RESUMEN
Rhabdoid Tumor Predisposition Syndrome 1 (RTPS1) confers an increased risk of developing rhabdoid tumors and is caused by germline mutations in SMARCB1. RTPS1 should be evaluated in all individuals with rhabdoid tumor and is more likely in those with a young age at presentation (occasionally congenital presentation), multiple primary tumors, or a family history of rhabdoid tumor or RTPS1. Proband genetic testing is the standard method for diagnosing RTPS1. Most known RTPS1-related SMARCB1 gene mutations are copy number variants (CNVs) or single nucleotide variants/indels, but structural variant analysis (SVA) is not usually included in the molecular evaluation. Here, we report two children with RTPS1 presenting with atypical teratoid/rhabdoid tumor (ATRT) who had constitutional testing showing balanced chromosome translocations involving SMARCB1. Patient 1 is a 23-year-old female diagnosed with pineal region ATRT at 7 months who was found to have a de novo, constitutional t(16;22)(p13.3;q11.2). Patient 2 is a 24-month-old male diagnosed with a posterior fossa ATRT at 14 months, with subsequent testing showing a constitutional t(5;22)(q14.1;q11.23). These structural rearrangements have not been previously reported in RTPS1. While rare, these cases suggest that structural variants should be considered in the evaluation of children with rhabdoid tumors to provide more accurate genetic counseling on the risks of developing tumors, the need for surveillance, and the risks of passing the disorder on to future children. Further research is needed to understand the prevalence, clinical features, and tumor risks associated with RTPS1-related constitutional balanced translocations.
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Neoplasias Encefálicas , Trastornos de los Cromosomas , Tumor Rabdoide , Teratoma , Niño , Femenino , Masculino , Humanos , Adulto Joven , Adulto , Lactante , Tumor Rabdoide/genética , Tumor Rabdoide/patología , Proteína SMARCB1/genética , Neoplasias Encefálicas/genética , Mutación de Línea Germinal , Translocación Genética , Teratoma/genética , Teratoma/patologíaRESUMEN
Congenital/neonatal bone neoplasms are extremely rare. We present the case of a patient with a neonatal bone tumor of the fibula that had osteoblastic differentiation and a novel PTBP1::FOSB fusion. FOSB fusions are described in several different tumor types, including osteoid osteoma and osteoblastoma; however, these tumors typically present in the second or third decade of life, with case reports as young as 4 months of age. Our case expands the spectrum of congenital/neonatal bone lesions. The initial radiologic, histologic, and molecular findings supported the decision for close clinical follow-up rather than more aggressive intervention. Since the time of diagnosis, this tumor has undergone radiologic regression without treatment.
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Neoplasias Óseas , Osteoblastoma , Osteoma Osteoide , Recién Nacido , Humanos , Osteoma Osteoide/diagnóstico , Osteoma Osteoide/patología , Osteoblastoma/diagnóstico , Osteoblastoma/patología , Neoplasias Óseas/patología , Diagnóstico Diferencial , Proteínas Proto-Oncogénicas c-fos/genética , Ribonucleoproteínas Nucleares Heterogéneas , Proteína de Unión al Tracto de PolipirimidinaRESUMEN
Oncogenic fusions formed through chromosomal rearrangements are hallmarks of childhood cancer that define cancer subtype, predict outcome, persist through treatment, and can be ideal therapeutic targets. However, mechanistic understanding of the etiology of oncogenic fusions remains elusive. Here we report a comprehensive detection of 272 oncogenic fusion gene pairs by using tumor transcriptome sequencing data from 5190 childhood cancer patients. We identify diverse factors, including translation frame, protein domain, splicing, and gene length, that shape the formation of oncogenic fusions. Our mathematical modeling reveals a strong link between differential selection pressure and clinical outcome in CBFB-MYH11. We discover 4 oncogenic fusions, including RUNX1-RUNX1T1, TCF3-PBX1, CBFA2T3-GLIS2, and KMT2A-AFDN, with promoter-hijacking-like features that may offer alternative strategies for therapeutic targeting. We uncover extensive alternative splicing in oncogenic fusions including KMT2A-MLLT3, KMT2A-MLLT10, C11orf95-RELA, NUP98-NSD1, KMT2A-AFDN and ETV6-RUNX1. We discover neo splice sites in 18 oncogenic fusion gene pairs and demonstrate that such splice sites confer therapeutic vulnerability for etiology-based genome editing. Our study reveals general principles on the etiology of oncogenic fusions in childhood cancer and suggests profound clinical implications including etiology-based risk stratification and genome-editing-based therapeutics.
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Subunidad alfa 2 del Factor de Unión al Sitio Principal , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Niño , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Fusión de Oncogenes , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Transcriptoma , Causalidad , Proteínas de Fusión Oncogénica/genéticaRESUMEN
BACKGROUND: Despite the process of DNA replication being mechanistically highly conserved, the location of origins of replication (ORI) may vary from one tissue to the next, or between rounds of replication in eukaryotes, suggesting flexibility in the choice of locations to initiate replication. Lists of human ORI therefore vary widely in number and location, and there are currently no methods available to compare them. Here, we propose a method of detection of ORI based on somatic mutation patterns generated by the mutator phenotype of damaged DNA polymerase epsilon (POLE). RESULTS: We report the genome-wide localization of constitutive ORI in POLE-mutated human tumors using whole genome sequencing data. Mutations accumulated after many rounds of replication of unsynchronized dividing cell populations in tumors allow to identify constitutive origins, which we show are shared with high fidelity between individuals and tumor types. Using a Smith-Waterman-like dynamic programming approach, we compared replication origin positions obtained from multiple different methods. The comparison allowed us to define a consensus set of replication origins, identified consistently by multiple ORI detection methods. Many DNA features co-localized with the consensus set of ORI, including chromatin loop anchors, G-quadruplexes, S/MARs, and CpGs. Among all features, the H2A.Z histone exhibited the most significant association. CONCLUSIONS: Our results show that mutation-based detection of replication origins is a viable approach to determining their location and associated sequence features.
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Replicación del ADN , Neoplasias , Humanos , Origen de Réplica , ADN Polimerasa II/genética , ADN , Histonas/genética , Neoplasias/genéticaRESUMEN
BACKGROUND: The existence of immunologically 'cold tumors' frequently found across a wide spectrum of tumor types represents a significant challenge for cancer immunotherapy. Cold tumors have poor baseline pan-leukocyte infiltration, including a low prevalence of cytotoxic lymphocytes, and not surprisingly respond unfavorably to immune checkpoint (IC) inhibitors. We hypothesized that cold tumors harbor a mechanism of immune escape upstream and independent of ICs that may be driven by tumor biology rather than differences in mutational neoantigen burden. METHODS: Using a bioinformatic approach to analyze TCGA (The Cancer Genome Atlas) RNA sequencing data we identified genes upregulated in cold versus hot tumors across four different smoking-related cancers, including squamous carcinomas from the oral cavity (OCSCC) and lung (LUSC), and adenocarcinomas of the bladder (BLCA) and lung (LUAD). Biological significance of the gene most robustly associated with a cold tumor phenotype across all four tumor types, glutathione peroxidase 2 (GPX2), was further evaluated using a combination of in silico analyses and functional genomic experiments performed both in vitro and in in vivo with preclinical models of oral cancer. RESULTS: Elevated RNA expression of five metabolic enzymes including GPX2, aldo-keto reductase family 1 members AKR1C1, AKR1C3, and cytochrome monoxygenases (CP4F11 and CYP4F3) co-occurred in cold tumors across all four smoking-related cancers. These genes have all been linked to negative regulation of arachidonic acid metabolism-a well-established inflammatory pathway-and are also known downstream targets of the redox sensitive Nrf2 transcription factor pathway. In OCSCC, LUSC, and LUAD, GPX2 expression was highly correlated with Nrf2 activation signatures, also elevated in cold tumors. In BLCA, however, GPX2 correlated more strongly than Nrf2 signatures with decreased infiltration of multiple leukocyte subtypes. GPX2 inversely correlated with expression of multiple pro- inflammatory cytokines/chemokines and NF-kB activation in cell lines and knockdown of GPX2 led to increased secretion of prostaglandin E2 (PGE2) and interleukin-6. Conversely, GPX2 overexpression led to reduced PGE2 production in a murine OCSCC model (MOC1). GPX2 overexpressing MOC1 tumors had a more suppressive tumor immune microenvironment and responded less favorably to anti-cytotoxic T-lymphocytes-associated protein 4 IC therapy in mice. CONCLUSION: GPX2 overexpression represents a novel potentially targetable effector of immune escape in cold tumors.
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Glutatión Peroxidasa/metabolismo , Inhibidores de Puntos de Control Inmunológico , Factor 2 Relacionado con NF-E2 , Animales , Dinoprostona , Glutatión Peroxidasa/genética , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Microambiente TumoralRESUMEN
Recent advancements in molecular characterisation have identified four principal molecular groups of medulloblastoma: WNT, SHH, group 3 and group 4. Each has its characteristic clinical features, signature genetic alterations and distinct DNA methylome profiles. Thus far, CTNNB1 mutations have been considered pathognomonic of WNT-activated medulloblastoma. Furthermore, it has been shown that CTNNB1 mutations dominantly drive the WNT-activated phenotype in medulloblastoma, even in the presence of alterations in the SHH pathway. We herein report an illustrative case that challenges this belief-a medulloblastoma with a pathogenic CTNNB1 mutation that otherwise showed the histopathology, immunophenotype and methylation and transcriptomic profiles of an SHH-activated medulloblastoma. Detailed molecular analyses, including whole exome sequencing, transcriptome analysis and DNA methylation profiling with DKFZ brain tumour classifier and St. Jude MLPnet neural network classifier analyses, have been performed on the tumour. Our example emphasises the diagnostic value of the immunohistochemistry panel with YAP1, GAB1 and ß-catenin and DNA methylation profiling, combined with exome sequencing, in the characterisation of medulloblastoma. CTNNB1 mutations are not specific for WNT-activated medulloblastoma, and different CTNNB1 mutations have diverse oncogenic potential.
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Neoplasias Cerebelosas , Meduloblastoma , beta Catenina , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/patología , Metilación de ADN , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Meduloblastoma/genética , Meduloblastoma/patología , Mutación , Transcriptoma , beta Catenina/genéticaRESUMEN
Transcriptome sequencing (RNA-seq) is widely used to detect gene rearrangements and quantitate gene expression in acute lymphoblastic leukemia (ALL), but its utility and accuracy in identifying copy number variations (CNVs) has not been well described. CNV information inferred from RNA-seq can be highly informative to guide disease classification and risk stratification in ALL due to the high incidence of aneuploid subtypes within this disease. Here we describe RNAseqCNV, a method to detect large scale CNVs from RNA-seq data. We used models based on normalized gene expression and minor allele frequency to classify arm level CNVs with high accuracy in ALL (99.1% overall and 98.3% for non-diploid chromosome arms, respectively), and the models were further validated with excellent performance in acute myeloid leukemia (accuracy 99.8% overall and 99.4% for non-diploid chromosome arms). RNAseqCNV outperforms alternative RNA-seq based algorithms in calling CNVs in the ALL dataset, especially in samples with a high proportion of CNVs. The CNV calls were highly concordant with DNA-based CNV results and more reliable than conventional cytogenetic-based karyotypes. RNAseqCNV provides a method to robustly identify copy number alterations in the absence of DNA-based analyses, further enhancing the utility of RNA-seq to classify ALL subtype.
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Variaciones en el Número de Copia de ADN , Secuenciación de Nucleótidos de Alto Rendimiento , Algoritmos , Variaciones en el Número de Copia de ADN/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Cariotipificación , RNA-SeqRESUMEN
BACKGROUND AND AIMS: Although many studies revealed transcriptomic subtypes of HCC, concordance of the subtypes are not fully examined. We aim to examine a consensus of transcriptomic subtypes and correlate them with clinical outcomes. APPROACH AND RESULTS: By integrating 16 previously established genomic signatures for HCC subtypes, we identified five clinically and molecularly distinct consensus subtypes. STM (STeM) is characterized by high stem cell features, vascular invasion, and poor prognosis. CIN (Chromosomal INstability) has moderate stem cell features, but high genomic instability and low immune activity. IMH (IMmune High) is characterized by high immune activity. BCM (Beta-Catenin with high Male predominance) is characterized by prominent ß-catenin activation, low miRNA expression, hypomethylation, and high sensitivity to sorafenib. DLP (Differentiated and Low Proliferation) is differentiated with high hepatocyte nuclear factor 4A activity. We also developed and validated a robust predictor of consensus subtype with 100 genes and demonstrated that five subtypes were well conserved in patient-derived xenograft models and cell lines. By analyzing serum proteomic data from the same patients, we further identified potential serum biomarkers that can stratify patients into subtypes. CONCLUSIONS: Five HCC subtypes are correlated with genomic phenotypes and clinical outcomes and highly conserved in preclinical models, providing a framework for selecting the most appropriate models for preclinical studies.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Masculino , Femenino , Carcinoma Hepatocelular/patología , beta Catenina/genética , Neoplasias Hepáticas/patología , Consenso , Proteómica , Genómica , FenotipoRESUMEN
SUMMARY: Small insertions and deletions (indels) in nucleotide sequence may be represented differently between mapping algorithms and variant callers, or in the flanking sequence context. Representational ambiguity is especially profound for complex indels, complicating comparisons between multiple mappings and call sets. Complex indels may additionally suffer from incomplete allele representation, potentially leading to critical misannotation of variant effect. We present indelPost, a Python library that harmonizes these ambiguities for simple and complex indels via realignment and read-based phasing. We demonstrate that indelPost enables accurate analysis of ambiguous data and can derive the correct complex indel alleles from the simple indel predictions provided by standard small variant detectors, with improved performance over a specialized tool for complex indel analysis. AVAILABILITY AND IMPLEMENTATION: indelPost is freely available at: https://github.com/stjude/indelPost. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Algoritmos , Programas Informáticos , Análisis de Secuencia de ADN , Mutación INDEL , Biblioteca de GenesRESUMEN
Genomic studies of pediatric cancer have primarily focused on specific tumor types or high-risk disease. Here, we used a three-platform sequencing approach, including whole-genome sequencing (WGS), whole-exome sequencing (WES), and RNA sequencing (RNA-seq), to examine tumor and germline genomes from 309 prospectively identified children with newly diagnosed (85%) or relapsed/refractory (15%) cancers, unselected for tumor type. Eighty-six percent of patients harbored diagnostic (53%), prognostic (57%), therapeutically relevant (25%), and/or cancer-predisposing (18%) variants. Inclusion of WGS enabled detection of activating gene fusions and enhancer hijacks (36% and 8% of tumors, respectively), small intragenic deletions (15% of tumors), and mutational signatures revealing of pathogenic variant effects. Evaluation of paired tumor-normal data revealed relevance to tumor development for 55% of pathogenic germline variants. This study demonstrates the power of a three-platform approach that incorporates WGS to interrogate and interpret the full range of genomic variants across newly diagnosed as well as relapsed/refractory pediatric cancers. SIGNIFICANCE: Pediatric cancers are driven by diverse genomic lesions, and sequencing has proven useful in evaluating high-risk and relapsed/refractory cases. We show that combined WGS, WES, and RNA-seq of tumor and paired normal tissues enables identification and characterization of genetic drivers across the full spectrum of pediatric cancers. This article is highlighted in the In This Issue feature, p. 2945.
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Neoplasias , Niño , ADN , Humanos , Mutación , Neoplasias/genética , Análisis de Secuencia de ARN , Secuenciación del ExomaRESUMEN
CONTEXT: Anaplastic thyroid cancer (ATC) is a rare, aggressive, and deadly disease. Robust preclinical thyroid cancer models are needed to adequately develop and study novel therapeutic agents. Patient-derived xenograft (PDX) models may resemble patient tumors by recapitulating key genetic alterations and gene expression patterns, making them excellent preclinical models for drug response evaluation. OBJECTIVE: We developed distinct ATC PDX models concurrently with cell lines and characterized them in vitro and in vivo. METHODS: Fresh thyroid tumor from patients with a preoperative diagnosis of ATC was surgically collected and divided for concurrent cell line and PDX model development. Cell lines were created by generating single cells through enzymatic digestion. PDX models were developed following direct subcutaneous implantation of fresh tumor on the flank of immune compromised/athymic mice. RESULTS: Six ATC PDX models and 4 cell lines were developed with distinct genetic profiles. Mutational characterization showed one BRAF/TP53/CDKN2A, one BRAF/CDKN2A, one BRAF/TP53, one TP53 only, one TERT-promoter/HRAS, and one TERT-promoter/KRAS/TP53/NF2/NFE2L2 mutated phenotype. Hematoxylin-eosin staining comparing the PDX models to the original patient surgical specimens show remarkable resemblance, while immunohistochemistry stains for important biomarkers were in full concordance (cytokeratin, TTF-1, PAX8, BRAF). Short tandem repeats DNA fingerprinting analysis of all PDX models and cell lines showed strong concordance with the original tumor. PDX successful establishment rate was 32%. CONCLUSION: We have developed and characterized 6 novel ATC PDX models with 4 matching cell lines. Each PDX model harbors a distinct genetic profile, making them excellent tools for preclinical therapeutic trials.
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Biomarcadores de Tumor/metabolismo , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica , Fenotipo , Carcinoma Anaplásico de Tiroides/patología , Neoplasias de la Tiroides/patología , Anciano , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Carcinoma Anaplásico de Tiroides/genética , Carcinoma Anaplásico de Tiroides/metabolismo , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Despite the use of aggressive multimodality treatment, most anaplastic thyroid carcinoma (ATC) patients die within a year of diagnosis. Although the combination of BRAF and MEK inhibitors has recently been approved for use in BRAF-mutated ATC, they remain effective in a minority of patients who are likely to develop drug resistance. There remains a critical clinical need for effective systemic agents for ATC with a reasonable toxicity profile to allow for rapid translational development. MATERIAL AND METHODS: Twelve human thyroid cancer cell lines with comprehensive genomic characterization were used in a high-throughput screening (HTS) of 257 compounds to select agents with maximal growth inhibition. Cell proliferation, colony formation, orthotopic thyroid models, and patient-derived xenograft (PDX) models were used to validate the selected agents. RESULTS: Seventeen compounds were effective, and docetaxel, LBH-589, and pralatrexate were selected for additional in vitro and in vivo analysis as they have been previously approved by the US Food and Drug Administration for other cancers. Significant tumor growth inhibition (TGI) was detected in all tested models treated with LBH-589; pralatrexate demonstrated significant TGI in the orthotopic papillary thyroid carcinoma model and 2 PDX models; and docetaxel demonstrated significant TGI only in the context of mutant TP53. CONCLUSIONS: HTS identified classes of systemic agents that demonstrate preferential effectiveness against aggressive thyroid cancers, particularly those with mutant TP53. Preclinical validation in both orthotopic and PDX models, which are accurate in vivo models mimicking tumor microenvironment, may support initiation of early-phase clinical trials in non-BRAF mutated or refractory to BRAF/MEK inhibition ATC.
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Antineoplásicos/farmacología , Ensayos Analíticos de Alto Rendimiento , Inhibidores de Proteínas Quinasas/farmacología , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/tratamiento farmacológico , Animales , Pruebas de Carcinogenicidad , Línea Celular Tumoral , Modelos Animales de Enfermedad , Humanos , Proteínas Proto-Oncogénicas B-raf/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacosRESUMEN
Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.
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Biomarcadores de Tumor/genética , Carcinoma Neuroendocrino/genética , Metilación de ADN , Epigénesis Genética , Epigenoma , Neoplasias Pancreáticas/genética , Carcinoma Neuroendocrino/metabolismo , Epigenómica , Predisposición Genética a la Enfermedad , Humanos , Clasificación del Tumor , Neoplasias Pancreáticas/patología , Fenotipo , Carga TumoralRESUMEN
ID/HIV physicians and other healthcare professionals advocate within the healthcare system to ensure adults and children receive effective treatment. These advocacy skills can be used to inform domestic and global infectious disease policies to improve healthcare systems and public health. ID/HIV physicians have a unique frontline perspective to share with federal policymakers regarding how programs and policies benefit patients and public health. Providing this input is critical to the enactment of legislation that will maximize the response to infectious diseases. This article discusses the advocacy of ID/HIV physicians and other healthcare professionals in federal health policy. Key issues include funding for ID/HIV programs; the protection of public health and access to health care; improving research opportunities; and advancing the field of ID/HIV, including supporting the next generation of ID/HIV clinicians. The article also describes best practices for advocacy and provides case studies illustrating the impact of ID/HIV physician advocacy.
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Enfermedades Transmisibles , Infecciones por VIH , Médicos , Adulto , Niño , Atención a la Salud , Infecciones por VIH/prevención & control , Política de Salud , HumanosRESUMEN
OBJECTIVES/HYPOTHESIS: Characterization of the localized adaptive immune response in the airway scar of patients with idiopathic subglottic stenosis (iSGS). STUDY DESIGN: Basic Science. METHODS: Utilizing 36 patients with subglottic stenosis (25 idiopathic subglottic stenosis [iSGS], 10 iatrogenic post-intubation stenosis [iLTS], and one granulomatosis with polyangiitis [GPA]) we applied immunohistochemical and immunologic techniques coupled with RNA sequencing. RESULTS: iSGS, iLTS, and GPA demonstrate a significant immune infiltrate in the subglottic scar consisting of adaptive cell subsets (T cells along with dendritic cells). Interrogation of T cell subtypes showed significantly more CD69+ CD103+ CD8+ tissue resident memory T cells (TRM ) in the iSGS airway scar than iLTS specimens (iSGS vs. iLTS; 50% vs. 28%, P = .0065). Additionally, subglottic CD8+ clones possessed T-cell receptor (TCR) sequences with known antigen specificity for viral and intracellular pathogens. CONCLUSIONS: The human subglottis is significantly enriched for CD8+ tissue resident memory T cells in iSGS, which possess TCR sequences proven to recognize viral and intracellular pathogens. These results inform our understanding of iSGS, provide a direction for future discovery, and demonstrate immunologic function in the human proximal airway. Laryngoscope, 131:610-617, 2021.
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Obstrucción de las Vías Aéreas/inmunología , Cicatriz/inmunología , Memoria Inmunológica/inmunología , Laringoestenosis/inmunología , Subgrupos de Linfocitos T/inmunología , Adulto , Anciano , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/inmunología , Antígenos CD8/inmunología , Constricción Patológica , Femenino , Glotis/inmunología , Glotis/patología , Humanos , Inmunohistoquímica , Cadenas alfa de Integrinas/inmunología , Lectinas Tipo C/inmunología , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Tumor molecular profiling from patients experiencing exceptional responses to systemic therapy may provide insights into cancer biology and improve treatment tailoring. This pilot study evaluates the feasibility of identifying exceptional responders retrospectively, obtaining pre-exceptional response treatment tumor tissues, and analyzing them with state-of-the-art molecular analysis tools to identify potential molecular explanations for responses. METHODS: Exceptional response was defined as partial (PR) or complete (CR) response to a systemic treatment with population PR or CR rate less than 10% or an unusually long response (eg, duration >3 times published median). Cases proposed by patients' clinicians were reviewed by clinical and translational experts. Tumor and normal tissue (if possible) were profiled with whole exome sequencing and, if possible, targeted deep sequencing, RNA sequencing, methylation arrays, and immunohistochemistry. Potential germline mutations were tracked for relevance to disease. RESULTS: Cases reflected a variety of tumors and standard and investigational treatments. Of 520 cases, 476 (91.5%) were accepted for further review, and 222 of 476 (46.6%) proposed cases met requirements as exceptional responders. Clinical data were obtained from 168 of 222 cases (75.7%). Tumor was provided from 130 of 168 cases (77.4%). Of 117 of the 130 (90.0%) cases with sufficient nucleic acids, 109 (93.2%) were successfully analyzed; 6 patients had potentially actionable germline mutations. CONCLUSION: Exceptional responses occur with standard and investigational treatment. Retrospective identification of exceptional responders, accessioning, and sequencing of pretreatment archived tissue is feasible. Data from molecular analyses of tumors, particularly when combining results from patients who received similar treatments, may elucidate molecular bases for exceptional responses.
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Neoplasias/tratamiento farmacológico , Neoplasias/genética , Transcriptoma/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Factibilidad , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , National Cancer Institute (U.S.) , Neoplasias/epidemiología , Neoplasias/patología , Proyectos Piloto , Medicina de Precisión , Estudios Retrospectivos , Análisis de Secuencia de ARN , Estados Unidos/epidemiología , Secuenciación del ExomaRESUMEN
A small fraction of cancer patients with advanced disease survive significantly longer than patients with clinically comparable tumors. Molecular mechanisms for exceptional responses to therapy have been identified by genomic analysis of tumor biopsies from individual patients. Here, we analyzed tumor biopsies from an unbiased cohort of 111 exceptional responder patients using multiple platforms to profile genetic and epigenetic aberrations as well as the tumor microenvironment. Integrative analysis uncovered plausible mechanisms for the therapeutic response in nearly a quarter of the patients. The mechanisms were assigned to four broad categories-DNA damage response, intracellular signaling, immune engagement, and genetic alterations characteristic of favorable prognosis-with many tumors falling into multiple categories. These analyses revealed synthetic lethal relationships that may be exploited therapeutically and rare genetic lesions that favor therapeutic success, while also providing a wealth of testable hypotheses regarding oncogenic mechanisms that may influence the response to cancer therapy.