BM-07 * GENOMIC CHARACTERIZATION OF BRAIN METASTASES REVEALS BRANCHED EVOLUTION AND METASTASIS-SPECIFIC MUTATIONS

Abstract

BACKGROUND: Brain metastases are the most common intracranial tumors in adults. We have a limited understanding of how brain metastases evolve from their primary tumor. Our objectives were to (1) elucidate the evolutionary patterns leading to brain metastases and (2) identify whether brain metastases are genetically distinct from their primary tumors. METHODS: We subjected 101 matched primary tumors, brain metastases, and normal tissue to whole exome sequencing. We developed novel computational tools to perform an integrative analysis of somatic mutations and copy-number alterations. This analysis allowed us to estimate the clonal architecture of the primary and metastases, and to reconstruct a phylogenetic tree relating the subclones from each patient. RESULTS: Every brain metastasis likely developed from a single clone. The brain metastasis and primary tumor shared a common ancestor yet both the primary tumor and brain metastasis continued to evolve independently. Subclonal mutations in the metastasis by definition occurred within the brain; these mutations displayed different mutational signatures than those acquired in the primary tumor. These contrasts were most pronounced in cases of lung cancer or melanoma, with tobacco and UV signatures prominent in these primaries and nearly absent from mutations acquired after metastasis. In order to understand the molecular drivers of clonal evolution and metastasis, we annotated each subclone with driver mutations identified using large numbers of cancer samples analyzed by the cancer genome atlas consortium. This produced a detailed portrait of each patient's cancer, with nearly every node in each phylogenetic tree associated with at least one known driver. We found novel drivers, many of which are known actionable targets, that were exclusive to brain metastases. CONCLUSIONS: This study sheds light on the evolutionary mechanisms in brain metastases. Our data suggests that single biopsies of primary tumors and metastases may not be sufficient to identify potential therapeutic targets.