The Genomic Landscape of NSCLC in Systemic Sclerosis Reveals Frequent TP53 Mutations and a Paucity of Actionable Oncogenes.

Background: Systemic sclerosis (SSc) is a chronic connective tissue disease associated with a significantly elevated and disproportionate risk of developing non-small cell lung cancer (NSCLC), yet the underlying molecular drivers remain poorly understood. Specifically, it is unclear how these tumors fit within the established molecular paradigms of lung cancer, particularly in relation to the patient's smoking status and its associated genomics. Here, we investigated the genomics of non-small cell lung cancer (NSCLC) in patients with SSc and other connective tissue diseases (CTDs) associated with interstitial lung disease (ILD).

Methods: We retrospectively identified SSc (n=27) and other inflammatory ILD-associated NSCLC patients (n=10) who underwent tumor genomic profiling. We collected clinical data (smoking, ILD features) and analyzed genomic alterations, tumor mutational burden (TMB), and mutational signatures, comparing them to a large NSCLC cohort.

Results: ILD (mostly NSIP) was present in all SSc never/light smokers but relatively infrequent in moderate/heavy smokers (p = 0.0016). NSCLC in SSc never/light smokers (n=16) showed a significant lack of canonical driver alterations enriched in never-smokers (mutations in EGFR or ERBB2, and oncogenic fusions) compared to non-SSc counterparts (0/16 vs. 474/1255, p=0.004) Conversely, TP53 mutations were enriched in this population (12/16, 75% vs. 639/1394, 45.8%; p=0.038). KRAS mutations were found in 7/27 patients and were identified in patients with light/never and moderate/heavy smoking history. SSc never/light smokers showed enrichment of APOBEC-attributable variants versus non-SSc controls (55% increase, p=0.02). Similar genomic findings were noted in a cohort of NSCLC arising in patients with other inflammatory ILD.

Conclusion: NSCLC in SSc and other inflammatory ILD, particularly in never/light smokers, displays distinct genomics: paucity of targetable drivers, frequent TP53 alterations, and APOBEC signature enrichment. This suggests a unique pathogenesis linked to chronic inflammation/autoimmunity, impacting therapeutic strategies.