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The National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) investigates tumors from a proteogenomic perspective, creating rich multi-omics datasets connecting genomic aberrations to cancer phenotypes. To facilitate pan-cancer investigations, we have generated harmonized genomic, transcriptomic, proteomic, and clinical data for >1000 tumors in 10 cohorts to create a cohesive and powerful dataset for scientific discovery. We outline efforts by the CPTAC pan-cancer working group in data harmonization, data dissemination, and computational resources for aiding biological discoveries. We also discuss challenges for multi-omics data integration and analysis, specifically the unique challenges of working with both nucleotide sequencing and mass spectrometry proteomics data., Competing Interests: Declaration of interests F.A. is an inventor on a patent application related to SignatureAnalyzer-GPU filed by the Broad Institute and is an employee and shareholder of Illumina Inc. since 8 November 2021., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Recent studies show that rare, deleterious variants (RDVs) in certain genes are critical determinants of heritable cancer risk. To more comprehensively understand RDVs, we performed the largest-to-date germline variant calling analysis in a case-control setting for a multi-cancer association study from whole-exome sequencing data of 20,789 participants, split into discovery and validation cohorts. We confirm and extend known associations between cancer risk and germline RDVs in specific gene-sets, including DNA repair (OR = 1.50; p-value = 8.30e-07; 95% CI: 1.28-1.77), cancer predisposition (OR = 1.51; p-value = 4.58e-08; 95% CI: 1.30-1.75), and somatic cancer drivers (OR = 1.46; p-value = 4.04e-06; 95% CI: 1.24-1.72). Furthermore, personal RDV load in these gene-sets associated with increased risk, younger age of onset, increased M1 macrophages in tumor and, increased tumor mutational burden in specific cancers. Our findings can be used towards identifying high-risk individuals, who can then benefit from increased surveillance, earlier screening, and treatments that exploit their tumor characteristics, improving prognosis., (© 2023. The Author(s).)

Background: The genetic factors that modulate risk for developing lung cancer have not been fully defined. Here, we sought to determine the prevalence and clinical significance of germline pathogenic/likely pathogenic variants (PV) in patients with advanced lung cancer., Methods: We studied clinical and tumor characteristics of germline PV in 5,118 patients who underwent prospective genomic profiling using paired tumor-normal tissue samples in 468 cancer genes., Results: Germline PV in high/moderate-penetrance genes were observed in 222 (4.3%) patients; of these, 193 patients had PV in DNA damage repair (DDR) pathway genes including BRCA2 (n = 54), CHEK2 (n = 30), and ATM (n = 26) that showed high rate of biallelic inactivation in tumors. BRCA2 heterozygotes with lung adenocarcinoma were more likely to be never smokers and had improved survival compared with noncarriers. Fourteen patients with germline PV in lung cancer predisposing genes (TP53, EGFR, BAP1, and MEN1) were diagnosed at younger age compared with noncarriers, and of tumor suppressors, 75% demonstrated biallelic inactivation in tumors. A significantly higher proportion of germline PV in high/moderate-penetrance genes were detected in high-risk patients who had either a family history of any cancer, multiple primary tumors, or early age at diagnosis compared with unselected patients (10.5% vs. 4.1%; P = 1.7e-04)., Conclusions: These data underscore the biological and clinical importance of germline mutations in highly penetrant DDR genes as a risk factor for lung cancer., Impact: The family members of lung cancer patients harboring PV in cancer predisposing genes should be referred for genetic counseling and may benefit from proactive surveillance., (©2022 American Association for Cancer Research.)

Introduction: Lung cancer is the leading cause of cancer deaths in the world, and lung adenocarcinoma (LUAD) is its most prevalent subtype. Symptoms are often found in advanced disease in which treatment options are limited. Identifying genetic risk factors will enable better identification of high-risk individuals., Methods: To identify LUAD risk genes, we performed a case-control association study for gene-level burden of rare, deleterious variants (RDVs) in germline whole-exome sequencing data of 1083 patients with LUAD and 7650 controls, split into discovery and validation cohorts. Of these, we performed whole-exome sequencing on 97 patients and acquired the rest from multiple public databases. We annotated all rare variants for pathogenicity conservatively, using the guidelines of the American College of Medical Genetics and Genomics and ClinVar curation, and investigated gene-level RDV burden using penalized logistic regression. All statistical tests were two-sided., Results: We discovered and replicated the finding that the burden of germline ATM RDVs was significantly higher in patients with LUAD versus controls (combined cohort OR = 4.6; p = 1.7e-04; 95% confidence interval = 2.2-9.5; 1.21% of cases; 0.24% of controls). Germline ATM RDVs were also enriched in an independent clinical cohort of 1594 patients from the MSK-IMPACT study (0.63%). In addition, we observed that an Ashkenazi Jewish (AJ) founder ATM variant, rs56009889, was statistically significantly more frequent in AJ cases versus AJ controls in our cohort (combined AJ cohort OR = 2.7, p = 6.9e-03, 95% confidence interval = 1.3-5.3)., Conclusions: Our results indicate that ATM is a moderate-penetrance LUAD risk gene and that LUAD may be a part of the ATM-related cancer syndrome spectrum. Individuals with ATM RDVs are at an elevated LUAD risk and can benefit from increased surveillance (particularly computed tomography scanning), early detection, and chemoprevention programs, improving prognosis., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide, igniting an unprecedented effort from the scientific community to understand the biological underpinning of COVID19 pathophysiology. In this Review, we summarize the current state of knowledge of innate and adaptive immune responses elicited by SARS-CoV-2 infection and the immunological pathways that likely contribute to disease severity and death. We also discuss the rationale and clinical outcome of current therapeutic strategies as well as prospective clinical trials to prevent or treat SARS-CoV-2 infection., Competing Interests: Declaration of Interests N.B. serves as an advisor/board member for Neon, Checkpoint Sciences, Primevax, Novartis, Array BioPharma, Roche, Avidea, Boeringer Ingelheim, Rome Therapeutics, Roswell Park, and the Parker Institute for Cancer Immunotherapy. N.B. receives research support from the Parker Insitute, Novocure, Celldex, Genentech, Oncovir, and Regeneron. M.M. serves as an advisor/board member for Celsius, Pionyr, Compugen, Myeloids and Innate pharma and ad hoc for Takeda. M.M. receives research support from Regeneron, Takeda, and Genentech. A.M. has equity in Gilead Sciences and Regeneron Pharmaceuticals., (Copyright © 2020 Elsevier Inc. All rights reserved.)

High mortality rates of glioblastoma (GBM) patients are partly attributed to the invasive behavior of tumor cells that exhibit extensive infiltration into adjacent brain tissue, leading to rapid, inevitable, and therapy-resistant recurrence. In this study, we analyzed transcriptome of motile (dispersive) and non-motile (core) GBM cells using an in vitro spheroid dispersal model and identified SERPINE1 as a modulator of GBM cell dispersal. Genetic or pharmacological inhibition of SERPINE1 reduced spheroid dispersal and cell adhesion by regulating cell-substrate adhesion. We examined TGFβ as a potential upstream regulator of SERPINE1 expression. We also assessed the significance of SERPINE1 in GBM growth and invasion using TCGA glioma datasets and a patient-derived orthotopic GBM model. SERPINE1 expression was associated with poor prognosis and mesenchymal GBM in patients. SERPINE1 knock-down in primary GBM cells suppressed tumor growth and invasiveness in the brain. Together, our results indicate that SERPINE1 is a key player in GBM dispersal and provide insights for future anti-invasive therapy design.

Purpose: Lung cancer is the leading cause of cancer deaths worldwide, with substantially better prognosis in early-stage as opposed to late-stage disease. Identifying genetic factors for lung squamous cell carcinoma (SqCC) risk will enable their use in risk stratification, and personalized intensive surveillance, early detection, and prevention strategies for high-risk individuals., Experimental Design: We analyzed whole-exome sequencing datasets of 318 cases and 814 controls (discovery cohort) and then validated our findings in an independent cohort of 444 patients and 3,479 controls (validation cohort), all of European descent. We also combined all the samples from both cohorts, which, after principal component analysis (PCA) and population stratification, included 765 cases and 4,344 controls (combined cohort). We focused on rare, pathogenic variants found in the ClinVar database and used penalized logistic regression to identify genes in which such variants are enriched in cases. All statistical tests were two-sided., Results: We observed an overall enrichment of rare, deleterious germline variants in Fanconi anemia genes in cases with SqCC [joint analysis odds ratio (OR) = 3.08; P = 1.4e-09; 95% confidence interval (CI), 2.2-4.3]. Consistent with previous studies, BRCA2 in particular exhibited an increased overall burden of rare, deleterious variants (joint OR = 3.2; P = 8.7e-08; 95% CI, 2.1-4.7). More importantly, rare, deleterious germline variants were enriched in Fanconi anemia genes even without the BRCA2 rs11571833 variant that is strongly enriched in lung SqCC cases (joint OR = 2.76; P = 7.0e-04; 95% CI, 1.6-4.7)., Conclusions: These findings can be used toward the development of a genetic diagnostic test in the clinic to identify SqCC high-risk individuals, who can benefit from personalized programs, improving prognosis., (©2018 American Association for Cancer Research.)

Melittin is a natural peptide that aggregates in aqueous solutions with paradigmatic monomer-to-tetramer and coil-to-helix transitions. Since little is known about the molecular mechanisms of melittin aggregation in solution, we simulated its self-aggregation process under various conditions. After confirming the stability of a melittin tetramer in solution, we observed—for the first time in atomistic detail—that four separated melittin monomers aggregate into a tetramer. Our simulated dependence of melittin aggregation on peptide concentration, temperature, and ionic strength is in good agreement with prior experiments. We propose that melittin mainly self-aggregates via a mechanism involving the sequential addition of monomers, which is supported by both qualitative and quantitative evidence obtained from unbiased and metadynamics simulations. Moreover, by combining computer simulations and a theory of the electrical double layer, we provide evidence to suggest why melittin aggregation in solution likely stops at the tetramer, rather than forming higher-order oligomers. Overall, our study not only explains prior experimental results at the molecular level but also provides quantitative mechanistic information that may guide the engineering of melittin for higher efficacy and safety.