Frank Weinberg

Background: Lung cancer remains the leading cause of cancer-related mortality in the United States, characterized by poor overall survival rates (OS), particularly for advanced-stage disease. While smoking is a primary risk factor, other contributors include environmental exposures, genetics, comorbidities, and socioeconomic factors. Methods: We included 232 patients with lung cancer (96% NSCLC). Patients were categorized into DNA damage response (DDR)-mutant (DDR^mt, n = 67, 29%) and DDR-wild-type (DDR^wt, n = 165, 71%) groups. We evaluated the correlations between individual and socioeconomic factors between DDR^mt and DDR^wt lung cancer patients. Results:Nineteen DDR genes were identified, with ARID1A(31.3%), CHEK2 (19.4%), ATM (14.9%), BRCA2 (14.9%), ATRX (11.9%), MUTYH (11.9%), ATR (8.9%), and MSH6 (5.9%) being the most common. The DDR^mt group had a significantly higher median tumor mutational burden (TMB) (12 vs. 9; p = 0.006) and a higher prevalence of adenocarcinoma (85.1% vs. 64.8%, p = 0.003). Logistic regression identified adenocarcinoma histology (OR = 10.03, p = 0.002) and lower area deprivation index (OR = 0.98, p = 0.04) as predictors of DDR mutation status. Having advanced stage at diagnosis was associated with, age (p = 0.03), lack of lung cancer screening (p < 0.001), and adenocarcinoma histology (p < 0.001). While median OS was 61 months for the DDR^mt group vs. 44 months for the DDR^wt group (p = 0.654), patients with ATR mutations had significantly shorter survival (13 vs. 67 months; p = 0.0008). Population-level factors, including food insecurity (HR = 2.33, p = 0.002), lack of insurance (HR = 2.39, p = 0.008), and proximity to potential chemical accidents (HR = 1.73, p = 0.037), were significant predictors of OS. Conclusions: These findings suggest that DDR^mt lung cancers represent a biologically distinct subgroup characterized by higher tumor mutational burden and enrichment for adenocarcinoma histology; however, DDR mutation status alone was not associated with overall survival. Instead, outcomes appeared to vary by individual DDR gene, with ATR alterations identifying a subgroup with particularly poor survival. In parallel, food insecurity, lack of insurance, and proximity to potential environmental hazards were associated with outcomes, highlighting the need to integrate genomic biomarkers with social and environmental determinants of health. These data suggest the need for future prospective studies incorporating treatment-response data, longitudinal social determinants of health (SDOH) assessment, and environmental exposure measures to define how DDR alterations can guide precision oncology strategies while addressing modifiable barriers to equitable cancer care.

Supplementary Figure S1 shows the generation of THP1-derived macrophages and preparation of stearic acid–treated conditioned media.

Supplementary Figure S13 shows the percentage distribution of cytokine-producing cells in untreated and stearic acid–stimulated THP1-derived macrophages.

Supplementary Figure S4 shows the correlations between microbial abundance and metabolite presence using Spearman’s rank correlation in affected and unaffected lobes.

Supplementary Figure S3 shows the HAllA analysis illustrating associations between OTU expression and metabolite levels in unaffected lobes.

Supplementary Figure S9 shows association plots between microbial taxa (OTUs) and cytokines in unaffected lobes.

Supplementary Figure S10 shows association plots between cytokines and metabolites in unaffected lobes.

Supplementary Figure S2 shows the agar layer setup used in the anchorage-independent colony formation assay.

Supplementary Figure S7 shows association plots between cytokines and metabolites in tumor lobes.

Supplementary Table S3. Cytokines included in Isoplexis assays