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

INTRODUCTION

Systemic sclerosis (SSc) is a chronic connective tissue disease associated with a significantly elevated and disproportionate risk of developing 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 NSCLC in patients with SSc and other connective tissue diseases associated with interstitial lung disease (ILD).

METHODS

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

RESULTS

ILD (mostly nonspecific interstitial pneumonia) was present in all SSc never/light smokers but relatively infrequent in moderate/heavy smokers (p = 0.0016). NSCLC in SSc never and light smokers (n = 16) demonstrated a significant lack of canonical driver alterations enriched in never-smokers (mutations in EGFR or ERBB2 and oncogenic fusions) compared with non-SSc counterparts (0/16 versus 474/1255, p = 0.004) Conversely, TP53 mutations were enriched in this population (12/16, 75% versus 639/1394, 45.8%; p = 0.038). KRAS mutations were found in seven of 27 patients and were identified in patients with never, light and moderate smoking history. NSCLC from never and light smokers with SSc had 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 and 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, affecting therapeutic strategies.