Genetic and Epigenetic Determinants of Lung Cancer Subtype: Adenocarcinoma to Small Cell Conversion

: We hypothesize that detailed analysis of paired samples derived from EGFR-mutant adenocarcinoma and small cell lung cancer (SCLC) from the same patient will provide substantial insight into the determinants of subtype specificity. Preliminary data on one such case demonstrates a methylation profile in the recurrent SCLC that is indistinguishable from that of de novo SCLC, suggesting that a primary determinant of this histologic shift may be epigenetic. Our primary objectives are to use comprehensive genomic and epigenomic profiling of these closely related tumor pairs (1) to define key factors determining histologic subtype, and (2) to define biological pathways contributing to this mechanism of acquired resistance. With these objectives in mind, the specific aims of this grant are to comprehensively define the genomic sequence alterations (Aim 1) and epigenomic DNA methylation changes (Aim 2) in paired samples from individual patients with EGFR-mutant adenocarcinoma and recurrent EGFR tyrosine kinase inhibitor-resistant SCLC.