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Inflammation is associated with DNA damage, cellular senescence, and aging. Cessation of the inflammatory cytokine response is mediated in part through cytokine mRNA degradation facilitated by RNA-binding proteins, including AUF1. We report a major function of AUF1-it activates telomerase expression, suppresses cellular senescence, and maintains normal aging. AUF1-deficient mice undergo striking telomere erosion, markedly increased DNA damage responses at telomere ends, pronounced cellular senescence, and rapid premature aging that increases with successive generations, which can be rescued in AUF1 knockout mice and their cultured cells by resupplying AUF1 expression. AUF1 binds and strongly activates the transcription promoter for telomerase catalytic subunit Tert. In addition to directing inflammatory cytokine mRNA decay, AUF1 destabilizes cell-cycle checkpoint mRNAs, preventing cellular senescence. Thus, a single gene, AUF1, links maintenance of telomere length and normal aging to attenuation of inflammatory cytokine expression and inhibition of cellular senescence.
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Senescencia Celular/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo D/genética , Telomerasa/genética , Telómero/genética , Activación Transcripcional , Animales , Animales Recién Nacidos , Anticipación Genética/genética , Células Cultivadas , Daño del ADN , Embrión de Mamíferos/citología , Embrión de Mamíferos/metabolismo , Femenino , Fibroblastos/citología , Fibroblastos/metabolismo , Ribonucleoproteína Nuclear Heterogénea D0 , Ribonucleoproteína Heterogénea-Nuclear Grupo D/deficiencia , Ribonucleoproteína Heterogénea-Nuclear Grupo D/metabolismo , Immunoblotting , Hibridación Fluorescente in Situ , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Confocal , Regiones Promotoras Genéticas/genética , Unión Proteica , Estabilidad del ARN/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Genomic test results collected during the provision of medical care and stored in Electronic Health Record (EHR) systems represent an opportunity for clinical research into disease heterogeneity and clinical outcomes. In this paper, we evaluate the use of genomic test reports ordered for cancer patients in order to derive cancer subtypes and to identify biological pathways predictive of poor survival outcomes. A novel method is proposed to calculate patient similarity based on affected biological pathways rather than gene mutations. We demonstrate that this approach identifies subtypes of prognostic value and biological pathways linked to survival, with implications for precision treatment selection and a better understanding of the underlying disease. We also share lessons learned regarding the opportunities and challenges of secondary use of observational genomic data to conduct such research.
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Genómica , Informática Médica/métodos , Neoplasias/diagnóstico , Neoplasias/genética , Pronóstico , Adolescente , Adulto , Algoritmos , Análisis por Conglomerados , Sistemas de Computación , Bases de Datos Factuales , Registros Electrónicos de Salud , Femenino , Variación Genética , Genoma Humano , Humanos , Masculino , Mutación , Medicina de Precisión/métodos , Estudios Retrospectivos , Adulto JovenRESUMEN
Anorectal melanoma is a rare disease that carries a poor prognosis. To date, limited genetic analyses confirmed KIT mutations as a recurrent genetic event similar to other mucosal melanomas, occurring in up to 30% of anorectal melanomas. Importantly, a subset of tumors harboring activating KIT mutations have been found to respond to c-Kit inhibitor-based therapy, with improved patient survival at advanced tumor stages. We performed comprehensive targeted exon sequencing analysis of 467 cancer-related genes in a larger series of 15 anorectal melanomas, focusing on potentially actionable variants based on gain- and loss-of-function mutations. We report the identification of oncogenic driver events in the majority (93%) of anorectal melanomas. These included variants in canonical MAPK pathway effectors rarely observed in cutaneous melanomas (including an HRAS mutation, as well as a BRAF mutation resulting in duplication of threonine 599), and recurrent mutations in the tumor suppressor NF1 in 20% of cases, which represented the second-most frequently mutated gene after KIT in our series. Furthermore, we identify SF3B1 mutations as a recurrent genetic event in mucosal melanomas. Our findings provide an insight into the genetic diversity of anorectal melanomas, and suggest significant potential for alternative targeted therapeutics in addition to c-Kit inhibitors for this melanoma subtype.
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Neoplasias del Ano/genética , Melanoma/genética , Fosfoproteínas/genética , Proteínas Proto-Oncogénicas B-raf/genética , Factores de Empalme de ARN/genética , Neoplasias del Recto/genética , Anciano , Anciano de 80 o más Años , Neoplasias del Ano/patología , Exones , Femenino , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Mutación , Neurofibromina 1/genética , Neoplasias del Recto/patología , Transducción de Señal/genéticaRESUMEN
Pre-analytical factors in molecular oncology diagnostics are reviewed. Issues around sample collection, storage, and transport that might affect the stability of nucleic acids and the ability to perform molecular testing are addressed. In addition, molecular methods used commonly in clinical diagnostic laboratories, including newer technologies such as next-generation sequencing and digital droplet polymerase chain reaction, as well as their applications, are reviewed. Finally, we discuss considerations in designing a molecular test menu to deliver accurate and timely results in an efficient and cost-effective manner.
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Técnicas de Diagnóstico Molecular , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
Intraductal tubulopapillary neoplasms (ITPNs) are rare pancreatic tumors with distinct histological and molecular features. Distinction of ITPN from other pancreatic neoplasms is crucial given the known favorable prognosis and the high frequency and diversity of potentially targetable fusions in ITPN. While the histological features of ITPN are well documented, there are few reports on the cytological features, and molecular characterization of ITPN. The authors reported three cases diagnosed in their laboratory between 2016 and 2021. Clinical data, cytomorphological and histological features, with immunophenotypic and molecular characterizations of these cases are described and compared with those reported in the literature. All 3 cases were diagnosed as ITPN based on the microscopic presence of intraductal nodules composed of tightly packed small tubular glands lined by cuboidal cells lacking apparent mucin. On molecular profiling KRAS and TP53 variants were found in Case 1, FGFR2-INA fusion in Case 2, and STARD3NL-BRAF fusion was detected in Case 3. Immunohistochemistry (IHC) revealed that the neoplastic cells in Case 1 were MUC2 positive and MUC6 negative, but in Cases 2 and 3, were negative for MUC2 and positive for MUC6. These results demonstrate the immunophenotypic and molecular variabilities of histologically similar pancreatic neoplasms. The absence of alterations characteristic of more common pancreatic neoplasms should prompt the consideration of fusion studies in morphologically relevant cases. The combination of morphological, IHC, and molecular analyses is important for reliable identification of ITPN given its potential clinical management implications.
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Biomarcadores de Tumor , Neoplasias Intraductales Pancreáticas , Neoplasias Pancreáticas , Humanos , Masculino , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Femenino , Anciano , Neoplasias Intraductales Pancreáticas/patología , Neoplasias Intraductales Pancreáticas/genética , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , InmunohistoquímicaRESUMEN
Next-generation sequencing is becoming increasingly important for the diagnosis, risk stratification, and management of patients with established or suspected myeloid malignancies. These tests are being incorporated into clinical practice guidelines and many genetic alterations now constitute disease classification criteria. However, the reimbursement for these tests is uncertain. This study analyzed the clinical impact, ordering practices, prior authorization, and reimbursement outcomes of 505 samples from 477 patients sequenced with a 50-gene myeloid next-generation sequencing panel or a 15-gene myeloproliferative neoplasm subpanel. Overall, 98% (496 of 505) of tests provided clinically useful data. Eighty-nine percent of test results, including negative findings, informed or clarified potential diagnoses, 94% of results informed potential prognoses, and 19% of tests identified a potential therapeutic target. Sequencing results helped risk-stratify patients whose bone marrow biopsy specimens were inconclusive for dysplasia, monitor genetic evolution associated with disease progression, and delineate patients with mutation-defined diagnoses. Despite the clinical value, prior authorization from commercial payors or managed government payors was approved for less than half (45%) of requests. Only 51% of all cases were reimbursed, with lack of medical necessity frequently cited as a reason for denial. This study demonstrates the existence of a substantial gap between clinical utility and payor policies on test reimbursement.
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Trastornos Mieloproliferativos , Neoplasias , Humanos , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , Mutación , Secuenciación de Nucleótidos de Alto Rendimiento/métodosRESUMEN
Tumor mutational burden (TMB) has been recognized as a predictive biomarker for immunotherapy response in several tumor types. Several laboratories offer TMB testing, but there is significant variation in how TMB is calculated, reported, and interpreted among laboratories. TMB standardization efforts are underway, but no published guidance for TMB validation and reporting is currently available. Recognizing the current challenges of clinical TMB testing, the Association for Molecular Pathology convened a multidisciplinary collaborative working group with representation from the American Society of Clinical Oncology, the College of American Pathologists, and the Society for the Immunotherapy of Cancer to review the laboratory practices surrounding TMB and develop recommendations for the analytical validation and reporting of TMB testing based on survey data, literature review, and expert consensus. These recommendations encompass pre-analytical, analytical, and postanalytical factors of TMB analysis, and they emphasize the relevance of comprehensive methodological descriptions to allow comparability between assays.
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Biomarcadores de Tumor , Mutación , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/terapia , Neoplasias/inmunología , Biomarcadores de Tumor/genética , Inmunoterapia/métodos , Patología Molecular/métodos , Consenso , Sociedades Médicas , Estados Unidos , Patólogos , Reproducibilidad de los Resultados , Análisis Mutacional de ADN/métodos , Análisis Mutacional de ADN/normasRESUMEN
Tumour mutational burden (TMB) is used to predict response to immunotherapies. Although several groups have proposed calculation methods for TMB, a clear consensus has not yet emerged. In this study, we explored TMB calculation approaches with a 586-gene cancer panel (1.75 Mb) benchmarked to TMB measured by whole-exome sequencing (WES), using 30 samples across a range of tumour types. We explored variant allelic fraction (VAF) cut-offs of 5% and 10%, population database filtering at 0.001, 0.0001 and 0.000025, as well as different combinations of synonymous, insertion/deletion and intronic (splice site) variants, as well as exclusion of hotspot mutations, and examined the effect on TMB correlation. Good correlation (Spearman, range 0.66-0.78) between WES and panel TMB was seen across all methods evaluated. Each method of TMB calculation evaluated showed good positive per cent agreement and negative per cent agreement using 10 mutations/Mb as a cut-off, suggesting that multiple TMB calculation approaches may yield comparable results.
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Benchmarking , Neoplasias , Humanos , Secuenciación del Exoma , Neoplasias/genética , Neoplasias/patología , Biomarcadores de Tumor/genética , Mutación , Biología Computacional , Secuenciación de Nucleótidos de Alto Rendimiento/métodosRESUMEN
This article covers analytical principles of cancer next generation sequencing (NGS). Cancer samples require special considerations due to the cancer-specific applications of testing, as well as cancer sample specific issues, including low input, low tumor purity, or fixation-related artifacts. Laboratories typically use a combination of approaches around specimen processing, assay design, and bioinformatics analysis to allow for successful detection of actionable biomarkers. Examples of these approaches for cancer NGS testing are discussed and reviewed here.
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Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias , Biología Computacional , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/patología , Manejo de EspecímenesRESUMEN
Targetable NTRK gene fusions can be detected across tumor types using methodologies such as pan-TRK IHC, DNA or RNA NGS testing, or FISH. Challenges for implementation of clinical testing for NTRK fusions may arise due to the range in NTRK fusion prevalence across tumors, endogenous levels of TRK expression in tissues, and the large number of potential fusion partners. In this study, we examined our experience evaluating driver mutation negative lung, urothelial or cholangiocarcinoma cases, in addition to cases with positive, equivocal, or weak staining by pan-TRK IHC for NTRK fusions. 63/127 (49.6%) of these cases were positive for pan-TRK IHC, of which 71.4% showed weak or focal staining, potentially due to physiologic or non-specific TRK expression. Of these 127 cases, 4 harbored a NTRK fusion (1 fusion was seen in two separate samples from the same patient) as confirmed by RNA fusion panel testing. Pan-TRK IHC was positive in 1 case with TPM3-NTRK1 fusion, equivocal in 1 case with GOLGA4-NTRK3 fusion, and negative in 2 samples with ADAM19-NTRK3 fusion. Our findings show that we were able to successfully identify NTRK fusions that resulted in targeted therapy. However, our results suggest limited sensitivity of pan-TRK IHC for NTRK3 fusions, and that the reduced specificity for pan-TRK IHC in tumors with physiologic or non-specific TRK expression, results in false positive samples that require confirmatory testing by RNA based NGS.
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Neoplasias , Receptor trkC , Biomarcadores de Tumor/genética , Fusión Génica , Reordenamiento Génico , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , ARN , Receptor trkA/genética , Receptor trkC/genéticaRESUMEN
Gynecologic cancers are routinely screened for DNA mismatch repair (MMR) gene mutations using immunohistochemistry (IHC) and/or polymerase chain reaction (PCR) for microsatellite instability (MSI) to enable selection of immune checkpoint inhibitor therapy and screen for Lynch syndrome. The limited data that compare IHC and MSI in endometrial tumors have shown discordance rates of 5-10%. We reviewed MMR/MSI results in gynecologic cancers and used next-generation sequencing (NGS) to interrogate discrepancies. Of the 328 cases with both IHC and MSI results, 256 (78.0%) were microsatellite stable (MSS) with preserved MMR (pMMR), 64 (19.5%) cases were MSI-High (MSI-H) with MMR deficient (dMMR), 2 cases showed subclonal loss of MLH1 and PMS2 with MSI-H, and 6 cases were discordant. Overall, there was a 98.2% (322/328) IHC/MSI concordance. Discordant cases were retested and/or subject to NGS. Of the six discrepant cases, five showed dMMR with MSS and one showed pMMR with MSI-H. One dMMR/MSI-L case showed loss of PMS2 with a germline pathogenic mutation. The pMMR/MSI-H case was found to harbor pathogenic variants in MLH1 and MSH6. One of the two cases with subclonal populations demonstrated MSI-H in the dMMR area and MSS in the pMMR area. These results emphasize the importance of selecting the appropriate tumor tissue for both IHC and molecular testing and demonstrate that NGS can help resolve discrepant MMR and MSI results.
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Biomarcadores de Tumor , Reparación de la Incompatibilidad de ADN , Neoplasias de los Genitales Femeninos/diagnóstico , Secuenciación de Nucleótidos de Alto Rendimiento , Inmunohistoquímica , Inestabilidad de Microsatélites , Reacción en Cadena de la Polimerasa , Adulto , Anciano , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Análisis Mutacional de ADN , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/genética , Bases de Datos Factuales , Femenino , Neoplasias de los Genitales Femeninos/enzimología , Neoplasias de los Genitales Femeninos/genética , Neoplasias de los Genitales Femeninos/patología , Humanos , Persona de Mediana Edad , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/análisis , Endonucleasa PMS2 de Reparación del Emparejamiento Incorrecto/genética , Homólogo 1 de la Proteína MutL/análisis , Homólogo 1 de la Proteína MutL/genética , Mutación , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
Background: Gangliogliomas arise very rarely in the pineal region, where their natural histories and pathologic features are poorly understood. Case Description: In this report, we describe a 36-year-old woman who presented with a seizure followed by worsening headache, dizziness, confusion, and intermittent left facial numbness over the next few weeks. A head CT scan showed a partially calcified pineal region mass with hydrocephalus. After an endoscopic third ventriculostomy, the patient underwent a resection of the tumor that contained dysplastic ganglion cells and piloid glial cells. Molecular profiling of this CNS WHO Grade 1 ganglioglioma revealed polysomies of chromosomes 7 and 9, and a BUB1 variant of uncertain significance, without known MAP kinase pathway alterations. From a review of the literature, we found two distinct age distributions for pineal ganglioglioma, with modes at 1 and 36 years of age. Conclusion: Although very rare, this tumor should be considered in the differential diagnosis of pineal region tumors in children and young adults.
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Pre-analytical factors in molecular oncology diagnostics are reviewed. Issues around sample collection, storage, and transport that might affect the stability of nucleic acids and the ability to perform molecular testing are addressed. In addition, molecular methods used commonly in clinical diagnostic laboratories, including newer technologies such as next-generation sequencing and digital droplet polymerase chain reaction, as well as their applications, are reviewed. Finally, we discuss considerations in designing a molecular test menu to deliver accurate and timely results in an efficient and cost-effective manner.
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Secuenciación de Nucleótidos de Alto Rendimiento , Técnicas de Diagnóstico Molecular , Humanos , Patología Molecular , Reacción en Cadena de la PolimerasaRESUMEN
Cerebrovascular disease appears to have implications on rheumatic diseases, including gout. Accumulating evidence suggests that hemiparesis exerts a protective effect against gout via the down-regulation of mechanical and neural modulators of inflammation in neurologically impaired extremities. We present 2 divergent cases of unilateral gout following cerebrovascular events. One patient with a hemorrhagic stroke developed polyarticular gout only on the ipsilateral side to his hemiparesis, while another patient with basilar artery thrombosis and locked-in syndrome suffered a polyarticular gout flare only on the side that had regained limited function. As suggested by these cases, the effect of hemiparesis on gout is complex. Further insight into the interplay between gouty flares and hemiparesis may lead to novel therapeutic strategies for gout.
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Gota/etiología , Paresia/complicaciones , Enfermedades Reumáticas/prevención & control , Accidente Cerebrovascular/complicaciones , Trombosis/complicaciones , Sistema Nervioso Central/fisiopatología , Gota/diagnóstico , Gota/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Paresia/fisiopatología , Accidente Cerebrovascular/fisiopatología , Trombosis/fisiopatología , Ácido Úrico/metabolismoRESUMEN
PURPOSE: The routine use of large next-generation sequencing (NGS) pan-cancer panels is required to identify the increasing number of, but often uncommon, actionable alterations to guide therapy. Inconsistent coverage and variable payment is hindering NGS adoption into clinical practice. A review of test utilization, clinical utility, coverage, and reimbursement was conducted in a cohort of patients diagnosed with high-risk cancer who received pan-cancer panel testing as part of their clinical care. MATERIALS AND METHODS: The Columbia Combined Cancer Panel (CCCP), a 467-gene panel designed to detect DNA variations in solid and liquid tumors, was performed in the Laboratory of Personalized Genomic Medicine at Columbia University Irving Medical Center. Utilization was characterized at test order. Results were reviewed by a molecular pathologist, followed by a multidisciplinary molecular tumor board where clinical utility was classified by consensus. Reimbursement was reviewed after payers provided final coverage decisions. RESULTS: NGS was performed on 359 high-risk tumors from 349 patients. Reimbursement data were available for 246 cases. The most common reason providers ordered CCCP testing was for patients diagnosed with a treatment-resistant or recurrent tumor (n = 214; 61%). Findings were clinically impactful for 229 cases (64%). Molecular alterations that may inform future therapy in the event of progression or relapse were found in 42% of cases, and a targeted therapy was initiated in 23 cases (6.6%). The majority of tests were denied coverage by payers (n = 190; 77%). On average, insurers reimbursed 10.75% of the total NGS service charge. CONCLUSION: CCCP testing identified clinically impactful alterations in 64% of cases. Limited coverage and low reimbursement remain barriers, and broader reimbursement policies are needed to adopt pan-cancer NGS testing that benefits patients into clinical practice.
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We report a case of a slow-growing, diffuse, infiltrating glioma in the right brainstem of a 9-yr-old boy. The tumor was negative by immunohistochemical staining for histone H3 K27M, BRAF V600E, and IDH1 R132H mutations. Fluorescence in situ hybridization did not reveal a BRAF duplication. Genomic profiling of the tumor, by DNA methylation array and cancer whole-exome and transcriptome sequencing, was performed. This analysis showed copy-number alterations, including gains of several chromosomes. In addition, a novel fusion involving the first 17 exons of FGFR2 fused to exon 2 of VPS35 was identified. This novel fusion is predicted to result in activation of fibroblast growth factor receptor (FGFR) signaling and is potentially targetable using FGFR inhibitors. This tumor expands the spectrum of pediatric diffuse gliomas.
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Glioma/genética , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Proteínas de Transporte Vesicular/genética , Neoplasias Encefálicas/genética , Niño , Humanos , Hibridación Fluorescente in Situ/métodos , Masculino , Mutación/genética , Secuenciación del Exoma/métodosRESUMEN
This multi-institutional study was undertaken to evaluate interrater reliability of the 2017 Association for Molecular Pathology/American Society of Clinical Oncology/College of American Pathologists guidelines for interpretation and reporting of oncology sequence variants and to assess current practices and perceptions surrounding these guidelines. Fifty-one variants were distributed to 20 participants from 10 institutions for classification using the new guidelines. Agreement was assessed using chance-corrected agreement (Cohen κ). κ was 0.35. To evaluate if data sharing could help resolve disagreements, a summary of variant classifications and additional information about each variant were distributed to all participants. κ improved to 0.7 after the original classifications were revised. Participants were invited to take a web-based survey regarding their perceptions of the guidelines. Only 20% (n = 3) of the survey respondents had prior experience with the guidelines in clinical practice. The main perceived barriers to guideline implementation included the complexity of the guidelines, discordance between clinical actionability and pathobiologic relevance, lack of familiarity with the new classifications, and uncertainty when applying criteria to potential germline variants. This study demonstrates noteworthy discordances between pathologists for variant classification in solid tumors when using the 2017 Association for Molecular Pathology/American Society of Clinical Oncology/College of American Pathologists guidelines. These findings highlight potential areas for clarification/refinement before mainstream clinical adoption.
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Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Variación Genética , Neoplasias/diagnóstico , Neoplasias/genética , Estudios de Asociación Genética/métodos , Estudios de Asociación Genética/normas , Pruebas Genéticas/métodos , Pruebas Genéticas/normas , Humanos , Guías de Práctica Clínica como Asunto , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Estados UnidosRESUMEN
Regulation of telomere length maintenance and capping are a critical cell functions in both normal and tumor cells. Tankyrase 2 (Tnks2) is a poly(ADP-ribose) polymerase (PARP) that has been shown to modify itself and TRF1, a telomere-binding protein. We show here by overexpression studies that tankyrase 2, like its closely related homolog tankyrase 1, can function as a positive regulator of telomere length in human cells, dependent on its catalytic PARP activity. To study the role of Tnks2 in vivo, we generated mice with the Tnks2 PARP domain deleted. These mice are viable and fertile but display a growth retardation phenotype. Telomere analysis by quantitative fluorescence in situ hybridization (FISH), flow-FISH, and restriction fragment analysis showed no change in telomere length or telomere capping in these mice. To determine the requirement for Tnks2 in long-term maintenance of telomeres, we generated embryonic stem cells with the Tnks2 PARP domain deleted and observed no change, even upon prolonged growth, in telomere length or telomere capping. Together, these results suggest that Tnks2 has a role in normal growth and development but is not essential for telomere length maintenance or telomere capping in mice.
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Crecimiento/genética , Tanquirasas/genética , Tanquirasas/metabolismo , Telómero/fisiología , Animales , Tamaño Corporal/genética , Células Cultivadas , Femenino , Humanos , Masculino , Ratones , Ratones Mutantes/crecimiento & desarrollo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Estructura Terciaria de Proteína , Valores de Referencia , Células Madre/citología , Células Madre/fisiologíaRESUMEN
Chromosomal rearrangements involving the NTRK1, NTRK2, and NTRK3 genes (NTRK genes), which encode the high-affinity nerve growth factor receptor (TRKA), brain-derived neurotrophic factor/neurotrophin-3 (BDNF/NT-3) growth factor receptor (TRKB), and neurotrophin-3 (NT-3) growth factor receptor (TRKC) tyrosine kinases (TRK proteins), act as oncogenic drivers in a broad range of pediatric and adult tumor types. NTRK gene fusions have been shown to be actionable genomic events that are predictive of response to TRK kinase inhibitors, making their routine detection an evolving clinical priority. In certain exceedingly rare tumor types, NTRK gene fusions may be seen in the overwhelming majority of cases, whereas in a range of common cancers, reported incidences are in the range of 0.1% to 2%. Herein, we review the structure of the three NTRK genes and the nature and incidence of NTRK gene fusions in different solid tumor types, and we summarize the clinical data showing the importance of identifying tumors harboring such genomic events. We also outline the laboratory techniques that can be used to diagnose NTRK gene fusions in clinical samples. Finally, we propose a diagnostic algorithm for solid tumors to facilitate the identification of patients with TRK fusion cancer. This algorithm accounts for the widely varying frequencies by tumor histology and the underlying prevalence of TRK expression in the absence of NTRK gene fusions and is based on a combination of fluorescence in situ hybridization, next-generation sequencing, and immunohistochemistry assays.
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Biomarcadores de Tumor , Pruebas Genéticas , Neoplasias/diagnóstico , Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , Receptores de Factor de Crecimiento Nervioso/genética , Algoritmos , Toma de Decisiones Clínicas , Biología Computacional/métodos , Frecuencia de los Genes , Pruebas Genéticas/métodos , Pruebas Genéticas/normas , Genómica/métodos , Genómica/normas , Humanos , Familia de Multigenes , Neoplasias/tratamiento farmacológico , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del TratamientoRESUMEN
Assessment of ALK gene rearrangements is strongly recommended by the Molecular Testing Guideline for Selection of Lung Cancer Patients proposed by IASLC, AMP, and CAP at the time of diagnosis for patients with advanced stage disease. Non-small-cell lung cancer (NSCLC) with ALK gene rearrangements or the resulting fusion proteins have been, for the most part, successfully targeted with ALK tyrosine kinase inhibitors (TKIs). The most frequent rearrangement, the EML4-ALK oncogenic fusion, has more than 10 distinct variants, each with a discrete breakpoint in EML4 Recent studies have suggested that EML4-ALK variants may have differential responses to TKIs. Additionally, non-EML4-ALK fusions that result from ALK rearrangements with diverse 5' partners could possibly have varied biologic and clinical implications in their therapeutic responses and outcomes of patients with NSCLC. Existing literature documents at least 20 non-EML4 fusion partners for ALK, and the clinical responsiveness to crizotinib ranges from increased sensitivity to resistance. This underscores the importance of identifying the precise 5' fusion partner to ALK before initiation of therapy. Herein we report the identification of a novel SLMAP-ALK fusion in a patient with NSCLC.