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Chromatin regulators play a broad role in regulating gene expression and, when gone awry, can lead to cancer. Here, we demonstrate that ablation of the histone demethylase LSD1 in cancer cells increases repetitive element expression, including endogenous retroviral elements (ERVs), and decreases expression of RNA-induced silencing complex (RISC) components. Significantly, this leads to double-stranded RNA (dsRNA) stress and activation of type 1 interferon, which stimulates anti-tumor T cell immunity and restrains tumor growth. Furthermore, LSD1 depletion enhances tumor immunogenicity and T cell infiltration in poorly immunogenic tumors and elicits significant responses of checkpoint blockade-refractory mouse melanoma to anti-PD-1 therapy. Consistently, TCGA data analysis shows an inverse correlation between LSD1 expression and CD8+ T cell infiltration in various human cancers. Our study identifies LSD1 as a potent inhibitor of anti-tumor immunity and responsiveness to immunotherapy and suggests LSD1 inhibition combined with PD-(L)1 blockade as a novel cancer treatment strategy.
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Retrovirus Endógenos/genética , Histona Desmetilases/metabolismo , Complexo de Inativação Induzido por RNA/genética , Animais , Linhagem Celular Tumoral , Cromatina , Terapia Combinada , Regulação da Expressão Gênica/genética , Histona Desmetilases/genética , Humanos , Imunidade Celular , Imunoterapia , Interferon Tipo I , Células MCF-7 , Camundongos , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , RNA de Cadeia Dupla/genética , Linfócitos TRESUMO
Importance: Less than 10% of patients with cancer have detectable pathogenic germline alterations, which may be partially due to incomplete pathogenic variant detection. Objective: To evaluate if deep learning approaches identify more germline pathogenic variants in patients with cancer. Design, Setting, and Participants: A cross-sectional study of a standard germline detection method and a deep learning method in 2 convenience cohorts with prostate cancer and melanoma enrolled in the US and Europe between 2010 and 2017. The final date of clinical data collection was December 2017. Exposures: Germline variant detection using standard or deep learning methods. Main Outcomes and Measures: The primary outcomes included pathogenic variant detection performance in 118 cancer-predisposition genes estimated as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The secondary outcomes were pathogenic variant detection performance in 59 genes deemed actionable by the American College of Medical Genetics and Genomics (ACMG) and 5197 clinically relevant mendelian genes. True sensitivity and true specificity could not be calculated due to lack of a criterion reference standard, but were estimated as the proportion of true-positive variants and true-negative variants, respectively, identified by each method in a reference variant set that consisted of all variants judged to be valid from either approach. Results: The prostate cancer cohort included 1072 men (mean [SD] age at diagnosis, 63.7 [7.9] years; 857 [79.9%] with European ancestry) and the melanoma cohort included 1295 patients (mean [SD] age at diagnosis, 59.8 [15.6] years; 488 [37.7%] women; 1060 [81.9%] with European ancestry). The deep learning method identified more patients with pathogenic variants in cancer-predisposition genes than the standard method (prostate cancer: 198 vs 182; melanoma: 93 vs 74); sensitivity (prostate cancer: 94.7% vs 87.1% [difference, 7.6%; 95% CI, 2.2% to 13.1%]; melanoma: 74.4% vs 59.2% [difference, 15.2%; 95% CI, 3.7% to 26.7%]), specificity (prostate cancer: 64.0% vs 36.0% [difference, 28.0%; 95% CI, 1.4% to 54.6%]; melanoma: 63.4% vs 36.6% [difference, 26.8%; 95% CI, 17.6% to 35.9%]), PPV (prostate cancer: 95.7% vs 91.9% [difference, 3.8%; 95% CI, -1.0% to 8.4%]; melanoma: 54.4% vs 35.4% [difference, 19.0%; 95% CI, 9.1% to 28.9%]), and NPV (prostate cancer: 59.3% vs 25.0% [difference, 34.3%; 95% CI, 10.9% to 57.6%]; melanoma: 80.8% vs 60.5% [difference, 20.3%; 95% CI, 10.0% to 30.7%]). For the ACMG genes, the sensitivity of the 2 methods was not significantly different in the prostate cancer cohort (94.9% vs 90.6% [difference, 4.3%; 95% CI, -2.3% to 10.9%]), but the deep learning method had a higher sensitivity in the melanoma cohort (71.6% vs 53.7% [difference, 17.9%; 95% CI, 1.82% to 34.0%]). The deep learning method had higher sensitivity in the mendelian genes (prostate cancer: 99.7% vs 95.1% [difference, 4.6%; 95% CI, 3.0% to 6.3%]; melanoma: 91.7% vs 86.2% [difference, 5.5%; 95% CI, 2.2% to 8.8%]). Conclusions and Relevance: Among a convenience sample of 2 independent cohorts of patients with prostate cancer and melanoma, germline genetic testing using deep learning, compared with the current standard genetic testing method, was associated with higher sensitivity and specificity for detection of pathogenic variants. Further research is needed to understand the relevance of these findings with regard to clinical outcomes.
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Análise Mutacional de DNA/métodos , Aprendizado Profundo , Testes Genéticos/métodos , Mutação em Linhagem Germinativa , Melanoma/genética , Neoplasias da Próstata/genética , Estudos Transversais , Feminino , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Redes Neurais de Computação , Valor Preditivo dos Testes , Sensibilidade e EspecificidadeRESUMO
MOTIVATION: Venn and Euler diagrams are a popular yet inadequate solution for quantitative visualization of set intersections. A scalable alternative to Venn and Euler diagrams for visualizing intersecting sets and their properties is needed. RESULTS: We developed UpSetR, an open source R package that employs a scalable matrix-based visualization to show intersections of sets, their size, and other properties. AVAILABILITY AND IMPLEMENTATION: UpSetR is available at https://github.com/hms-dbmi/UpSetR/ and released under the MIT License. A Shiny app is available at https://gehlenborglab.shinyapps.io/upsetr/ . CONTACT: nils@hms.harvard.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Biologia Computacional/métodos , Software , Técnicas de Genotipagem/métodos , Análise de Sequência de DNA/métodosRESUMO
The diversity of structural variants (SVs) in melanoma and how they impact oncogenesis are incompletely known. We performed harmonized analysis of SVs across melanoma histologic and genomic subtypes, and we identified distinct global properties between subtypes. These included the frequency and size of SVs and SV classes, their relation to chromothripsis events, and the impact on cancer-related genes of SVs that alter topologically associated domain (TAD) boundaries. Following our prior identification of double-stranded break repair deficiency in a subset of triple-wild-type cutaneous melanoma, we identified MRE11 and NBN loss-of-function SVs in melanomas with this mutational signature. Experimental knockouts of MRE11 and NBN, followed by olaparib cell viability assays in melanoma cells, indicated that dysregulation of each of these genes may cause sensitivity to PARP inhibitors in cutaneous melanomas. Broadly, harmonized analysis of melanoma SVs revealed distinct global genomic properties and molecular drivers, which may have biological and therapeutic impact.
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Melanoma , Melanoma/genética , Melanoma/patologia , Melanoma/metabolismo , Humanos , Linhagem Celular Tumoral , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/metabolismo , Carcinogênese/genética , Proteína Homóloga a MRE11/genética , Proteína Homóloga a MRE11/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Ftalazinas/farmacologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Variação Estrutural do Genoma/genética , Piperazinas/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologiaRESUMO
While alterations in nucleus size, shape, and color are ubiquitous in cancer, comprehensive quantification of nuclear morphology across a whole-slide histologic image remains a challenge. Here, we describe the development of a pan-tissue, deep learning-based digital pathology pipeline for exhaustive nucleus detection, segmentation, and classification and the utility of this pipeline for nuclear morphologic biomarker discovery. Manually-collected nucleus annotations were used to train an object detection and segmentation model for identifying nuclei, which was deployed to segment nuclei in H&E-stained slides from the BRCA, LUAD, and PRAD TCGA cohorts. Interpretable features describing the shape, size, color, and texture of each nucleus were extracted from segmented nuclei and compared to measurements of genomic instability, gene expression, and prognosis. The nuclear segmentation and classification model trained herein performed comparably to previously reported models. Features extracted from the model revealed differences sufficient to distinguish between BRCA, LUAD, and PRAD. Furthermore, cancer cell nuclear area was associated with increased aneuploidy score and homologous recombination deficiency. In BRCA, increased fibroblast nuclear area was indicative of poor progression-free and overall survival and was associated with gene expression signatures related to extracellular matrix remodeling and anti-tumor immunity. Thus, we developed a powerful pan-tissue approach for nucleus segmentation and featurization, enabling the construction of predictive models and the identification of features linking nuclear morphology with clinically-relevant prognostic biomarkers across multiple cancer types.
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Nonalcoholic steatohepatitis (NASH) is the most common chronic liver disease globally and a leading cause for liver transplantation in the US. Its pathogenesis remains imprecisely defined. We combined two high-resolution modalities to tissue samples from NASH clinical trials, machine learning (ML)-based quantification of histological features and transcriptomics, to identify genes that are associated with disease progression and clinical events. A histopathology-driven 5-gene expression signature predicted disease progression and clinical events in patients with NASH with F3 (pre-cirrhotic) and F4 (cirrhotic) fibrosis. Notably, the Notch signaling pathway and genes implicated in liver-related diseases were enriched in this expression signature. In a validation cohort where pharmacologic intervention improved disease histology, multiple Notch signaling components were suppressed.
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Aprendizado Profundo , Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/complicações , Transcriptoma/genética , Progressão da Doença , Cirrose Hepática/genética , Cirrose Hepática/tratamento farmacológicoRESUMO
The extent to which clinical and genomic characteristics associate with prostate cancer clonal architecture, tumor evolution, and therapeutic response remains unclear. Here, we reconstructed the clonal architecture and evolutionary trajectories of 845 prostate cancer tumors with harmonized clinical and molecular data. We observed that tumors from patients who self-reported as Black had more linear and monoclonal architectures, despite these men having higher rates of biochemical recurrence. This finding contrasts with prior observations relating polyclonal architecture to adverse clinical outcomes. Additionally, we utilized a novel approach to mutational signature analysis that leverages clonal architecture to uncover additional cases of homologous recombination and mismatch repair deficiency in primary and metastatic tumors and link the origin of mutational signatures to specific subclones. Broadly, prostate cancer clonal architecture analysis reveals novel biological insights that may be immediately clinically actionable and provide multiple opportunities for subsequent investigation. Statement of significance: Tumors from patients who self-reported as Black demonstrate linear and monoclonal evolutionary trajectories yet experience higher rates of biochemical recurrence. In addition, analysis of clonal and subclonal mutational signatures identifies additional tumors with potentially actionable alterations such as deficiencies in mismatch repair and homologous recombination.
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BACKGROUND: Muscle-invasive bladder cancer (MIBC) is a rare but serious event following definitive radiation for prostate cancer. Radiation-associated MIBC (RA-MIBC) can be difficult to manage given the challenges of delivering definitive therapy to a previously irradiated pelvis. The genomic landscape of RA-MIBC and whether it is distinct from non-RA-MIBC are unknown. OBJECTIVE: To define mutational features of RA-MIBC and compare the genomic landscape of RA-MIBC with that of non-RA-MIBC. DESIGN, SETTING, AND PARTICIPANTS: We identified patients from our institution who received radiotherapy for prostate cancer and subsequently developed MIBC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We performed whole exome sequencing of bladder tumors from RA-MIBC patients. Tumor genetic alterations including mutations, copy number alterations, and mutational signatures were identified and were compared with genetic features of non-RA-MIBC. We used the Kaplan-Meier method to estimate recurrence-free (RFS) and overall (OS) survival. RESULTS AND LIMITATIONS: We identified 19 RA-MIBC patients with available tumor tissue (n = 22 tumors) and clinical data. The median age was 76 yr, and the median time from prostate cancer radiation to RA-MIBC was 12 yr. The median RFS was 14.5 mo and the median OS was 22.0 mo. Compared with a cohort of non-RA-MIBC analyzed in parallel, there was no difference in tumor mutational burden, but RA-MIBCs had a significantly increased number of short insertions and deletions (indels) consistent with previous radiation exposure. We identified mutation signatures characteristic of APOBEC-mediated mutagenesis, aging, and homologous recombination deficiency. The frequency of mutations in many known bladder cancer genes, including TP53, KDM6A, and RB1, as well as copy number alterations such as CDKN2A loss was similar in RA-MIBC and non-RA-MIBC. CONCLUSIONS: We identified unique mutational properties that likely contribute to the distinct biological and clinical features of RA-MIBC. PATIENT SUMMARY: Bladder cancer is a rare but serious diagnosis following radiation for prostate cancer. We characterized genetic features of bladder tumors arising after prostate radiotherapy, and identify similarities with and differences from bladder tumors from patients without previous radiation.
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Neoplasias da Próstata , Neoplasias da Bexiga Urinária , Idoso , Feminino , Genômica/métodos , Humanos , Masculino , Músculos/patologia , Invasividade Neoplásica , Próstata/patologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/radioterapia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/radioterapiaRESUMO
Gene fusions frequently result from rearrangements in cancer genomes. In many instances, gene fusions play an important role in oncogenesis; in other instances, they are thought to be passenger events. Although regulatory element rearrangements and copy number alterations resulting from these structural variants are known to lead to transcriptional dysregulation across cancers, the extent to which these events result in functional dependencies with an impact on cancer cell survival is variable. Here we used CRISPR-Cas9 dependency screens to evaluate the fitness impact of 3,277 fusions across 645 cell lines from the Cancer Dependency Map. We found that 35% of cell lines harbored either a fusion partner dependency or a collateral dependency on a gene within the same topologically associating domain as a fusion partner. Fusion-associated dependencies revealed numerous novel oncogenic drivers and clinically translatable alterations. Broadly, fusions can result in partner and collateral dependencies that have biological and clinical relevance across cancer types. SIGNIFICANCE: This study provides insights into how fusions contribute to fitness in different cancer contexts beyond partner-gene activation events, identifying partner and collateral dependencies that may have direct implications for clinical care.
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Sobrevivência Celular/genética , Fusão Gênica/genética , Neoplasias/genética , HumanosRESUMO
High-risk localized prostate cancer (HRLPC) is associated with a substantial risk of recurrence and disease mortality. Recent clinical trials have shown that intensifying anti-androgen therapies administered before prostatectomy can induce pathologic complete responses or minimal residual disease, called exceptional response, although the molecular determinants of these clinical outcomes are largely unknown. Here, we perform whole-exome and transcriptome sequencing on pre-treatment multi-regional tumor biopsies from exceptional responders (ERs) and non-responders (NRs, pathologic T3 or lymph node-positive disease) to intensive neoadjuvant anti-androgen therapies. Clonal SPOP mutation and SPOPL copy-number loss are exclusively observed in ERs, while clonal TP53 mutation and PTEN copy-number loss are exclusively observed in NRs. Transcriptional programs involving androgen signaling and TGF-ß signaling are enriched in ERs and NRs, respectively. These findings may guide prospective validation studies of these molecular features in large HRLPC clinical cohorts treated with neoadjuvant anti-androgens to improve patient stratification.
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Antagonistas de Androgênios/uso terapêutico , Proteínas Nucleares/efeitos dos fármacos , Antígeno Prostático Específico/efeitos dos fármacos , Neoplasias da Próstata/tratamento farmacológico , Proteínas Repressoras/efeitos dos fármacos , Proteínas Adaptadoras de Transporte Vesicular , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Humanos , Masculino , Terapia Neoadjuvante/métodos , Prostatectomia/métodos , Neoplasias da Próstata/patologia , RiscoRESUMO
Tumor molecular profiling of single gene-variant ('first-order') genomic alterations informs potential therapeutic approaches. Interactions between such first-order events and global molecular features (for example, mutational signatures) are increasingly associated with clinical outcomes, but these 'second-order' alterations are not yet accounted for in clinical interpretation algorithms and knowledge bases. We introduce the Molecular Oncology Almanac (MOAlmanac), a paired clinical interpretation algorithm and knowledge base to enable integrative interpretation of multimodal genomic data for point-of-care decision making and translational-hypothesis generation. We benchmarked MOAlmanac to a first-order interpretation method across multiple retrospective cohorts and observed an increased number of clinical hypotheses from evaluation of molecular features and profile-to-cell line matchmaking. When applied to a prospective precision oncology trial cohort, MOAlmanac nominated a median of two therapies per patient and identified therapeutic strategies administered in 47% of patients. Overall, we present an open-source computational method for integrative clinical interpretation of individualized molecular profiles.
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Neoplasias , Genômica/métodos , Humanos , Neoplasias/diagnóstico , Medicina de Precisão , Estudos Prospectivos , Estudos RetrospectivosRESUMO
PURPOSE: We report results from a phase II study assessing the efficacy of the WEE1 inhibitor adavosertib with cisplatin in metastatic triple-negative breast cancer (mTNBC). PATIENTS AND METHODS: Patients with mTNBC treated with 0-1 prior lines of chemotherapy received cisplatin 75 mg/m2 i.v. followed 21 days later by cisplatin plus adavosertib 200 mg oral twice daily for five doses every 21 days. The study had 90% power to detect the difference between null (20%) and alternative (40%) objective response rates (ORR) with a one-sided type I error of 0.1: an ORR >30% was predefined as making the regimen worthy of further study. RNA sequencing and multiplex cyclic immunofluorescence on pre- and post-adavosertib tumor biopsies, as well as targeted next-generation sequencing on archival tissue, were correlated with clinical benefit, defined as stable disease ≥6 months or complete or partial response. RESULTS: A total of 34 patients initiated protocol therapy; median age was 56 years, 2 patients (6%) had BRCA2 mutations, and 14 (41%) had one prior chemotherapy. ORR was 26% [95% confidence interval (CI), 13-44], and median progression-free survival was 4.9 months (95% CI, 2.3-5.7). Treatment-related grade 3-5 adverse events occurred in 53% of patients, most commonly diarrhea in 21%. One death occurred because of sepsis, possibly related to study therapy. Tumors from patients with clinical benefit demonstrated enriched immune gene expression and T-cell infiltration. CONCLUSIONS: Among patients with mTNBC treated with 0-1 prior lines, adavosertib combined with cisplatin missed the prespecified ORR cutoff of >30%. The finding of immune-infiltrated tumors in patients with clinical benefit warrants validation.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cisplatino/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinonas/administração & dosagem , Neoplasias de Mama Triplo Negativas/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Proteínas de Ciclo Celular/antagonistas & inibidores , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Cisplatino/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/efeitos adversos , Pirimidinonas/efeitos adversos , Neoplasias de Mama Triplo Negativas/patologia , Adulto JovemRESUMO
Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results (n = 88) from a randomized phase 2 trial of eribulin ± pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors (n = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity (n = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95% CI 0.59-1.55, p = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Furanos/uso terapêutico , Cetonas/uso terapêutico , Adulto , Idoso , Apresentação de Antígeno/genética , Antígeno B7-H1/metabolismo , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Citocinas/sangue , Citocinas/imunologia , Resistencia a Medicamentos Antineoplásicos/genética , Estrogênios/metabolismo , Feminino , Perfilação da Expressão Gênica , Heterogeneidade Genética , Genoma Humano/genética , Genômica , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Transdução de Sinais/genética , Taxa de Sobrevida , Resultado do TratamentoRESUMO
Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Here, we combined FACS-based genome-wide CRISPR screens with a data-mining approach to identify drugs that can upregulate MHC-I without inducing PD-L1. CRISPR screening identified TRAF3, a suppressor of the NFκB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3-knockout gene expression signature is associated with better survival in ICB-naïve patients with cancer and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified Second Mitochondria-derived Activator of Caspase (SMAC) mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T cell-dependent killing, and adds to ICB efficacy. Our findings provide preclinical rationale for treating tumors expressing low MHC-I expression with SMAC mimetics to enhance sensitivity to immunotherapy. The approach used in this study can be generalized to identify other drugs that enhance immunotherapy efficacy. SIGNIFICANCE: MHC-I loss or downregulation in cancer cells is a major mechanism of resistance to T cell-based immunotherapies. Our study reveals that birinapant may be used for patients with low baseline MHC-I to enhance ICB response. This represents promising immunotherapy opportunities given the biosafety profile of birinapant from multiple clinical trials.This article is highlighted in the In This Issue feature, p. 1307.
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Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Antígeno B7-H1/metabolismo , Mineração de Dados , Perfilação da Expressão Gênica , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia , Microambiente Tumoral/efeitos dos fármacosRESUMO
We performed harmonized molecular and clinical analysis on 1,048 melanomas and discovered markedly different global genomic properties among subtypes (BRAF, (N)RAS, NF1, triple wild-type (TWT)), subtype-specific preferences for secondary driver genes and active mutational processes previously unreported in melanoma. Secondary driver genes significantly enriched in specific subtypes reflected preferential dysregulation of additional pathways, such as induction of transforming growth factor-ß signaling in BRAF melanomas and inactivation of the SWI/SNF complex in (N)RAS melanomas, and select co-mutation patterns coordinated selective response to immune checkpoint blockade. We also defined the mutational landscape of TWT melanomas and revealed enrichment of DNA-repair-defect signatures in this subtype, which were associated with transcriptional downregulation of key DNA-repair genes, and may revive previously discarded or currently unconsidered therapeutic modalities for genomically stratified melanoma patient subsets. Broadly, harmonized meta-analysis of melanoma whole exomes revealed distinct molecular drivers that may point to multiple opportunities for biological and therapeutic investigation.
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Distúrbios no Reparo do DNA/genética , GTP Fosfo-Hidrolases/genética , Melanoma/genética , Proteínas de Membrana/genética , Neurofibromina 1/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Reparo do DNA/genética , Predisposição Genética para Doença/genética , Humanos , Melanoma/patologia , Transdução de Sinais/genética , Neoplasias Cutâneas/patologia , Sequenciamento do ExomaRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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PURPOSE: Next-generation sequencing (NGS) of tumor and germline DNA is foundational for precision oncology, with rapidly expanding diagnostic, prognostic, and therapeutic implications. Although few question the importance of NGS in modern oncology care, the process of gathering primary molecular data, integrating it into electronic health records, and optimally using it as part of a clinical workflow remains far from seamless. Numerous challenges persist around data standards and interoperability, and clinicians frequently face difficulties in managing the growing amount of genomic knowledge required to care for patients and keep up to date. METHODS: This review provides a descriptive analysis of genomic data workflows for NGS data in clinical oncology and issues that arise from the inconsistent use of standards for sharing data across systems. Potential solutions are described. RESULTS: NGS technology, especially for somatic genomics, is well established and widely used in routine patient care, quality measurement, and research. Available genomic knowledge bases play an evolving role in patient management but lack harmonization with one another. Questions about their provenance and timeliness of updating remain. Potentially useful standards for sharing genomic data, such as HL7 FHIR and mCODE, remain primarily in the research and/or development stage. Nonetheless, their impact will likely be seen as uptake increases across care settings and laboratories. The specific use case of ASCO CancerLinQ, as a clinicogenomic database, is discussed. CONCLUSION: Because the electronic health records of today seem ill suited for managing genomic data, other solutions are required, including universal data standards and applications that use application programming interfaces, along with a commitment on the part of sequencing laboratories to consistently provide structured genomic data for clinical use.
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Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.
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Antígeno CTLA-4/imunologia , Melanoma/tratamento farmacológico , Melanoma/genética , Receptor de Morte Celular Programada 1/imunologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Apresentação de Antígeno/genética , Apresentação de Antígeno/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Masculino , Melanoma/imunologia , Melanoma/patologia , Mutação/genética , Metástase Neoplásica , Nivolumabe/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Transcriptoma/genética , Transcriptoma/imunologia , Sequenciamento do ExomaRESUMO
Immune checkpoint blockade (ICB) therapies, which potentiate the body's natural immune response against tumor cells, have shown immense promise in the treatment of various cancers. Currently, tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are the primary biomarkers evaluated for clinical management of cancer patients across histologies. However, the wide range of responses has demonstrated that the specific molecular and genetic characteristics of each patient's tumor and immune system must be considered to maximize treatment efficacy. Here, we review the various biological pathways and emerging biomarkers implicated in response to PD-(L)1 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) therapies, including oncogenic signaling pathways, human leukocyte antigen (HLA) variability, mutation and neoantigen burden, microbiome composition, endogenous retroviruses (ERV), and deficiencies in chromatin remodeling and DNA damage repair (DDR) machinery. We also discuss several mechanisms that have been observed to confer resistance to ICB, such as loss of phosphatase and tensin homolog (PTEN), loss of major histocompatibility complex (MHC) I/II expression, and activation of the indoleamine 2,3-dioxygenase 1 (IDO1) and transforming growth factor beta (TGFß) pathways. Clinical trials testing the combination of PD-(L)1 or CTLA-4 blockade with molecular mediators of these pathways are becoming more common and may hold promise for improving treatment efficacy and response. Ultimately, some of the genes and molecular mechanisms highlighted in this review may serve as novel biological targets or therapeutic vulnerabilities to improve clinical outcomes in patients.