SCLC is characterized by oncogenic TP73 rearrangements and inactivating mutations in NOTCH genes.

  • Major finding: SCLC is characterized by oncogenic TP73 rearrangements and inactivating mutations in NOTCH genes.

  • Concept: Comprehensive analysis revealed complex rearrangements and universal TP53 and RB1 inactivation.

  • Impact: Rare mutations in kinase genes suggest potential therapeutic targets in individual patients.

Patients with small cell lung cancer (SCLC) initially respond to chemotherapy, the most common treatment strategy for SCLC, but inevitably experience lethal recurrence, demonstrating the need to discover new therapeutic targets in SCLC. Past whole-exome sequencing efforts have identified only a few recurrent mutations in SCLC. To identify the complex genomic rearrangements that contribute to SCLC pathogenesis, George, Lim, and colleagues performed whole-genome sequencing (WGS) of 110 human SCLC tumors, as well as transcriptome and copy-number analysis of a subset of these tumors and WGS or whole-exome sequencing of 8 SCLC tumors from mice carrying conditional alleles for Trp53, Rb1, and Rbl2. This comprehensive analysis identified biallelic inactivation of TP53 and RB1 via missense mutations or complex genomic translocations in all but two human SCLCs, a frequency higher than that previously reported. In addition, two tumors with wild-type RB1 were affected by chromothripsis and exhibited overexpression of cyclin D1, suggesting that RB1 inactivation in SCLC can result via an alternative mechanism. WGS also revealed rare mutations in kinase genes, such as BRAF and PIK3CA, which suggest that individual patients may benefit from targeted therapies. TP73 was altered in 13% of human SCLCs by somatic mutations or genomic rearrangements, the latter resulting in oncogenic N-terminally truncated TP73 transcript variants, including p73Δex2/3, which have been shown to exert a dominant-negative effect on TP53. Furthermore, inactivating genomic alterations in NOTCH family genes were identified in 25% of human SCLC tumors. Activation of NOTCH signaling reduced the number of SCLC tumors and increased survival in a Trp53;Rb1;Rbl2–deficient mouse model of SCLC and abolished neuroendocrine gene expression in SCLC cell lines. Together, these results show that universal inactivation of TP53 and RB1 is required for SCLC pathogenesis, identify NOTCH genes as tumor suppressors and regulators of neuroendocrine differentiation in SCLC, and suggest new therapeutic targets for SCLC.

George J, Lim JS, Jang SJ, Cun Y, Ozretić L, Kong G, et al. Comprehensive genomic profiles of small cell lung cancer. Nature 2015;524:47–53.

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