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Single-cell RNA sequencing studies have suggested that total mRNA content correlates with tumor phenotypes. Technical and analytical challenges, however, have so far impeded at-scale pan-cancer examination of total mRNA content. Here we present a method to quantify tumor-specific total mRNA expression (TmS) from bulk sequencing data, taking into account tumor transcript proportion, purity and ploidy, which are estimated through transcriptomic/genomic deconvolution. We estimate and validate TmS in 6,590 patient tumors across 15 cancer types, identifying significant inter-tumor variability. Across cancers, high TmS is associated with increased risk of disease progression and death. TmS is influenced by cancer-specific patterns of gene alteration and intra-tumor genetic heterogeneity as well as by pan-cancer trends in metabolic dysregulation. Taken together, our results indicate that measuring cell-type-specific total mRNA expression in tumor cells predicts tumor phenotypes and clinical outcomes., (© 2022. The Author(s).)

We have established considerable expertise in studying the role of platelets in cancer biology. From this expertise, we were keen to recognize the numerous venous-, arterial-, microvascular-, and macrovascular thrombotic events and immunologic disorders are caused by severe, acute-respiratory-syndrome coronavirus 2 (SARS-CoV-2) infections. With this offering, we explore the evolutionary connections that place platelets at the center of hemostasis, immunity, and adaptive phylogeny. Coevolutionary changes have also occurred in vertebrate viruses and their vertebrate hosts that reflect their respective evolutionary interactions. As mammals adapted from aquatic to terrestrial life and the heavy blood loss associated with placentalization-based live birth, platelets evolved phylogenetically from thrombocytes toward higher megakaryocyte-blebbing-based production rates and the lack of nuclei. With no nuclei and robust RNA synthesis, this adaptation may have influenced viral replication to become less efficient after virus particles are engulfed. Human platelets express numerous receptors that bind viral particles, which developed from archetypal origins to initiate aggregation and exocytic-release of thrombo-, immuno-, angiogenic-, growth-, and repair-stimulatory granule contents. Whether by direct, evolutionary, selective pressure, or not, these responses may help to contain virus spread, attract immune cells for eradication, and stimulate angiogenesis, growth, and wound repair after viral damage. Because mammalian and marsupial platelets became smaller and more plate-like their biophysical properties improved in function, which facilitated distribution near vessel walls in fluid-shear fields. This adaptation increased the probability that platelets could then interact with and engulf shedding virus particles. Platelets also generate circulating microvesicles that increase membrane surface-area encounters and mark viral targets. In order to match virus-production rates, billions of platelets are generated and turned over per day to continually provide active defenses and adaptation to suppress the spectrum of evolving threats like SARS-CoV-2., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: DNA polymerase epsilon is critical to DNA proofreading and replication. Mutations in POLE have been associated with hypermutated tumors and antitumor response to immune checkpoint inhibitor (ICI) therapy. We present a clinicopathologic analysis of patients with advanced cancers harboring POLE mutations, the pattern of co-occurring mutations, and their response to ICI therapy within the context of mutation pathogenicity., Methods: We conducted a retrospective analysis of next-generation sequencing data at MD Anderson Cancer Center to identify patient tumors with POLE mutations and their co-occurring mutations. The pathogenicity of each mutation was annotated using InterVar and ClinVar. Differences in therapeutic response to ICI, survival, and co-occurring mutations were reported by POLE pathogenicity status., Results: Four hundred fifty-eight patient tumors with POLE mutations were identified from 14,229 next-generation sequencing reports; 15.0% of POLE mutations were pathogenic, 15.9% benign, and 69.1% variant of unknown significance. Eighty-two patients received either programmed death 1 or programmed death ligand-1 inhibitors as monotherapy or in combination with cytotoxic T-cell lymphocyte-4 inhibitors. Patients with pathogenic POLE mutations had improved clinical benefit rate (82.4% v 30.0%; P = .013), median progression-free survival (15.1 v 2.2 months; P < .001), overall survival (29.5 v 6.8 months; P < .001), and longer treatment duration (median 15.5 v 2.5 months; P < .001) compared to those with benign variants. Progression-free survival and overall survival remained superior when adjusting for number of co-occurring mutations (≥ 10 v < 10) and/or microsatellite instability status (proficient mismatch repair v deficient mismatch repair). The number of comutations was not associated with response to ICI (clinical benefit v progressive disease: median 13 v 11 comutations; P = .18)., Conclusion: Pathogenic POLE mutations were associated with clinical benefit to ICI therapy. Further studies are warranted to validate POLE mutation as a predictive biomarker of ICI therapy., Competing Interests: Benjamin GarmezyUncompensated Relationships: AVEO (Inst) Xianli JiangPatents, Royalties, Other Intellectual Property: I am in the process of a patent application, which is nonrelevant to this study. The application is for United States Letters Patent, Serial No. 63/015,317 Patrick G. PiliéConsulting or Advisory Role: NovartisPatents, Royalties, Other Intellectual Property: Patent pending-biomarker Kenna R. ShawConsulting or Advisory Role: Guidepoint GlobalResearch Funding: Guardant Health (Inst), Tempus (Inst), Philips Healthcare (Inst) Jordi RodonConsulting or Advisory Role: Peptomyc, Kelun, Merck Sharp & Dohme, Spectrum Pharmaceuticals, Pfizer, Roche/Genentech, Ellipses Pharma, Ionctura, Novartis, Lilly, Orion, Servier, Molecular Partners, NovellusDx, Certara, Bayer, KisoJi BiotechnologyResearch Funding: Novartis, Bayer, Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, Genmab, CytomX Therapeutics, Kelun, Takeda/Millennium, GlaxoSmithKline, Ipsen, Blueprint MedicinesTravel, Accommodations, Expenses: ESMO, Department of Defense, Louisiana State University, Huntsman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute, King Abdullah International Medical Research Center, Molecular Partners, Merck Sharp & Dohme, Kelun Pharmaceuticals/Klus Pharma, Bayer, WIN Consortium, JanssenOther Relationship: European Journal of Cancer, Chinese University of Hong Kong, SOLTI, Elsevier, GlaxoSmithKline, Vall d'Hebron University Hospital Institute of Oncology, VHIO/Ministero De Empleo Y Seguridad Social John-Paul ShenStock and Other Ownership Interests: Agios, SyndaxConsulting or Advisory Role: Engine BiosciencesResearch Funding: Celsius Therapeutics Ying YuanHonoraria: Ono PharmaceuticalConsulting or Advisory Role: Boehringer Ingelheim, Amgen, AbbVie, Servier, Starpax Medical, Vertex, MicuRx Pharmaceuticals, BeyondSpring Pharmaceuticals, Bristol Myers Squibb/Celgene/Juno Funda Meric-BernstamEmployment: MD Anderson Cancer CenterHonoraria: Rutgers Cancer Institute of New JerseyConsulting or Advisory Role: Samsung Bioepis, Xencor, Debiopharm Group, Silverback Therapeutics, IBM Watson Health, Roche, PACT Pharma, eFFECTOR Therapeutics, Kolon Life Sciences, Tyra Biosciences, Zymeworks, Puma Biotechnology, Zentalis, Alkermes, Infinity Pharmaceuticals, AbbVie, Black Diamond Therapeutics, Eisai, OnCusp Therapeutics, Lengo Therapeutics, Tallac Therapeutics, Karyopharm Therapeutics, BiovicaSpeakers' Bureau: Chugai PharmaResearch Funding: Novartis (Inst), AstraZeneca (Inst), Taiho Pharmaceutical (Inst), Genentech (Inst), Calithera Biosciences (Inst), Debiopharm Group (Inst), Bayer (Inst), Aileron Therapeutics (Inst), PUMA Biotechnology (Inst), CytomX Therapeutics (Inst), Jounce Therapeutics (Inst), Zymeworks (Inst), Curis (Inst), Pfizer (Inst), eFFECTOR Therapeutics (Inst), AbbVie (Inst), Boehringer Ingelheim, Guardant Health (Inst), Daiichi Sankyo (Inst), GlaxoSmithKline (Inst), Seattle Genetics (Inst), Klus Pharma (Inst), Takeda (Inst)Travel, Accommodations, Expenses: Beth Israel Deaconess Medical Center Timothy A. YapConsulting or Advisory Role: Pfizer, EMD Serono, Clovis Oncology, Ignyta, AstraZeneca, Atrin Pharmaceuticals, Aduro Biotech, Merck, Almac Diagnstics, Bayer, Bristol Myers Squibb, Calithera Biosciences, Cybrexa Therapeutics, Janssen, Roche, Seattle Genetics, Axiom Biotechnologies, F-Star, Guidepoint Global, I-Mab, Repare Therapeutics, Rubius Therapeutics, Schrodinger, Varian Medical Systems, Zai LabResearch Funding: AstraZeneca (Inst), Vertex (Inst), Pfizer (Inst), Bayer (Inst), Tesaro (Inst), Jounce Therapeutics (Inst), Seattle Genetics (Inst), Kyowa Hakko Kirin (Inst), Constellation Pharmaceuticals (Inst), Lilly (Inst), Artios (Inst), Clovis Oncology (Inst), Cyteir (Inst), EMD Serono (Inst), Forbius (Inst), F-Star (Inst), GlaxoSmithKline (Inst), Genentech (Inst), ImmuneSensor Therapeutics (Inst), Ipsen (Inst), Karyopharm Therapeutics (Inst), Merck (Inst), Novartis (Inst), Ribon Therapeutics (Inst), Regeneron (Inst), Repare Therapeutics (Inst), Sanofi (Inst), Scholar Rock (Inst)No other potential conflicts of interest were reported.

A targeted cancer therapy is only useful if there is a way to accurately identify the tumors that are susceptible to that therapy. Thus rapid expansion in the number of available targeted cancer treatments has been accompanied by a robust effort to subdivide the traditional histological and anatomical tumor classifications into molecularly defined subtypes. This review highlights the history of the paired evolution of targeted therapies and biomarkers, reviews currently used methods for subtype identification, and discusses challenges to the implementation of precision oncology as well as possible solutions., (© 2021 The Author(s).)

Many recent efforts to analyze cancer genomes involve aggregation of mutations within reference maps of molecular pathways and protein networks. Here, we find these pathway studies are impeded by molecular interactions that are functionally irrelevant to cancer or the patient's tumor type, as these interactions diminish the contrast of driver pathways relative to individual frequently mutated genes. This problem can be addressed by creating stringent tumor-specific networks of biophysical protein interactions, identified by signatures of epistatic selection during tumor evolution. Using such an evolutionarily selected pathway (ESP) map, we analyze the major cancer genome atlases to derive a hierarchical classification of tumor subtypes linked to characteristic mutated pathways. These pathways are clinically prognostic and predictive, including the TP53-AXIN-ARHGEF17 combination in liver and CYLC2-STK11-STK11IP in lung cancer, which we validate in independent cohorts. This ESP framework substantially improves the definition of cancer pathways and subtypes from tumor genome data.

Synthetic lethal interactions, in which the simultaneous loss of function of two genes produces a lethal phenotype, are being explored as a means to therapeutically exploit cancer-specific vulnerabilities and expand the scope of precision oncology. Currently, three Food and Drug Administration-approved drugs work by targeting the synthetic lethal interaction between BRCA1/2 and PARP. This review examines additional efforts to discover networks of synthetic lethal interactions and discusses both challenges and opportunities regarding the translation of new synthetic lethal interactions into the clinic., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Although cancer genomes are replete with noncoding mutations, the effects of these mutations remain poorly characterized. Here we perform an integrative analysis of 930 tumor whole genomes and matched transcriptomes, identifying a network of 193 noncoding loci in which mutations disrupt target gene expression. These 'somatic eQTLs' (expression quantitative trait loci) are frequently mutated in specific cancer tissues, and the majority can be validated in an independent cohort of 3,382 tumors. Among these, we find that the effects of noncoding mutations on DAAM1, MTG2 and HYI transcription are recapitulated in multiple cancer cell lines and that increasing DAAM1 expression leads to invasive cell migration. Collectively, the noncoding loci converge on a set of core pathways, permitting a classification of tumors into pathway-based subtypes. The somatic eQTL network is disrupted in 88% of tumors, suggesting widespread impact of noncoding mutations in cancer.

Chemical inhibitors of the checkpoint kinases have shown promise in the treatment of cancer, yet their clinical utility may be limited by a lack of molecular biomarkers to identify specific patients most likely to respond to therapy. To this end, we screened 112 known tumor suppressor genes for synthetic lethal interactions with inhibitors of the CHEK1 and CHEK2 checkpoint kinases. We identified eight interactions, including the Replication Factor C (RFC)-related protein RAD17. Clonogenic assays in RAD17 knockdown cell lines identified a substantial shift in sensitivity to checkpoint kinase inhibition (3.5-fold) as compared to RAD17 wild-type. Additional evidence for this interaction was found in a large-scale functional shRNA screen of over 100 genotyped cancer cell lines, in which CHEK1/2 mutant cell lines were unexpectedly sensitive to RAD17 knockdown. This interaction was widely conserved, as we found that RAD17 interacts strongly with checkpoint kinases in the budding yeast Saccharomyces cerevisiae. In the setting of RAD17 knockdown, CHEK1/2 inhibition was found to be synergistic with inhibition of WEE1, another pharmacologically relevant checkpoint kinase. Accumulation of the DNA damage marker γH2AX following chemical inhibition or transient knockdown of CHEK1, CHEK2 or WEE1 was magnified by knockdown of RAD17. Taken together, our data suggest that CHEK1 or WEE1 inhibitors are likely to have greater clinical efficacy in tumors with RAD17 loss-of-function.

Many forms of cancer have multiple subtypes with different causes and clinical outcomes. Somatic tumor genome sequences provide a rich new source of data for uncovering these subtypes but have proven difficult to compare, as two tumors rarely share the same mutations. Here we introduce network-based stratification (NBS), a method to integrate somatic tumor genomes with gene networks. This approach allows for stratification of cancer into informative subtypes by clustering together patients with mutations in similar network regions. We demonstrate NBS in ovarian, uterine and lung cancer cohorts from The Cancer Genome Atlas. For each tissue, NBS identifies subtypes that are predictive of clinical outcomes such as patient survival, response to therapy or tumor histology. We identify network regions characteristic of each subtype and show how mutation-derived subtypes can be used to train an mRNA expression signature, which provides similar information in the absence of DNA sequence.