Abstract
BACKGROUND: Epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (LUAD) is the most common subtype among non-small cell lung cancer (NSCLC) and targeted therapies are the primary approach for treatment. However, the development of resistance to therapy and histological transformation into small cell lung cancer (SCLC) present significant challenges. Understanding the mechanisms underlying this transformation is crucial for effective differential diagnosis and the formulation of treatment strategies. METHODS: In this study, we collected tissue from 5 primary LUAD before SCLC transformation, 12 transformed SCLC after EGFR tyrosine kinase inhibitor (TKI) treatment, and 18 de novo SCLC from lung cancer patients treated at Beijing Chest Hospital, Capital Medical University from January 2015 to December 2021. Whole-exome sequencing was performed on these samples to compare the genomic alterations of these three tumor types, elucidating their similarities, differences, and connections. Statistical analyses were conducted using the Fisher exact test and performed with R v4.2.1 environment. RESULTS: Among 12 transformed SCLC cases, the majority were female (10/12, 83.3%), non-smokers (10/12, 83.3%) and harbored EGFR 19del mutations (11/12, 91.7%). Four were with limited stage and 8 with extensive stage. TP53 mutations and RB1 loss are important but not necessary for SCLC transformation. The mutation rates of TP53 were 60% (3/5) in primary LUAD, 70% (7/10) in transformed SCLC, and 89% (16/18) in de novo SCLC. RB1 loss rates were 40% (2/5) in primary LUAD, 30% (3/10) in transformed SCLC, and 50% (9/18) in de novo SCLC. Additionally, mutations in COL22A1 and ALMS1 were only observed in transformed SCLC and de novo SCLC. In contrast, mutations in PTCH2, CNGB3, SPTBN5, CROCC, and MYO15A were more common in transformed SCLC, whereas PABPC3 and MUC19 mutations were more frequent in de novo SCLC. Smoking-related mutations (SBS4) were only found in de novo SCLC, with no changes observed in transformed SCLC. TMB levels were significantly lower in transformed SCLC compared to de novo SCLC (p = 0.01). Genomic instability was significantly higher in transformed SCLC compared to primary LUAD and de novo SCLC. This was supported by higher levels of homologous recombination deficiency (HRD, p = 0.025), uniparental disomy (UPD, p = 0.003), loss of heterozygosity (LOH, p = 0.008), and telomeric allelic imbalance (TAI, p = 0.02). The increased frequency of UPD events in transformed SCLC suggests that UPD may act as a "second hit" in Knudson's model, leading to biallelic inactivation of tumor suppressor genes. High similarity was observed in genetic alterations related to DNA damage repair (DDR) and Notch signaling pathways between transformed SCLC and de novo SCLC. CONCLUSIONS: The identification of these specific genomic alterations in transformed SCLC contributes to a better understanding of the mechanisms driving this transformation. This knowledge may guide future predicting the transformation of SCLC and the development of personalized treatment strategies for these patients.