Genome Sequencing Reveals Somatic Evolution in Murine SCLC

Despite major cancer genome sequencing efforts, distinguishing common driver mutations from passenger mutations in small-cell lung carcinoma (SCLC) has remained difficult due to the high tobacco mutagen-induced mutation rate and paucity of clinical samples. In an effort to investigate the mechanisms that underlie tumor progression in SCLC, McFadden and colleagues characterized a series of matched primary and metastatic tumors isolated from a genetically engineered SCLC mouse model driven by deletion of Trp53 and Rb1, which are commonly mutated in human SCLC. Exome sequencing of 27 primary murine SCLCs, metastases, and matched control DNA as well as whole-genome sequencing of 14 tumors and paired control DNA revealed frequent whole-chromosome alterations, including loss of chromosome 19, which harbors Pten, in 9 of 17 primary tumors, and an enrichment of protein-altering point mutations affecting the PTEN–PI3K network. Interestingly, a cross-species comparison with human SCLC genomes showed recurrent inactivating mutations in PTEN, further suggesting that disruption of PTEN function may play an important role in SCLC progression. Indeed, AKT phosphorylation was increased in the majority of Trp53/Rb1-deficient murine SCLCs, and deletion of Trp53, Rb1, and Pten in pulmonary neuroendocrine cells significantly reduced SCLC latency and overall survival and increased tumor volume and tumor burden. In an effort to understand tumor lineage relationships, matched primary tumor and metastasis pairs were analyzed for shared genomic alterations. Analysis of the relative fraction of cancer cells that share mutations revealed evidence for clonal heterogeneity and multiple mechanisms of metastasis, including parallel and polyclonal seeding, as well as the distant spread of tumor subclones from metastatic lymph nodes. Together, these findings demonstrate the feasibility of using genomic analyses of genetically engineered mouse models to gain insight into the evolution of human cancers and implicate PTEN disruption as a major driver of SCLC progression.

McFadden DG, Papagiannakopoulos T, Taylor-Weiner A, Stewart C, Carter SL, Cibulskis K, et al. Genetic and clonal dissection of murine small cell lung carcinoma progression by genome sequencing. Cell 2014;156:1298–311.