Integrative Analysis of a Large Real-World Cohort of Small Cell Lung Cancer Identifies Distinct Genetic Subtypes and Insights into Histologic Transformation

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 genetic subtypes, including STK11-mutant tumors (1.7%) and TP53/RB1 wild-type tumors (5.5%), as well as rare cases that 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.

Lineage-specific intolerance to oncogenic drivers restricts histological transformation

“…5E). True paired cases of human LUAD before and after HT are limited, but some studies have compared unrelated de novo LUAD with transformed SCLC (T-SCLC) in an attempt to understand this phenomenon as it relates to de novo SCLC tumorigenesis ( 1 , 3 , 59 , 60 ). We reanalyzed a publicly available cohort and could demonstrate that Myc target genes were differentially increased in T-SCLC as compared with LUAD, suggesting that Myc may have a role in facilitating HT in a clinical setting (Fig.…”

“…A more recent study relied on putative HT samples in which a LUAD oncogenic driver was detected in a histologically confirmed SCLC. When compared to de novo SCLC, these cases were enriched for mutations that activate the PI3K signaling pathway ( 61 ). Consistent with this result, we found that loss of Pten or activation of Pik3ca was sufficient to break a barrier in the AT2 lineage to transformation by Myc but insufficient to lead to neuroendocrine transformation.…”

“…Second, there are processes in human cells not found in the mouse that may be critical for HT, including the role for APOBEC-mediated hypermutation. Studies of EGFR-mutated LUAD have found APOBEC mutagenesis signatures after treatment with EGFR-targeted therapies ( 11 , 73 , 74 ), and this mutational signature is enriched after HT ( 1 , 61 ). It is unclear whether APOBEC mutations are directly responsible for activating the PI3K signaling pathway, (hypothetically) relieving intolerance of the AT2 cell to Myc ( 1 , 59 , 61 ); however, other studies would suggest that this is possible ( 75 , 76 ).…”

“…Studies of EGFR-mutated LUAD have found APOBEC mutagenesis signatures after treatment with EGFR-targeted therapies ( 11 , 73 , 74 ), and this mutational signature is enriched after HT ( 1 , 61 ). It is unclear whether APOBEC mutations are directly responsible for activating the PI3K signaling pathway, (hypothetically) relieving intolerance of the AT2 cell to Myc ( 1 , 59 , 61 ); however, other studies would suggest that this is possible ( 75 , 76 ). Lastly, we were unable to initiate tumorigenesis in the ERPMT model with the Spc CreERT2 allele.…”

“Non-viral CRISPR/Cas9 Mutagenesis for Streamlined Generation of Mouse Lung Cancer Models.”

“…Large-scale genomic analysis of lung tumors has identified many recurrent gene mutations with unclear roles in tumor development ( [1][2][3]. Therefore, it is essential to generate models that facilitate the rapid introduction of sets of mutations into lung tissue to assess their importance in disease progression.…”