A comprehensive genomic analysis of 110 small cell lung cancer (SCLC) tumors revealed widespread inactivation of TP53 and RB1, which are essential for tumor suppression. These genes were mutated in nearly all tumors, with some cases showing complex genomic rearrangements. Additionally, somatic rearrangements of TP73 generated an oncogenic variant, TP73Δex2/3, which may contribute to SCLC progression. Mutations in kinase genes were found in rare cases, suggesting potential therapeutic opportunities. Inactivating mutations in NOTCH family genes were observed in 25% of human SCLC, and activation of Notch signaling in a preclinical SCLC mouse model reduced tumor burden and improved survival. Notch activity also abrogated neuroendocrine gene expression in SCLC cells. These findings highlight key biological processes and potential therapeutic targets in SCLC. SCLC accounts for about 15% of all lung cancers and is highly aggressive, with poor prognosis. Previous studies using exome sequencing identified few recurrently mutated genes. Whole-genome sequencing of 110 SCLC tumors and matched normal DNA revealed high mutation rates, with C:G>A:T transversions indicative of heavy smoking. The study identified recurrent somatic alterations, including mutations in TP53, RB1, CREBBP, and other genes. These mutations were associated with significant clustering, suggesting functional relevance. The study also identified mutations in NOTCH family genes, which were linked to reduced tumor burden and prolonged survival in preclinical models. Notch signaling was shown to inhibit neuroendocrine gene expression in SCLC cells. The study also identified TP73Δex2/3 as an oncogenic variant, which lacks a functional transactivation domain and acts as a dominant-negative on wild-type TP73 and p53. This variant was found in 13% of cases. The study further confirmed the role of NOTCH family genes as tumor suppressors in SCLC, with activation of Notch signaling inhibiting tumor growth in preclinical models. These findings suggest that Notch signaling may be a therapeutic target in SCLC. The study identified several key biological processes and candidate therapeutic targets in SCLC, including the inactivation of TP53 and RB1, the generation of TP73Δex2/3, and the role of NOTCH family genes. These findings provide a comprehensive understanding of the genomic alterations in SCLC and highlight potential therapeutic strategies for this deadly cancer.A comprehensive genomic analysis of 110 small cell lung cancer (SCLC) tumors revealed widespread inactivation of TP53 and RB1, which are essential for tumor suppression. These genes were mutated in nearly all tumors, with some cases showing complex genomic rearrangements. Additionally, somatic rearrangements of TP73 generated an oncogenic variant, TP73Δex2/3, which may contribute to SCLC progression. Mutations in kinase genes were found in rare cases, suggesting potential therapeutic opportunities. Inactivating mutations in NOTCH family genes were observed in 25% of human SCLC, and activation of Notch signaling in a preclinical SCLC mouse model reduced tumor burden and improved survival. Notch activity also abrogated neuroendocrine gene expression in SCLC cells. These findings highlight key biological processes and potential therapeutic targets in SCLC. SCLC accounts for about 15% of all lung cancers and is highly aggressive, with poor prognosis. Previous studies using exome sequencing identified few recurrently mutated genes. Whole-genome sequencing of 110 SCLC tumors and matched normal DNA revealed high mutation rates, with C:G>A:T transversions indicative of heavy smoking. The study identified recurrent somatic alterations, including mutations in TP53, RB1, CREBBP, and other genes. These mutations were associated with significant clustering, suggesting functional relevance. The study also identified mutations in NOTCH family genes, which were linked to reduced tumor burden and prolonged survival in preclinical models. Notch signaling was shown to inhibit neuroendocrine gene expression in SCLC cells. The study also identified TP73Δex2/3 as an oncogenic variant, which lacks a functional transactivation domain and acts as a dominant-negative on wild-type TP73 and p53. This variant was found in 13% of cases. The study further confirmed the role of NOTCH family genes as tumor suppressors in SCLC, with activation of Notch signaling inhibiting tumor growth in preclinical models. These findings suggest that Notch signaling may be a therapeutic target in SCLC. The study identified several key biological processes and candidate therapeutic targets in SCLC, including the inactivation of TP53 and RB1, the generation of TP73Δex2/3, and the role of NOTCH family genes. These findings provide a comprehensive understanding of the genomic alterations in SCLC and highlight potential therapeutic strategies for this deadly cancer.