Whole-genome sequencing of lung neuroendocrine neoplasms reveals a TP53 WT / RB1 WT subtype with CCND amplification

Background: Lung neuroendocrine neoplasms (LNENs) comprise a spectrum of entities, including typical/atypical carcinoid, large cell neuroendocrine carcinoma (LCNEC), and small cell lung cancer (SCLC). Data from both whole-genome sequencing (WGS) and targeted panel sequencing show that SCLC is typically associated with biallelic inactivation of TP53 and RB1 in 91% of cases. While SCLC has been extensively profiled using WGS, other LNEN subtypes have largely been investigated using targeted panels or whole-exome sequencing, limiting comprehensive genomic characterization. To advance the understanding of early-stage LNEN biology, we performed WGS on a surgically resected cohort spanning the full spectrum of LNENs. Methods: We analyzed ~30× WGS data from 58 surgically resected LNENs at Seoul National University Hospital (carcinoid n=11; LCNEC n=22; SCLC n=25). Somatic single-nucleotide variants (SNVs), structural variants (SVs), copy-number profiles, and mutational signatures were evaluated. Results : Across the cohort, median SV/SNV burdens were 0.015 [28/1,929] for carcinoids, 0.006 [186/28,954] for LCNECs, and 0.002 [62/36,181] for SCLCs. Three SCLC samples exhibited markedly elevated SV/SNV ratios compared with other SCLCs (patient #135: 0.092 [345/3,750]; patient #144: 0.158 [331/2,098]; patient #147: 0.031 [94/3,053]; other SCLCs: 0.000-0.005). This pattern was absent in LCNECs but was detected in one carcinoid sample (patient #126: 0.024 [50/2,128]). These four cases (three SCLCs, one carcinoid) uniformly lacked tobacco-associated mutational signatures and were TP53 WT / RB1 WT . Two samples from patients #126 and #135 demonstrated chromothripsis involving chromosomes 3 and 11, whereas the remaining two from patients #144 and #147 showed dense rearrangements between chromosomes 12 and 20 with prominent copy-number oscillations. These alterations converged on amplification of CCND1 (chr11) or CCND2 and CDK4 (chr12), with shared losses involving FHIT , TGFBR2 , and additional copy-number alterations on partner chromosomes. Pathologic review further revealed coexisting atypical carcinoid and SCLC components in one SCLC case (patient #135). Conclusions: All four cases displayed convergent CCND - CDK4 pathway activation and characteristic complex SV-driven genome remodeling. Together with the histological coexistence of atypical carcinoid and SCLC in patient #135, these data raise the possibility that CCND -dependent SCLC may evolve from a carcinoid precursor. The observation of one carcinoid in patient #126 provides independent evidence of CCND -dependent tumorigenesis. Although limited by sample size, our findings highlight a distinct, early-stage LNEN subset defined by catastrophic SV events and G1-S checkpoint dysregulation, suggesting potential therapeutic vulnerability to cell-cycle-targeted strategies.