Predicting response to checkpoint blockade therapy for lung cancer has largely focused on measuring programmed death-ligand 1 (PD-L1) expression on tumor cells. PD-L1 expression is geographically ...heterogeneous within many tumors, however, and we questioned whether small tissue samples, such as biopsies, might be sufficiently representative of PD-L1 expression for evaluating this marker in lung cancer tumors. To evaluate the extent of variability of PD-L1 expression in small tissue samples, and how that variability affects accuracy of overall assessment of PD-L1 in lung cancer, we scored immunohistochemical staining for PD-L1 in tissue microarray cores from a series of 79 squamous cell lung cancers and 71 pulmonary adenocarcinomas. Our study found substantial inconsistencies for the percentages of cells staining positive for PD-L1 among different tissue microarray cores in many cases of both adenocarcinoma and squamous cell carcinoma. This variable scoring was seen at both high levels and low levels of PD-L1 expression, and by further evaluation of cases with discordant results on full-face sections to assess geographic distribution of staining, we found that discordant results among different tissue microarray cores reflected geographic variation of PD-L1 expression in those tumors. Moreover, we found that as a result of heterogeneous expression, the sensitivity of a single small tissue sample can be as low as 85% for detecting PD-L1 expression at scoring thresholds commonly used in clinical practice. Based on these studies, we conclude that many cases of lung cancer could be inaccurately or variably scored for PD-L1 expression with a single biopsy sample. Accordingly, lung cancer patients can be inconsistently classified for PD-L1 expression status, particularly when a threshold for the percentage of positive cells is used to determine eligibility for checkpoint blockade therapy.
Early detection and intervention are likely to be the most effective means for reducing morbidity and mortality of human cancer. However, development of methods for noninvasive detection of ...early-stage tumors has remained a challenge. We have developed an approach called targeted error correction sequencing (TEC-Seq) that allows ultrasensitive direct evaluation of sequence changes in circulating cell-free DNA using massively parallel sequencing. We have used this approach to examine 58 cancer-related genes encompassing 81 kb. Analysis of plasma from 44 healthy individuals identified genomic changes related to clonal hematopoiesis in 16% of asymptomatic individuals but no alterations in driver genes related to solid cancers. Evaluation of 200 patients with colorectal, breast, lung, or ovarian cancer detected somatic mutations in the plasma of 71, 59, 59, and 68%, respectively, of patients with stage I or II disease. Analyses of mutations in the circulation revealed high concordance with alterations in the tumors of these patients. In patients with resectable colorectal cancers, higher amounts of preoperative circulating tumor DNA were associated with disease recurrence and decreased overall survival. These analyses provide a broadly applicable approach for noninvasive detection of early-stage tumors that may be useful for screening and management of patients with cancer.
Glioblastoma (GBM) is the most aggressive nervous system cancer. Understanding its molecular pathogenesis is crucial to improving diagnosis and treatment. Integrated analysis of genomic, proteomic, ...post-translational modification and metabolomic data on 99 treatment-naive GBMs provides insights to GBM biology. We identify key phosphorylation events (e.g., phosphorylated PTPN11 and PLCG1) as potential switches mediating oncogenic pathway activation, as well as potential targets for EGFR-, TP53-, and RB1-altered tumors. Immune subtypes with distinct immune cell types are discovered using bulk omics methodologies, validated by snRNA-seq, and correlated with specific expression and histone acetylation patterns. Histone H2B acetylation in classical-like and immune-low GBM is driven largely by BRDs, CREBBP, and EP300. Integrated metabolomic and proteomic data identify specific lipid distributions across subtypes and distinct global metabolic changes in IDH-mutated tumors. This work highlights biological relationships that could contribute to stratification of GBM patients for more effective treatment.
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•Phosphorylated PTPN11 and PLCG1 represent a signaling hub in RTK-altered tumors•Four immune GBM subtypes exist, characterized by distinct immune cell populations•Mesenchymal subtype EMT signature is specific to tumor cells but not to stroma•Histone H2B acetylation is enriched in classical GBMs with low macrophage content
Wang et al. perform integrated proteogenomic analysis of adult glioblastoma (GBM), including metabolomics, lipidomics, and single nuclei RNA-Seq, revealing insights into the immune landscape of GBM, cell-specific nature of EMT signatures, histone acetylation in classical GBM, and the existence of signaling hubs which could provide therapeutic vulnerabilities.
To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization of 110 tumors and 101 matched normal ...adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, and acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, and gender. Proteomic and phosphoproteomic data illuminated biology downstream of copy number aberrations, somatic mutations, and fusions and identified therapeutic vulnerabilities associated with driver events involving KRAS, EGFR, and ALK. Immune subtyping revealed a complex landscape, reinforced the association of STK11 with immune-cold behavior, and underscored a potential immunosuppressive role of neutrophil degranulation. Smoking-associated LUADs showed correlation with other environmental exposure signatures and a field effect in NATs. Matched NATs allowed identification of differentially expressed proteins with potential diagnostic and therapeutic utility. This proteogenomics dataset represents a unique public resource for researchers and clinicians seeking to better understand and treat lung adenocarcinomas.
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•Comprehensive LUAD proteogenomics exposes multi-omic clusters and immune subtypes•Phosphoproteomics identifies candidate ALK-fusion diagnostic markers and targets•Candidate drug targets: PTPN11 (EGFR), SOS1 (KRAS), neutrophil degranulation (STK11)•Phospho and acetyl modifications denote tumor-specific markers and druggable proteins
Comprehensive proteogenomic characterization of lung adenocarcinomas and paired normal adjacent tissues from patients of diverse smoking status and country of origin yields insights into cancer taxonomy, oncogenesis, and immune response; offers novel candidate biomarkers and therapeutic targets; and provides a community resource for further discovery.
We present a proteogenomic study of 108 human papilloma virus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs). Proteomic analysis systematically catalogs HNSCC-associated proteins and ...phosphosites, prioritizes copy number drivers, and highlights an oncogenic role for RNA processing genes. Proteomic investigation of mutual exclusivity between FAT1 truncating mutations and 11q13.3 amplifications reveals dysregulated actin dynamics as a common functional consequence. Phosphoproteomics characterizes two modes of EGFR activation, suggesting a new strategy to stratify HNSCCs based on EGFR ligand abundance for effective treatment with inhibitory EGFR monoclonal antibodies. Widespread deletion of immune modulatory genes accounts for low immune infiltration in immune-cold tumors, whereas concordant upregulation of multiple immune checkpoint proteins may underlie resistance to anti-programmed cell death protein 1 monotherapy in immune-hot tumors. Multi-omic analysis identifies three molecular subtypes with high potential for treatment with CDK inhibitors, anti-EGFR antibody therapy, and immunotherapy, respectively. Altogether, proteogenomics provides a systematic framework to inform HNSCC biology and treatment.
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•A systematic inventory of HNSCC-associated proteins, phosphosites, and pathways•Three multi-omic subtypes linked to targeted treatment approaches and immunotherapy•Widespread deletion of immune modulatory genes accounts for loss of immunogenicity•Two modes of EGFR activation inform response to anti-EGFR monoclonal antibodies
Huang et al. report a proteogenomic study on 108 HPV-negative head and neck squamous cell carcinomas (HNSCCs). In addition to creating a comprehensive resource for pathogenic insights, multi-omic analysis identifies therapeutic hypotheses that may inform more precise approaches to treatment.
Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape of LSCC, providing a deeper exposition of LSCC ...biology with potential therapeutic implications. We identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 tumors overexpressing the therapeutic target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such as LSD1 and EZH2 to target SOX2-overexpressing tumors. Our data support complex regulation of metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related proteogenomic observations suggest directions for further investigation. Proteogenomic dissection of CDKN2A mutations argue for more nuanced assessment of RB1 protein expression and phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation between LSCC, LUAD, and HNSCC identified both unique and common therapeutic vulnerabilities. These observations and proteogenomics data resources may guide research into the biology and treatment of LSCC.
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