRUM-Asia). We also studied preclinical Ba/F3 models expressing EGFR-K745_E746insIPVAIK (Ba/F3-IPVAIK) to investigate their sensitivity to 1st-, 2nd-, 3rd-generation, and EGFR exon 20 insertion-active TKIs. RESULTS: In LC-SCRUM-Asia, 16,204 NSCLC patients were enrolled from March 2015 to December 2023. EGFRex19ins were detected in 13 samples (0.1 % of NSCLC). The median age was 72 years (range, 38-80); most patients were female (77 %), had adenocarcinoma (92 %), and were never-smokers (62 %). Twelve patients (93 %) had EGFR-K745_E746insIPVAIK, while one (7 %) had EGFR-K745_E746insVPVAIK. The most frequent co-mutation was TP53 (62 %); no patients had other driver alterations. Six patients (46 %) tested positive for EGFR exon 19 deletions with PCR-based Cobas EGFR test, likely due to cross-reactivity arising from sequence homology. Twelve patients received EGFR-TKIs; five (42 %) experienced partial response. In the preclinical study, Ba/F3-IPVAIK showed the highest sensitivity to 2nd-generation EGFR-TKIs compared to other EGFR-TKIs. Structural studies supported these consistent results. When broken down by EGFR-TKI generations, response rates for 1st-, 2nd-, and 3rd-generation TKIs were 50 % (1/2), 80 % (4/5), and 0 % (0/5), respectively. The median PFS for 1st-, 2nd-, and 3rd-generation TKIs were 8.7 (95 % CI, 7.4-NR), 14.7 (95 % CI, 8.0-NR), and 4.4 (95 % CI, 3.4-NR) months, respectively. CONCLUSION: Our preclinical, structural, and clinical findings indicate 2nd-generation EGFR-TKIs are more effective for EGFRex19ins compared to other TKIs.

Adult↗

PubMed2026

Anaplastic lymphoma kinase immunohistochemical positivity in high-grade pulmonary neuroendocrine carcinoma: an actionable signal or merely a shadow?

AIMS: Anaplastic lymphoma kinase (ALK) rearrangements are actionable drivers in non-small cell lung carcinoma (NSCLC), but the biological significance of ALK-immunohistochemistry (IHC) positivity in high-grade pulmonary neuroendocrine carcinoma (NEC) remains unclear. This study evaluated the diagnostic and therapeutic implications of discordant ALK IHC and genomic findings and the role of multimodal molecular testing in resolving them. METHODS: We retrospectively analysed eight South Asian patients (Indian and Nepali) with de novo high-grade pulmonary NEC and diffuse ALK immunoreactivity treated at a tertiary cancer centre in India. Comprehensive molecular profiling using DNA- and RNA-based next-generation sequencing (NGS) and ALK fluorescence in situ hybridisation (where tissue was adequate) was performed. Clinical outcomes and responses to ALK-targeted tyrosine kinase inhibitors (TKIs) were assessed. RESULTS: ALK IHC positivity was observed in 8 of 100 selectively tested cases among 319 high-grade pulmonary NECs diagnosed between 2019 and 2025. The cohort included seven SCLCs (one combined adenocarcinoma-SCLC) and one large-cell neuroendocrine carcinoma (LCNEC). Median age was 51 years; 75% were female and 87.5% never-smokers. Among five comprehensively profiled cases, true ALK rearrangements were confirmed in two (one LCNEC and one SCLC), both detectable only by RNA sequencing. Durable benefit from ALK-TKI therapy was seen only in the molecularly confirmed LCNEC case (>16 months), whereas ALK IHC-positive but NGS-negative cases progressed rapidly. CONCLUSIONS: True ALK rearrangements in high-grade pulmonary NEC are rare but highly actionable. ALK IHC alone is an unreliable predictor of therapeutic benefit. RNA-based sequencing is essential for fusion detection. Comprehensive molecular confirmation, with RNA sequencing as the preferred modality, should precede any initiation of ALK-targeted therapy in high-grade pulmonary NEC.

IMMUNOHISTOCHEMISTRY↗

PubMed2026

Uric Acid-to-HDL Cholesterol Ratio is Associated with Hepatic Steatosis but Not Fibrosis in Nonobese Adults: A NHANES 2017-2020 Study.

BACKGROUND: Although metabolic dysfunction-associated steatotic liver disease (MASLD) has traditionally been regarded as a disease closely related to obesity, its prevalence is gradually rising in nonobese populations. The uric acid-to-high-density lipoprotein cholesterol ratio (UHR) is a novel metabolic biomarker that has been shown to be associated with MASLD. However, its role in nonobese individuals remains unclear. This study aimed to investigate the association between UHR and nonobese MASLD. METHODS: Data from the 2017 to 2020 National Health and Nutrition Examination Survey (NHANES) were analyzed. UHR was calculated as the serum uric acid (UA) divided by the high-density lipoprotein cholesterol (HDL). Liver steatosis (using controlled attenuation parameters, CAP) and fibrosis (using liver stiffness measurement, LSM) were evaluated through vibration-controlled transient elastography (VCTE). Multivariate linear regression was employed to evaluate associations. Nonlinear relationships were examined using smoothed curve fitting. RESULTS: This analysis included 3573 participants (47.41% male; aged 20-80 years). Log2-UHR was positively associated with CAP (β = 9.96, 95% CI: 6.93-12.98, P < 0.001) and MASLD prevalence (OR = 1.64, 95% CI: 1.38-1.95, P < 0.001). Subgroup analyses revealed significant interactions by sex, age, ethnicity, and smoking status (all P for interaction < 0.05), with stronger associations in females, adults aged 40-59 years, individuals of other Hispanic ethnicity, and never-smokers. Moreover, the association between log2-UHR and CAP was linear and positive (P < 0.01). No significant association was found between log2-UHR and LSM (P > 0.05). CONCLUSIONS: UHR is independently associated with hepatic steatosis but not fibrosis in nonobese US adults, suggesting its potential utility as an early risk assessment to tool. Large scale prospective studies are needed in the future to further validate the conclusions of this study.

Humans↗

PubMed2025

Inherited rare epidermal growth factor receptor mutation and somatic mutations in patients with non-small cell lung cancer: a case report.

BACKGROUND: Recent advances in molecular oncology have increasingly illuminated the role of germline EGFR mutations in non-small cell lung cancer (NSCLC). This case report presents the presence of a unique familial occurrence of EGFR mutations in patients with NSCLC. CASE DESCRIPTION: A mother and son, both never-smokers of Caucasian ethnicity, were diagnosed with advanced metastatic lung adenocarcinoma. In one patient, tumor molecular analysis by next generation sequencing (NGS) identified two EGFR mutations: the activating mutation c.2573T > G; p.Leu858Arg (p.L858R) in exon 21 of the EGFR gene, and the somatic non-pathogenic mutation c.2612 C > A; p.Ala871Glu (p.A871E) in exon 21 of the EGFR gene. The second patient also harbored the same two EGFR mutations. The patient underwent genetic testing which revealed the germline origin of the A871E mutation. Whether the presence of this mutations was associated with increased predisposition to cancer has yet to be determined. Our case report highlights the need for further exploration of the role of germline mutations, including the A871E mutation, in tumorigenesis and its implications for treatment response and inheritance patterns. CONCLUSIONS: The investigation and comprehension of the significance of each individual EGFR mutation hold the promise for potential in cancer prevention or early diagnosis within family cohorts and understanding the mechanisms of tumorigenesis in sporadic cases.

Humans↗

PubMed2026

Lifestyle, anthropometric factors and clinically significant prostate cancer diagnosis in men with suspected prostate cancer.

OBJECTIVE: Lifestyle and anthropometric factors may influence prostate cancer (PCa) risk, yet evidence remains inconclusive. This study reports the associations between lifestyle and anthropometric factors and clinically significant PCa (csPCa; ISUP grade > 1) among men with clinical suspicion of PCa. MATERIALS AND METHODS: In this registered (NCT06116851), single-institution, prospective cohort trial, men referred for PCa diagnostics due to elevated prostate-specific antigen or abnormal digital rectal examination were included. Subjects underwent prostate diagnostics and completed detailed surveys of lifestyle, medical and family history. Physical activity was measured using a triaxial accelerometer. Anthropometric assessments included body mass index, waist circumference and magnetic resonance imaging-based body composition analyses. RESULTS: Among 298 included men, 143 (48%) were diagnosed with csPCa. In multivariate logistic regression, higher physical activity, measured by step count (odds ratio [OR]: 0.91, 95% confidence interval [CI]: 0.82-0.99) and active smoking compared to never-smokers (OR: 0.38, 95% CI: 0.14-0.96) were inversely associated with detection of csPCa. Higher prostate-specific antigen density was associated with increased risk (OR: 1.78, 95% CI: 1.39-2.35). Body composition was not associated with csPCa. Study strengths include comprehensive data collection. Primary limitation is partial reliance on self-reported data. CONCLUSIONS: Higher measured physical activity was inversely associated with detection of csPCa in men with suspicion of PCa. Active smoking also showed an inverse association. Both findings merit further investigation.

Aged↗