Passage Adaptation Correlates With the Reduced Efficacy of the Influenza Vaccine.

BACKGROUND:As a dominant seasonal influenza virus, H3N2 virus rapidly evolves in humans and is a constant threat to public health. Despite sustained research efforts, the efficacy of H3N2 vaccine has decreased rapidly. Even though antigenic drift and passage adaptation (substitutions accumulated during vaccine production in embryonated eggs) have been implicated in reduced vaccine efficacy (VE), their respective contributions to the phenomenon remain controversial. METHODS:We utilized mutational mapping, a powerful probabilistic method for studying sequence evolution, to analyze patterns of substitutions in different passage conditions for an unprecedented amount of H3N2 hemagglutinin sequences (n = 32 278). RESULTS:We found that passage adaptation in embryonated eggs is driven by repeated convergent evolution over 12 codons. Based on substitution patterns at these sites, we developed a metric, adaptive distance (AD), to quantify the strength of passage adaptation and subsequently identified a strong negative correlation between AD and VE. CONCLUSIONS:The high correlation between AD and VE implies that passage adaptation in embryonated eggs may be a strong contributor to the recent reduction in H3N2 VE. We developed a computational package called MADE (Measuring Adaptive Distance and vaccine Efficacy based on allelic barcodes) to measure the strength of passage adaptation and predict the efficacy of a candidate vaccine strain. Our findings shed light on strategies for reducing Darwinian evolution within the passaging medium in order to potentially restore an effective vaccine program in the future

Genomic landscape of lung adenocarcinoma in East Asians

Lung cancer is the world's leading cause of cancer death and shows strong ancestry disparities. By sequencing and assembling a large genomic and transcriptomic dataset of lung adenocarcinoma (LUAD) in individuals of East Asian ancestry (EAS; n = 305), we found that East Asian LUADs had more stable genomes characterized by fewer mutations and fewer copy number alterations than LUADs from individuals of European ancestry. This difference is much stronger in smokers as compared to nonsmokers. Transcriptomic clustering identified a new EAS-specific LUAD subgroup with a less complex genomic profile and upregulated immune-related genes, allowing the possibility of immunotherapy-based approaches. Integrative analysis across clinical and molecular features showed the importance of molecular phenotypes in patient prognostic stratification. EAS LUADs had better prediction accuracy than those of European ancestry, potentially due to their less complex genomic architecture. This study elucidated a comprehensive genomic landscape of EAS LUADs and highlighted important ancestry differences between the two cohorts. Genomic and transcriptomic analysis of lung adenocarcinoma (LUAD) in Asia indicates that Asian LUADs have fewer mutations, lower driver prevalence and fewer copy number alterations than European LUADs

Dynamic phenotypic heterogeneity and the evolution of multiple RNA subtypes in hepatocellular carcinoma: the PLANET study

Intra-tumor heterogeneity (ITH) is a key challenge in cancer treatment, but previous studies have focused mainly on the genomic alterations without exploring phenotypic (transcriptomic and immune) heterogeneity. Using one of the largest prospective surgical cohorts for hepatocellular carcinoma (HCC) with multi-region sampling, we sequenced whole genomes and paired transcriptomes from 67 HCC patients (331 samples). We found that while genomic ITH was rather constant across stages, phenotypic ITH had a very different trajectory and quickly diversified in stage II patients. Most strikingly, 30% of patients were found to contain more than one transcriptomic subtype within a single tumor. Such phenotypic ITH was found to be much more informative in predicting patient survival than genomic ITH and explains the poor efficacy of single-target systemic therapies in HCC. Taken together, we not only revealed an unprecedentedly dynamic landscape of phenotypic heterogeneity in HCC, but also highlighted the importance of studying phenotypic evolution across cancer types.National Medical Research Council (NMRC)National Research Foundation (NRF)Published versionThis work is supported in part by the Singapore National Medical Research Council grants (TCR/015-NCC/2016, CIRG18may-0057l, NMRC/CSA-SI/0018/2017, and NMRC/ OFIRG/0064/2017) and the National Research Foundation, Singapore (NRF-NRFF2015-04). W.Z. is supported in part by the National Key R&D Program of China (2018YFC1406902 and 2018YFC0910400), the National Natural Science Foundation of China (31970566), and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDPB17). H.Y. is supported by the National Natural Science Foundation of China (32000407)