Abstract 748: Genomic characterization of recurrent small cell lung cancer through research autopsy reveals clonal diversity and candidate driver of chemoresistance

Genomic characterization of recurrent small cell lung cancer (SCLC) is needed to dissect the molecular mechanisms of relapse, metastatic dissemination, and chemoresistance. SCLC is a highly aggressive, lethal neuroendocrine cancer arising from the bronchial epithelium that develops in heavy smokers. Although many SCLC patients demonstrate sensitivity to first-line platinum-doublet chemotherapy, the response is short-lived and nearly all patients progress during therapy or relapse within several months of completing treatment. Treatment options beyond first-line chemotherapy are limited and ineffective. Metastatic SCLC has a poor prognosis and is associated with a 5-year overall survival rate of 5-10%. A well-characterized genetic hallmark of SCLC is the concurrent inactivation of tumor suppressor genes TP53 and RB1. Additional SCLC candidate driver genes have been reported and include CREBBP, MLL, NOTCH1-4, SOX2 and MYC. However, most SCLC tumors profiled in these studies were obtained from treatment-naïve patients. Therefore, genomic alterations that are acquired during therapy and drive the development of chemoresistance in recurrent SCLC remain undefined. We present results from whole exome sequencing (WES) of multiple metastatic tumors procured from five treatment-refractory SCLC patients who underwent research autopsy. WES was also performed on pre-treatment samples from three of these patients. Our results showed universal TP53 alterations and to a lesser extent RB1 mutations in our SCLC cohort. Next, we utilized bioinformatics methods to analyze clonal heterogeneity and evolution in these SCLC patients. This analysis demonstrated the existence of multiple clones of tumor cells in both the pre-treatment and treatment-resistant autopsy SCLC samples, suggesting that tumor heterogeneity occurs early in SCLC development and is subsequently maintained. Furthermore, allele-specific analysis of copy number variations in our SCLC cohort demonstrated near universal deletion of a region on chromosome 5q containing the tumor suppressor APC, consistent with a recently reported role for deregulated WNT signaling in chemoresistance development in relapsed SCLC. Finally, in one SCLC patient, we identified PTEN deletion (loss of heterozygosity) as a potential mechanism of metastasis specifically to the brain. In conclusion, we have performed genomic characterization of recurrent SCLC, defined by significant clonal diversity, through research autopsy and identified c