ABSTRACT Small cell lung cancer (SCLC) is a recalcitrant neuroendocrine carcinoma with dismal survival outcomes. A major barrier in the field has been the relative paucity of human tumors studied. Here we provide an integrated analysis of 3,600 “real-world” SCLC cases. This large cohort allowed us to identify new recurrent alterations and new genetic subtypes, including STK11- mutant tumors (1.7%) and TP53/RB1 wild-type tumors (5.5%), of which 12.7% were human papillomavirus-positive. In our cohort, gene amplifications on 4q12 are associated with increased overall survival while CCNE1 amplification is associated with decreased overall survival. We also identify more frequent alterations in the PTEN pathway in brain metastases. Finally, profiling cases of SCLC containing oncogenic drivers typically associated with NSCLC demonstrates that SCLC transformation may occur across multiple distinct molecular cohorts of NSCLC. These novel and unsuspected genetic features of SCLC may help personalize treatment approaches for this fatal form of cancer. STATEMENT OF SIGNIFICANCE Minimal changes in therapy and survival outcomes have occurred in SCLC for the past four decades. The identification of new genetic subtypes, novel recurrent mutations, and an improved understanding of the mechanisms of transformation to SCLC from NSCLC may guide the development of personalized therapies for subsets of patients with SCLC.

Integrative analysis of a large real-world cohort of small cell lung cancer identifies distinct genetic subtypes and insights into histological transformation