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Extensive genomic characterization of human cancers presents the problem of inference from genomic abnormalities to cancer phenotypes. To address this problem, we analysed proteomes of colon and rectal tumours characterized previously by The Cancer Genome Atlas (TCGA) and perform integrated proteogenomic analyses. Somatic variants displayed reduced protein abundance compared to germline variants. Messenger RNA transcript abundance did not reliably predict protein abundance differences between tumours. Proteomics identified five proteomic subtypes in the TCGA cohort, two of which overlapped with the TCGA ‘microsatellite instability/CpG island methylation phenotype’ transcriptomic subtype, but had distinct mutation, methylation and protein expression patterns associated with different clinical outcomes. Although copy number alterations showed strong cis - and trans -effects on mRNA abundance, relatively few of these extend to the protein level. Thus, proteomics data enabled prioritization of candidate driver genes. The chromosome 20q amplicon was associated with the largest global changes at both mRNA and protein levels; proteomics data highlighted potential 20q candidates, including HNF4A (hepatocyte nuclear factor 4, alpha), TOMM34 (translocase of outer mitochondrial membrane 34) and SRC (SRC proto-oncogene, non-receptor tyrosine kinase). Integrated proteogenomic analysis provides functional context to interpret genomic abnormalities and affords a new paradigm for understanding cancer biology. Proteome analysis of The Cancer Genome Atlas (TCGA) colorectal cancer specimens reveals that DNA- or RNA-level measurements cannot reliably predict protein abundance, colorectal tumours can be separated into distinct proteotypes, and that copy number alterations drive mRNA abundance changes but few extend to protein-level changes. Proteomics/genomics of colorectal tumours A team from the Clinical Proteomics Tumor Analysis Consortium has now analysed the proteomes of 95 colon and rectal tumours previously characterized by the Cancer Genome Atlas project. Integration of the proteomics with the original genomic data demonstrates that protein abundance cannot be reliably predicted from DNA- or RNA-level measurements, and that mRNA and protein levels are modestly correlated. Proteomics identified five colorectal cancer subtypes that reflect known biological characteristics, yet capture differences that are not evident at the transcriptome level. Integrated proteogenomic analysis of this type can provide functional context to interpret genomic abnormalities in terms of cancer biology.

Hepatocellular carcinoma (HCC) is one of the most prevalent and fatal digestive tumors. Treatment for this disease has been constraint by heterogeneity of this group of tumors, which has greatly limited the progress in personalized therapy. Although existing studies have revealed the genetic and epigenetic blueprints that drive HCCs, many of the molecular mechanisms that lead to HCCs remain elusive. Recent advances in techniques for studying functional genomics, such as genome sequencing and transcriptomic analyses, have led to the discovery of molecular mechanisms that participate in the initiation and evolution of HCC. Integrative multi‐omics analyses have identified several molecular subtypes of HCC associated with specific molecular characteristics and clinical outcomes. Deciphering similar molecular features among highly heterogeneous HCC patients is a prerequisite to implementation of personalized therapeutics. This review summarizes the current research progresses in precision therapy on the backbone of molecular subtypes of HCC.

Background Urothelial carcinoma (UC) is the most common pathological type of bladder cancer, a malignant tumor. However, an integrated multi-omics analysis of the Chinese UC patient cohort is lacking. Methods We performed an integrated multi-omics analysis, including whole-exome sequencing, RNA-seq, proteomic, and phosphoproteomic analysis of 116 Chinese UC patients, comprising 45 non-muscle-invasive bladder cancer patients (NMIBCs) and 71 muscle-invasive bladder cancer patients (MIBCs). Result Proteogenomic integration analysis indicated that SND1 and CDK5 amplifications on chromosome 7q were associated with the activation of STAT3, which was relevant to tumor proliferation. Chromosome 5p gain in NMIBC patients was a high-risk factor, through modulating actin cytoskeleton implicating in tumor cells invasion. Phosphoproteomic analysis of tumors and morphologically normal human urothelium produced UC-associated activated kinases, including CDK1 and PRKDC. Proteomic analysis identified three groups, U-I, U-II, and U-III, reflecting distinct clinical prognosis and molecular signatures. Immune subtypes of UC tumors revealed a complex immune landscape and suggested the amplification of TRAF2 related to the increased expression of PD-L1. Additionally, increased GARS, related to subtype U-II, was validated to promote pentose phosphate pathway by inhibiting activities of PGK1 and PKM2. Conclusions This study provides a valuable resource for researchers and clinicians to further identify molecular pathogenesis and therapeutic opportunities in urothelial carcinoma of the bladder.

Background Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with poor prognosis. Proteogenomic characterization and integrative proteomic analysis provide a functional context to annotate genomic abnormalities with prognostic value. Methods We performed an integrated multi-omics analysis, including whole-exome sequencing, RNA-seq, proteomic, and phosphoproteomic analysis of 217 PDAC tumors with paired non-tumor adjacent tissues. In vivo functional experiments were performed to further illustrate the biological events related to PDAC tumorigenesis and progression. Results A comprehensive proteogenomic landscape revealed that TP53 mutations upregulated the CDK4-mediated cell proliferation process and led to poor prognosis in younger patients. Integrative multi-omics analysis illustrated the proteomic and phosphoproteomic alteration led by genomic alterations such as KRAS mutations and ADAM9 amplification of PDAC tumorigenesis. Proteogenomic analysis combined with in vivo experiments revealed that the higher amplification frequency of ADAM9 ( 8p11.22 ) could drive PDAC metastasis, though downregulating adhesion junction and upregulating WNT signaling pathway. Proteome-based stratification of PDAC revealed three subtypes (S-I, S-II, and S-III) related to different clinical and molecular features. Immune clustering defined a metabolic tumor subset that harbored FH amplicons led to better prognosis. Functional experiments revealed the role of FH in altering tumor glycolysis and in impacting PDAC tumor microenvironments. Experiments utilizing both in vivo and in vitro assay proved that loss of HOGA1 promoted the tumor growth via activating LARP7-CDK1 pathway. Conclusions This proteogenomic dataset provided a valuable resource for researchers and clinicians seeking for better understanding and treatment of PDAC.

Colorectal liver metastasis (CRLM) is one of the leading death causes among colorectal cancer (CRC) patients, yet its underlying molecular events remain poorly understood, particularly at the proteomic and phosphoproteomic levels. A proteogenomic analysis combining genomics, transcriptomics, proteomics, and phosphoproteomics is performed on 102 samples from 34 treatment‐naïve CRLM patients, including primary CRC, adjacent normal colorectal, and matched liver metastasis tissues. CRC cell lines, organoids, mouse models, and an independent patient cohort are used to validate the findings. Proteomics and phosphoproteomics show profoundly dysregulated pathways in liver metastasis tissues, notably disruptions in carbon metabolism. Functional validation using CRC organoids and mouse models demonstrates that the one‐carbon metabolism enzyme SHMT1 promotes CRC tumorigenesis and metastasis via formate‐mediated AMPK inhibition, whereas PIM kinase‐dependent NDRG1 Ser330 phosphorylation exacerbates liver metastasis by promoting ubiquitin‐dependent degradation of NDRG1. Unsupervised clustering identifies two proteomic subtypes of liver metastasis samples with distinct clinical outcomes: a poor‐prognosis C1 (metabolism) subtype and a better‐prognosis C2 (RNA function) subtype. Considering expression frequency, specificity, and functional relevance, FTCD, GPD1, SOD2, and EIF4B Ser422 phosphorylation are further identified and validated as subtype prognostic biomarkers. This study provides critical insights into the molecular mechanisms underlying CRLM and offers resources for high‐risk metastatic CRC.

Antibodies that bind to both H1 and H3 influenza strains exist in the pre-vaccination serum repertoire of healthy adults; most vaccine-elicited clonotypes bind either H1 or H3 strains. Molecular understanding of serological immunity to influenza has been confounded by the complexity of the polyclonal antibody response in humans. Here we used high-resolution proteomics analysis of immunoglobulin (referred to as Ig-seq) coupled with high-throughput sequencing of transcripts encoding B cell receptors (BCR-seq) to quantitatively determine the antibody repertoire at the individual clonotype level in the sera of young adults before and after vaccination with trivalent seasonal influenza vaccine. The serum repertoire comprised between 40 and 147 clonotypes that were specific to each of the three monovalent components of the trivalent influenza vaccine, with boosted pre-existing clonotypes accounting for ∼60% of the response. An unexpectedly high fraction of serum antibodies recognized both the H1 and H3 monovalent vaccines. Recombinant versions of these H1 + H3 cross-reactive antibodies showed broad binding to hemagglutinins (HAs) from previously circulating virus strains; several of these antibodies, which were prevalent in the serum of multiple donors, recognized the same conserved epitope in the HA head domain. Although the HA-head-specific H1 + H3 antibodies did not show neutralization activity in vitro , they protected mice against infection with the H1N1 and H3N2 virus strains when administered before or after challenge. Collectively, our data reveal unanticipated insights regarding the serological response to influenza vaccination and raise questions about the added benefits of using a quadrivalent vaccine instead of a trivalent vaccine.

Background Chickens are susceptible to infection with a limited number of Influenza A viruses and are a potential source of a human influenza pandemic. In particular, H5 and H7 haemagglutinin subtypes can evolve from low to highly pathogenic strains in gallinaceous poultry. Ducks on the other hand are a natural reservoir for these viruses and are able to withstand most avian influenza strains. Results Transcriptomic sequencing of lung and ileum tissue samples from birds infected with high (H5N1) and low (H5N2) pathogenic influenza viruses has allowed us to compare the early host response to these infections in both these species. Chickens (but not ducks) lack the intracellular receptor for viral ssRNA, RIG-I and the gene for an important RIG-I binding protein, RNF135. These differences in gene content partly explain the differences in host responses to low pathogenic and highly pathogenic avian influenza virus in chicken and ducks. We reveal very different patterns of expression of members of the interferon-induced transmembrane protein ( IFITM ) gene family in ducks and chickens. In ducks, IFITM1, 2 and 3 are strongly up regulated in response to highly pathogenic avian influenza, where little response is seen in chickens. Clustering of gene expression profiles suggests IFITM1 and 2 have an anti-viral response and IFITM3 may restrict avian influenza virus through cell membrane fusion. We also show, through molecular phylogenetic analyses, that avian IFITM1 and IFITM3 genes have been subject to both episodic and pervasive positive selection at specific codons. In particular, avian IFITM1 showed evidence of positive selection in the duck lineage at sites known to restrict influenza virus infection. Conclusions Taken together these results support a model where the IFITM123 protein family and RIG-I all play a crucial role in the tolerance of ducks to highly pathogenic and low pathogenic strains of avian influenza viruses when compared to the chicken.

Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT. Using a multi-OMICS approach, Haas et al identify 54 human genes and 16 host-targeting chemical compounds that regulate influenza A virus infection in lung epithelial cells, including AHNAK and COBP1 which are also essential for SARS-CoV-2 infection.

H5N1 influenza viruses, which cause disease in humans, have unusually high pathogenicity. The temporal response of primary human monocyte-derived macrophages infected with highly pathogenic H5N1 and seasonal H1N1 influenza viruses was evaluated using mass spectrometry-based quantitative proteomic profiling. This was done in order to demonstrate significant perturbation of the host proteome upon viral infection, as early as 1 hour after infection. This early host response distinguished H5N1 infection from H1N1 infection, the latter inducing less of a response. The most pronounced effect was observed on the translational machinery, suggesting that H5N1 might gain advantage in replication by using the cell protein synthesis machinery early in the infection.

Since 2010 the WHO has held a series of informal consultations to explore ways of improving the currently highly complex and time-pressured influenza vaccine virus selection and development process. In November 2015 experts from around the world met to review the current status of efforts in this field. Discussion topics included strengthening influenza surveillance activities to increase the availability of candidate vaccine viruses and improve the extent, timeliness and quality of surveillance data. Consideration was also given to the development and potential application of newer laboratory assays to better characterize candidate vaccine viruses, the potential importance of antibodies directed against influenza virus neuraminidase, and the role of vaccine effectiveness studies. Advances in next generation sequencing and whole genome sequencing of influenza viruses were also discussed, along with associated developments in synthetic genomics technologies, evolutionary analysis and predictive mathematical modelling. Discussions were also held on the late emergence of an antigenic variant influenza A(H3N2) virus in mid-2014 that could not be incorporated in time into the 2014–15 northern hemisphere vaccine. There was broad recognition that given the current highly constrained influenza vaccine development and production timeline it would remain impossible to incorporate any variant virus which emerged significantly long after the relevant WHO biannual influenza vaccine composition meetings. Discussions were also held on the development of pandemic and broadly protective vaccines, and on associated regulatory and manufacturing requirements and constraints. With increasing awareness of the health and economic burdens caused by seasonal influenza, the ever-present threat posed by zoonotic influenza viruses, and the significant impact of the 2014–15 northern hemisphere seasonal influenza vaccine mismatch, this consultation provided a very timely opportunity to share developments and exchange views. In all areas, a renewed and strengthened emphasis was placed on developing concrete and measurable actions and identifying the key stakeholders responsible for their implementation.