Brain metastases from lung adenocarcinoma (BM-LUAD) cause significant patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary lung adenocarcinomas. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12% vs 6%), YAP1 (7% vs 0.8%), and MMP13 (10% vs 0.6%) and significantly more frequent deletions in CDKN2A/B (27% vs 13%). We confirmed that amplification frequencies of MYC and YAP1 / MMP13 were elevated in an independent cohort of 105 patients. Functional assessment in patient-derived xenograft mouse models validated that MYC , YAP1 or MMP13 overexpression increased the brain metastasis incidence. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a large number of metastatic tumors can reveal novel metastatic drivers.

Understanding the fine-structure molecular architecture of bacterial epidemics has been a long-sought goal of infectious disease research. We used short-read-length DNA sequencing coupled with mass spectroscopy analysis of SNPs to study the molecular pathogenomics of three successive epidemics of invasive infections involving 344 serotype M3 group A Streptococcus in Ontario, Canada. Sequencing the genome of 95 strains from the three epidemics, coupled with analysis of 280 biallelic SNPs in all 344 strains, revealed an unexpectedly complex population structure composed of a dynamic mixture of distinct clonally related complexes. We discovered that each epidemic is dominated by micro-and macrobursts of multiple emergent clones, some with distinct strain genotype-patient phenotype relationships. On average, strains were differentiated from one another by only 49 SNPs and 11 insertion-deletion events (indels) in the core genome. Ten percent of SNPs are strain specific; that is, each strain has a unique genome sequence. We identified nonrandom temporal-spatial patterns of strain distribution within and between the epidemic peaks. The extensive full-genome data permitted us to identify genes with significantly increased rates of nonsynonymous (amino acid-altering) nucleotide polymorphisms, thereby providing clues about selective forces operative in the host. Comparative expression microarray analysis revealed that closely related strains differentiated by seemingly modest genetic changes can have significantly divergent transcriptomes. We conclude that enhanced understanding of bacterial epidemics requires a deep-sequencing, geographically centric, comparative pathogenomics strategy.Streptococcus pyogenes | evolution | invasive disease | phylogeography | population genetics