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1.
Cell ; 183(2): 363-376.e13, 2020 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-33007267

RESUMEN

Although treatment of non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs) can produce remarkably durable responses, most patients develop early disease progression. Furthermore, initial response assessment by conventional imaging is often unable to identify which patients will achieve durable clinical benefit (DCB). Here, we demonstrate that pre-treatment circulating tumor DNA (ctDNA) and peripheral CD8 T cell levels are independently associated with DCB. We further show that ctDNA dynamics after a single infusion can aid in identification of patients who will achieve DCB. Integrating these determinants, we developed and validated an entirely noninvasive multiparameter assay (DIREct-On, Durable Immunotherapy Response Estimation by immune profiling and ctDNA-On-treatment) that robustly predicts which patients will achieve DCB with higher accuracy than any individual feature. Taken together, these results demonstrate that integrated ctDNA and circulating immune cell profiling can provide accurate, noninvasive, and early forecasting of ultimate outcomes for NSCLC patients receiving ICIs.


Asunto(s)
Biomarcadores Farmacológicos/sangre , ADN Tumoral Circulante/análisis , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Adulto , Antineoplásicos Inmunológicos/farmacología , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/genética , Linfocitos T CD8-positivos/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , ADN Tumoral Circulante/genética , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/inmunología , Inhibidores de Puntos de Control Inmunológico/metabolismo , Inmunoterapia/métodos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/metabolismo
2.
Nature ; 625(7996): 778-787, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38081297

RESUMEN

The scarcity of malignant Hodgkin and Reed-Sternberg cells hampers tissue-based comprehensive genomic profiling of classic Hodgkin lymphoma (cHL). By contrast, liquid biopsies show promise for molecular profiling of cHL due to relatively high circulating tumour DNA (ctDNA) levels1-4. Here we show that the plasma representation of mutations exceeds the bulk tumour representation in most cases, making cHL particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumours, we demonstrate Hodgkin and Reed-Sternberg ctDNA shedding to be shaped by DNASE1L3, whose increased tumour microenvironment-derived expression drives high ctDNA concentrations. Using this insight, we comprehensively profile 366 patients, revealing two distinct cHL genomic subtypes with characteristic clinical and prognostic correlates, as well as distinct transcriptional and immunological profiles. Furthermore, we identify a novel class of truncating IL4R mutations that are dependent on IL-13 signalling and therapeutically targetable with IL-4Rα-blocking antibodies. Finally, using PhasED-seq5, we demonstrate the clinical value of pretreatment and on-treatment ctDNA levels for longitudinally refining cHL risk prediction and for detection of radiographically occult minimal residual disease. Collectively, these results support the utility of noninvasive strategies for genotyping and dynamic monitoring of cHL, as well as capturing molecularly distinct subtypes with diagnostic, prognostic and therapeutic potential.


Asunto(s)
ADN Tumoral Circulante , Genoma Humano , Genómica , Enfermedad de Hodgkin , Humanos , Enfermedad de Hodgkin/sangre , Enfermedad de Hodgkin/clasificación , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/genética , Mutación , Células de Reed-Sternberg/metabolismo , Microambiente Tumoral , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Análisis de Expresión Génica de una Sola Célula , Genoma Humano/genética
3.
Nature ; 616(7957): 553-562, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37055640

RESUMEN

Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung cancer (NSCLC). Here we developed ctDNA methods tracking a median of 200 mutations identified in resected NSCLC tissue across 1,069 plasma samples collected from 197 patients enrolled in the TRACERx study2. A lack of preoperative ctDNA detection distinguished biologically indolent lung adenocarcinoma with good clinical outcome. Postoperative plasma analyses were interpreted within the context of standard-of-care radiological surveillance and administration of cytotoxic adjuvant therapy. Landmark analyses of plasma samples collected within 120 days after surgery revealed ctDNA detection in 25% of patients, including 49% of all patients who experienced clinical relapse; 3 to 6 monthly ctDNA surveillance identified impending disease relapse in an additional 20% of landmark-negative patients. We developed a bioinformatic tool (ECLIPSE) for non-invasive tracking of subclonal architecture at low ctDNA levels. ECLIPSE identified patients with polyclonal metastatic dissemination, which was associated with a poor clinical outcome. By measuring subclone cancer cell fractions in preoperative plasma, we found that subclones seeding future metastases were significantly more expanded compared with non-metastatic subclones. Our findings will support (neo)adjuvant trial advances and provide insights into the process of metastatic dissemination using low-ctDNA-level liquid biopsy.


Asunto(s)
Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Neoplasias Pulmonares , Mutación , Metástasis de la Neoplasia , Carcinoma Pulmonar de Células Pequeñas , Humanos , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Estudios de Cohortes , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Metástasis de la Neoplasia/diagnóstico , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Filogenia , Carcinoma Pulmonar de Células Pequeñas/patología , Biopsia Líquida
4.
CA Cancer J Clin ; 71(2): 176-190, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33165928

RESUMEN

The application of genomic profiling assays using plasma circulating tumor DNA (ctDNA) is rapidly evolving in the management of patients with advanced solid tumors. Diverse plasma ctDNA technologies in both commercial and academic laboratories are in routine or emerging use. The increasing integration of such testing to inform treatment decision making by oncology clinicians has complexities and challenges but holds significant potential to substantially improve patient outcomes. In this review, the authors discuss the current role of plasma ctDNA assays in oncology care and provide an overview of ongoing research that may inform real-world clinical applications in the near future.


Asunto(s)
Biomarcadores de Tumor/sangre , ADN Tumoral Circulante/sangre , Oncología Médica/métodos , Neoplasias/diagnóstico , Biomarcadores de Tumor/genética , ADN Tumoral Circulante/genética , Toma de Decisiones Clínicas , Humanos , Biopsia Líquida/métodos , Biopsia Líquida/normas , Biopsia Líquida/tendencias , Oncología Médica/normas , Oncología Médica/tendencias , Mutación , Estadificación de Neoplasias/métodos , Estadificación de Neoplasias/tendencias , Neoplasias/sangre , Neoplasias/genética , Neoplasias/terapia , Guías de Práctica Clínica como Asunto , Sociedades Médicas/normas , Estados Unidos
5.
Nature ; 608(7921): 199-208, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35859180

RESUMEN

Circulating tumour DNA (ctDNA) in blood plasma is an emerging tool for clinical cancer genotyping and longitudinal disease monitoring1. However, owing to past emphasis on targeted and low-resolution profiling approaches, our understanding of the distinct populations that comprise bulk ctDNA is incomplete2-12. Here we perform deep whole-genome sequencing of serial plasma and synchronous metastases in patients with aggressive prostate cancer. We comprehensively assess all classes of genomic alterations and show that ctDNA contains multiple dominant populations, the evolutionary histories of which frequently indicate whole-genome doubling and shifts in mutational processes. Although tissue and ctDNA showed concordant clonally expanded cancer driver alterations, most individual metastases contributed only a minor share of total ctDNA. By comparing serial ctDNA before and after clinical progression on potent inhibitors of the androgen receptor (AR) pathway, we reveal population restructuring converging solely on AR augmentation as the dominant genomic driver of acquired treatment resistance. Finally, we leverage nucleosome footprints in ctDNA to infer mRNA expression in synchronously biopsied metastases, including treatment-induced changes in AR transcription factor signalling activity. Our results provide insights into cancer biology and show that liquid biopsy can be used as a tool for comprehensive multi-omic discovery.


Asunto(s)
ADN Tumoral Circulante , Resistencia a Antineoplásicos , Genoma Humano , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Mutación , Neoplasias de la Próstata , Antagonistas de Receptores Androgénicos/farmacología , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Células Clonales/metabolismo , Células Clonales/patología , Progresión de la Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Marcadores Genéticos/genética , Genoma Humano/genética , Genómica/métodos , Humanos , Biopsia Líquida/métodos , Masculino , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Nucleosomas/genética , Nucleosomas/metabolismo , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , ARN Mensajero/análisis , ARN Mensajero/genética , ARN Neoplásico/análisis , ARN Neoplásico/genética , Receptores Androgénicos/metabolismo
6.
Nature ; 595(7867): 432-437, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34135506

RESUMEN

Minimally invasive approaches to detect residual disease after surgery are needed to identify patients with cancer who are at risk for metastatic relapse. Circulating tumour DNA (ctDNA) holds promise as a biomarker for molecular residual disease and relapse1. We evaluated outcomes in 581 patients who had undergone surgery and were evaluable for ctDNA from a randomized phase III trial of adjuvant atezolizumab versus observation in operable urothelial cancer. This trial did not reach its efficacy end point in the intention-to-treat population. Here we show that ctDNA testing at the start of therapy (cycle 1 day 1) identified 214 (37%) patients who were positive for ctDNA and who had poor prognosis (observation arm hazard ratio = 6.3 (95% confidence interval: 4.45-8.92); P < 0.0001). Notably, patients who were positive for ctDNA had improved disease-free survival and overall survival in the atezolizumab arm versus the observation arm (disease-free survival hazard ratio = 0.58 (95% confidence interval: 0.43-0.79); P = 0.0024, overall survival hazard ratio = 0.59 (95% confidence interval: 0.41-0.86)). No difference in disease-free survival or overall survival between treatment arms was noted for patients who were negative for ctDNA. The rate of ctDNA clearance at week 6 was higher in the atezolizumab arm (18%) than in the observation arm (4%) (P = 0.0204). Transcriptomic analysis of tumours from patients who were positive for ctDNA revealed higher expression levels of cell-cycle and keratin genes. For patients who were positive for ctDNA and who were treated with atezolizumab, non-relapse was associated with immune response signatures and basal-squamous gene features, whereas relapse was associated with angiogenesis and fibroblast TGFß signatures. These data suggest that adjuvant atezolizumab may be associated with improved outcomes compared with observation in patients who are positive for ctDNA and who are at a high risk of relapse. These findings, if validated in other settings, would shift approaches to postoperative cancer care.


Asunto(s)
Adyuvantes Farmacéuticos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , ADN Tumoral Circulante/sangre , Inmunoterapia , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , ADN Tumoral Circulante/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/genética , Cuidados Posoperatorios , Pronóstico , Recurrencia , Análisis de Supervivencia , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/inmunología
7.
Trends Genet ; 39(4): 285-307, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36792446

RESUMEN

Liquid biopsies (LBs), particularly using circulating tumor DNA (ctDNA), are expected to revolutionize precision oncology and blood-based cancer screening. Recent technological improvements, in combination with the ever-growing understanding of cell-free DNA (cfDNA) biology, are enabling the detection of tumor-specific changes with extremely high resolution and new analysis concepts beyond genetic alterations, including methylomics, fragmentomics, and nucleosomics. The interrogation of a large number of markers and the high complexity of data render traditional correlation methods insufficient. In this regard, machine learning (ML) algorithms are increasingly being used to decipher disease- and tissue-specific signals from cfDNA. Here, we review recent insights into biological ctDNA features and how these are incorporated into sophisticated ML applications.


Asunto(s)
Ácidos Nucleicos Libres de Células , ADN Tumoral Circulante , Neoplasias Hematológicas , Neoplasias , Humanos , Ácidos Nucleicos Libres de Células/genética , Neoplasias/genética , Medicina de Precisión , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/análisis , Aprendizaje Automático
8.
Blood ; 143(6): 522-534, 2024 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-37946299

RESUMEN

ABSTRACT: State-of-the-art response assessment of central nervous system lymphoma (CNSL) by magnetic resonance imaging is challenging and an insufficient predictor of treatment outcomes. Accordingly, the development of novel risk stratification strategies in CNSL is a high unmet medical need. We applied ultrasensitive circulating tumor DNA (ctDNA) sequencing to 146 plasma and cerebrospinal fluid (CSF) samples from 67 patients, aiming to develop an entirely noninvasive dynamic risk model considering clinical and molecular features of CNSL. Our ultrasensitive method allowed for the detection of CNSL-derived mutations in plasma ctDNA with high concordance to CSF and tumor tissue. Undetectable plasma ctDNA at baseline was associated with favorable outcomes. We tracked tumor-specific mutations in plasma-derived ctDNA over time and developed a novel CNSL biomarker based on this information: peripheral residual disease (PRD). Persistence of PRD after treatment was highly predictive of relapse. Integrating established baseline clinical risk factors with assessment of radiographic response and PRD during treatment resulted in the development and independent validation of a novel tool for risk stratification: molecular prognostic index for CNSL (MOP-C). MOP-C proved to be highly predictive of outcomes in patients with CNSL (failure-free survival hazard ratio per risk group of 6.60; 95% confidence interval, 3.12-13.97; P < .0001) and is publicly available at www.mop-c.com. Our results highlight the role of ctDNA sequencing in CNSL. MOP-C has the potential to improve the current standard of clinical risk stratification and radiographic response assessment in patients with CNSL, ultimately paving the way toward individualized treatment.


Asunto(s)
Neoplasias del Sistema Nervioso Central , ADN Tumoral Circulante , Linfoma no Hodgkin , Humanos , ADN Tumoral Circulante/genética , Recurrencia Local de Neoplasia , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/genética , Neoplasias del Sistema Nervioso Central/terapia , Pronóstico , Biomarcadores de Tumor/genética , Sistema Nervioso Central
9.
Blood ; 143(23): 2401-2413, 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38427753

RESUMEN

ABSTRACT: It remains elusive how driver mutations, including those detected in circulating tumor DNA (ctDNA), affect prognosis in relapsed/refractory multiple myeloma (RRMM). Here, we performed targeted-capture sequencing using bone marrow plasma cells (BMPCs) and ctDNA of 261 RRMM cases uniformly treated with ixazomib, lenalidomide, and dexamethasone in a multicenter, prospective, observational study. We detected 24 and 47 recurrently mutated genes in BMPC and ctDNA, respectively. In addition to clonal hematopoiesis-associated mutations, varying proportion of driver mutations, particularly TP53 mutations (59.2% of mutated cases), were present in only ctDNA, suggesting their subclonal origin. In univariable analyses, ctDNA mutations of KRAS, TP53, DIS3, BRAF, NRAS, and ATM were associated with worse progression-free survival (PFS). BMPC mutations of TP53 and KRAS were associated with inferior PFS, whereas KRAS mutations were prognostically relevant only when detected in both BMPC and ctDNA. A total number of ctDNA mutations in the 6 relevant genes was a strong prognostic predictor (2-year PFS rates: 57.3%, 22.7%, and 0% for 0, 1, and ≥2 mutations, respectively) and independent of clinical factors and plasma DNA concentration. Using the number of ctDNA mutations, plasma DNA concentration, and clinical factors, we developed a prognostic index, classifying patients into 3 categories with 2-year PFS rates of 57.9%, 28.6%, and 0%. Serial analysis of ctDNA mutations in 94 cases revealed that TP53 and KRAS mutations frequently emerge after therapy. Thus, we clarify the genetic characteristics and clonal architecture of ctDNA mutations and demonstrate their superiority over BMPC mutations for prognostic prediction in RRMM. This study is a part of the C16042 study, which is registered at www.clinicaltrials.gov as #NCT03433001.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Compuestos de Boro , ADN Tumoral Circulante , Dexametasona , Glicina , Lenalidomida , Mieloma Múltiple , Humanos , Lenalidomida/administración & dosificación , Lenalidomida/uso terapéutico , Femenino , Glicina/análogos & derivados , Glicina/administración & dosificación , Glicina/uso terapéutico , Masculino , Anciano , Persona de Mediana Edad , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Pronóstico , Dexametasona/administración & dosificación , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Compuestos de Boro/uso terapéutico , Compuestos de Boro/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano de 80 o más Años , Mutación , Adulto , Estudios Prospectivos , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Biomarcadores de Tumor/genética
10.
Blood ; 144(3): 272-282, 2024 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-38620072

RESUMEN

ABSTRACT: The phase 2 CLL2-BAAG trial tested the measurable residual disease (MRD)-guided triple combination of acalabrutinib, venetoclax, and obinutuzumab after optional bendamustine debulking in 45 patients with relapsed/refractory chronic lymphocytic leukemia (CLL). MRD was measured by flow cytometry (FCM; undetectable MRD <10-4) in peripheral blood (PB) and circulating tumor DNA (ctDNA) using digital droplet polymerase chain reaction of variable-diversity-joining (VDJ) rearrangements and CLL-related mutations in plasma. The median number of previous treatments was 1 (range, 1-4); 18 patients (40%) had received a Bruton tyrosine kinase inhibitor (BTKi) and/or venetoclax before inclusion, 14 of 44 (31.8%) had TP53 aberrations, and 34 (75.6%) had unmutated immunoglobulin heavy-chain variable region genes. With a median observation time of 36.3 months and all patients off-treatment for a median of 21.9 months, uMRD <10-4 in PB was achieved in 42 of the 45 patients (93.3%) at any time point, including 17 of 18 (94.4%) previously exposed to venetoclax/BTKi and 13 of 14 (92.9%) with TP53 aberrations. The estimated 3-year progression-free and overall survival rates were 85.0% and 93.8%, respectively. Overall, 585 paired FCM/ctDNA samples were analyzed and 18 MRD recurrences (5 with and 13 without clinical progression) occurred after the end of treatment. Twelve samples were first detected by ctDNA, 3 by FCM, and 3 synchronously. In conclusion, time-limited MRD-guided acalabrutinib, venetoclax, and obinutuzumab achieved deep remissions in almost all patients with relapsed/refractory CLL. The addition of ctDNA-based analyses to FCM MRD assessment seems to improve early detection of relapses. This trial was registered at www.clinicaltrials.gov as #NCT03787264.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Compuestos Bicíclicos Heterocíclicos con Puentes , ADN Tumoral Circulante , Leucemia Linfocítica Crónica de Células B , Neoplasia Residual , Pirazinas , Sulfonamidas , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , Sulfonamidas/administración & dosificación , Sulfonamidas/uso terapéutico , Anciano , Persona de Mediana Edad , Femenino , Masculino , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Pirazinas/administración & dosificación , Pirazinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Benzamidas/administración & dosificación , Benzamidas/uso terapéutico , Adulto , Recurrencia
11.
Nature ; 580(7802): 245-251, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32269342

RESUMEN

Radiologic screening of high-risk adults reduces lung-cancer-related mortality1,2; however, a small minority of eligible individuals undergo such screening in the United States3,4. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)5, a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.


Asunto(s)
ADN Tumoral Circulante/análisis , ADN Tumoral Circulante/genética , Detección Precoz del Cáncer/métodos , Genoma Humano/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Mutación , Estudios de Cohortes , Femenino , Hematopoyesis/genética , Humanos , Pulmón/metabolismo , Pulmón/patología , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados
12.
Nucleic Acids Res ; 52(13): 7539-7555, 2024 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-38783375

RESUMEN

The exchange of genes between cells is known to play an important physiological and pathological role in many organisms. We show that circulating tumor DNA (ctDNA) facilitates cell-specific gene transfer between human cancer cells and explain part of the mechanisms behind this phenomenon. As ctDNA migrates into the nucleus, genetic information is transferred. Cell targeting and ctDNA integration require ERVL, SINE or LINE DNA sequences. Chemically manufactured AluSp and MER11C sequences replicated multiple myeloma (MM) ctDNA cell targeting and integration. Additionally, we found that ctDNA may alter the treatment response of MM and pancreatic cancer models. This study shows that retrotransposon DNA sequences promote cancer gene transfer. However, because cell-free DNA has been detected in physiological and other pathological conditions, our findings have a broader impact than just cancer. Furthermore, the discovery that transposon DNA sequences mediate tissue-specific targeting will open up a new avenue for the delivery of genes and therapies.


Asunto(s)
ADN Tumoral Circulante , Elementos Transponibles de ADN , Humanos , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Elementos Transponibles de ADN/genética , Línea Celular Tumoral , Mieloma Múltiple/genética , Mieloma Múltiple/terapia , Animales , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Ratones , Especificidad de Órganos/genética , Retroelementos/genética , Técnicas de Transferencia de Gen
13.
Brief Bioinform ; 24(2)2023 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-36869848

RESUMEN

Sampling circulating tumor DNA (ctDNA) using liquid biopsies offers clinically important benefits for monitoring cancer progression. A single ctDNA sample represents a mixture of shed tumor DNA from all known and unknown lesions within a patient. Although shedding levels have been suggested to hold the key to identifying targetable lesions and uncovering treatment resistance mechanisms, the amount of DNA shed by any one specific lesion is still not well characterized. We designed the Lesion Shedding Model (LSM) to order lesions from the strongest to the poorest shedding for a given patient. By characterizing the lesion-specific ctDNA shedding levels, we can better understand the mechanisms of shedding and more accurately interpret ctDNA assays to improve their clinical impact. We verified the accuracy of the LSM under controlled conditions using a simulation approach as well as testing the model on three cancer patients. The LSM obtained an accurate partial order of the lesions according to their assigned shedding levels in simulations and its accuracy in identifying the top shedding lesion was not significantly impacted by number of lesions. Applying LSM to three cancer patients, we found that indeed there were lesions that consistently shed more than others into the patients' blood. In two of the patients, the top shedding lesion was one of the only clinically progressing lesions at the time of biopsy suggesting a connection between high ctDNA shedding and clinical progression. The LSM provides a much needed framework with which to understand ctDNA shedding and to accelerate discovery of ctDNA biomarkers. The LSM source code has been available in the IBM BioMedSciAI Github (https://github.com/BiomedSciAI/Geno4SD).


Asunto(s)
ADN Tumoral Circulante , Neoplasias , Humanos , Biomarcadores de Tumor/genética , Neoplasias/tratamiento farmacológico , ADN de Neoplasias/genética , ADN Tumoral Circulante/genética , Biopsia , Mutación
14.
Nat Rev Genet ; 20(2): 71-88, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30410101

RESUMEN

Precision oncology seeks to leverage molecular information about cancer to improve patient outcomes. Tissue biopsy samples are widely used to characterize tumours but are limited by constraints on sampling frequency and their incomplete representation of the entire tumour bulk. Now, attention is turning to minimally invasive liquid biopsies, which enable analysis of tumour components (including circulating tumour cells and circulating tumour DNA) in bodily fluids such as blood. The potential of liquid biopsies is highlighted by studies that show they can track the evolutionary dynamics and heterogeneity of tumours and can detect very early emergence of therapy resistance, residual disease and recurrence. However, the analytical validity and clinical utility of liquid biopsies must be rigorously demonstrated before this potential can be realized.


Asunto(s)
ADN Tumoral Circulante/genética , Células Neoplásicas Circulantes/patología , Medicina de Precisión/métodos , ADN Tumoral Circulante/sangre , Humanos , Biopsia Líquida/métodos , Neoplasia Residual
15.
Nature ; 570(7761): 385-389, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-31142840

RESUMEN

Cell-free DNA in the blood provides a non-invasive diagnostic avenue for patients with cancer1. However, characteristics of the origins and molecular features of cell-free DNA are poorly understood. Here we developed an approach to evaluate fragmentation patterns of cell-free DNA across the genome, and found that profiles of healthy individuals reflected nucleosomal patterns of white blood cells, whereas patients with cancer had altered fragmentation profiles. We used this method to analyse the fragmentation profiles of 236 patients with breast, colorectal, lung, ovarian, pancreatic, gastric or bile duct cancer and 245 healthy individuals. A machine learning model that incorporated genome-wide fragmentation features had sensitivities of detection ranging from 57% to more than 99% among the seven cancer types at 98% specificity, with an overall area under the curve value of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation-based cell-free DNA analyses detected 91% of patients with cancer. The results of these analyses highlight important properties of cell-free DNA and provide a proof-of-principle approach for the screening, early detection and monitoring of human cancer.


Asunto(s)
ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Fragmentación del ADN , Genoma Humano/genética , Neoplasias/diagnóstico , Neoplasias/genética , Estudios de Casos y Controles , Estudios de Cohortes , Análisis Mutacional de ADN , Humanos , Aprendizaje Automático , Mutación , Neoplasias/sangre , Neoplasias/patología
16.
Gut ; 73(11): 1870-1882, 2024 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-39054058

RESUMEN

OBJECTIVE: Circulating tumour DNA (ctDNA) is a promising non-invasive biomarker in cancer. We aim to assess the dynamic of ctDNA in patients with hepatocellular carcinoma (HCC). DESIGN: We analysed 772 plasmas from 173 patients with HCC collected at the time of diagnosis or treatment (n=502), 24 hours after locoregional treatment (n=154) and during follow-up (n=116). For controls, 56 plasmas from patients with chronic liver disease without HCC were analysed. All samples were analysed for cell free DNA (cfDNA) concentration, and for mutations in TERT promoter, CTNNB1, TP53, PIK3CA and NFE2L2 by sequencing and droplet-based digital PCR. Results were compared with 232 corresponding tumour samples. RESULTS: In patients with active HCC, 40.2% of the ctDNA was mutated vs 14.6% in patients with inactive HCC and 1.8% in controls (p<0.001). In active HCC, we identified 27.5% of mutations in TERT promoter, 21.3% in TP53, 13.1% in CTNNB1, 0.4% in PIK3CA and 0.2% in NFE2L2, most of the times similar to those identified in the corresponding tumour. CtDNA mutation rate increased with advanced tumour stages (p<0.001). In 103 patients treated by percutaneous ablation, the presence and number of mutations in the ctDNA before treatment were associated with higher risk of death (p=0.001) and recurrence (p<0.001). Interestingly, cfDNA concentration and detectable mutations increased 24 hours after a locoregional treatment. Among 356 plasmas collected in 53 patients treated by systemic treatments, we detected mutations at baseline in 60.4% of the cases. In patients treated by atezolizumab-bevacizumab, persistence of mutation in ctDNA was associated with radiological progression (63.6% vs 36.4% for disappearance, p=0.019). In two patients progressing under systemic treatments, we detected the occurrence of mutations in CTNNB1 in the plasma that was subclonal in the tumour for one patient and not detectable in the tumour for the other one. CONCLUSION: ctDNA offers dynamic information reflecting tumour biology. It represents a non-invasive tool useful to guide HCC clinical management.


Asunto(s)
Biomarcadores de Tumor , Carcinoma Hepatocelular , ADN Tumoral Circulante , Neoplasias Hepáticas , Mutación , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patología , Masculino , Femenino , ADN Tumoral Circulante/sangre , ADN Tumoral Circulante/genética , Persona de Mediana Edad , Anciano , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Estadificación de Neoplasias , Telomerasa/genética , beta Catenina/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Adulto , Proteína p53 Supresora de Tumor/genética , Factor 2 Relacionado con NF-E2/genética
17.
J Cell Mol Med ; 28(14): e18576, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39054569

RESUMEN

Diagnosis of intravascular large B-cell lymphoma (IVLBCL) is a challenge due to its heterogeneous clinical presentation and lack of specific markers. This retrospective study investigated the utility of circulating tumour DNA (ctDNA) sequencing for diagnosing IVLBCL and analysing its mutation landscape. A cohort of 34 IVLBCL patients enrolled and underwent plasma ctDNA targeted sequencing. The median plasma ctDNA concentration was 135.0 ng/mL, significantly higher than that in diffuse large B-cell lymphoma (DLBCL) controls. Correlations were found between ctDNA concentration and disease severity indicators, LDH and SF. Mutation analysis revealed frequent mutations in B-cell receptor and NF-κB signalling pathways, including MYD88 (56%), CD79B (44%), TNFAIP3 (38%) and IRF4 (29%). CNS involvement was significantly related with BCL6 and CD58 mutation. Patients with complicated hemophagocytic lymphohistiocytosis had significantly higher mutation rates in B2M. Comparison with DLBCL subtypes showed distinctive mutation profiles in IVLBCL. Moreover, plasma ctDNA detected more mutations with higher variant allele fraction than tissue DNA, suggesting its superiority in sensitivity and accessibility. Dynamic monitoring of ctDNA during treatment correlated with therapeutic responses. This study revealed the role of ctDNA in IVLBCL diagnosis, mutation analysis, and treatment monitoring, offering a promising avenue for improving patient diagnosis in this rare lymphoma subtype.


Asunto(s)
Biomarcadores de Tumor , ADN Tumoral Circulante , Linfoma de Células B Grandes Difuso , Mutación , Humanos , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Femenino , Masculino , Persona de Mediana Edad , Anciano , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/sangre , Análisis Mutacional de ADN/métodos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Adulto , Estudios Retrospectivos , Anciano de 80 o más Años
18.
J Cell Mol Med ; 28(19): e70126, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39384181

RESUMEN

B-cell acute lymphoblastic leukaemia (B-ALL) is the most prevalent hematologic malignancy in children and a leading cause of mortality. Managing B-ALL remains challenging due to its heterogeneity and relapse risk. This study aimed to delineate the molecular features of paediatric B-ALL and explore the clinical utility of circulating tumour DNA (ctDNA). We analysed 146 patients with paediatric B-ALL who received systemic chemotherapy. The mutational landscape was profiled in bone marrow (BM) and plasma samples using next-generation sequencing. Minimal residual disease (MRD) testing on day 19 of induction therapy evaluated treatment efficacy. RNA sequencing identified gene fusions in 61% of patients, including 37 novel fusions. Specifically, the KMT2A-TRIM29 novel fusion was validated in a boy who responded well to initial therapy but relapsed after 1 year. Elevated mutation counts and maximum variant allele frequency in baseline BM were associated with significantly poorer chemotherapy response (p = 0.0012 and 0.028, respectively). MRD-negative patients exhibited upregulation of immune-related pathways (p < 0.01) and increased CD8+ T cell infiltration (p = 0.047). Baseline plasma ctDNA exhibited high mutational concordance with the paired BM samples and was significantly associated with chemotherapy efficacy. These findings suggest that ctDNA and BM profiling offer promising prognostic insights for paediatric B-ALL management.


Asunto(s)
Biomarcadores de Tumor , Mutación , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Masculino , Niño , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Femenino , Preescolar , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Adolescente , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Lactante , Pronóstico , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Médula Ósea/patología , Médula Ósea/metabolismo , Proteína de la Leucemia Mieloide-Linfoide/genética , N-Metiltransferasa de Histona-Lisina/genética
19.
BMC Genomics ; 25(1): 827, 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39227777

RESUMEN

BACKGROUND: Circulating tumour DNA (ctDNA) is a subset of cell free DNA (cfDNA) released by tumour cells into the bloodstream. Circulating tumour DNA has shown great potential as a biomarker to inform treatment in cancer patients. Collecting ctDNA is minimally invasive and reflects the entire genetic makeup of a patient's cancer. ctDNA variants in NGS data can be difficult to distinguish from sequencing and PCR artefacts due to low abundance, particularly in the early stages of cancer. Unique Molecular Identifiers (UMIs) are short sequences ligated to the sequencing library before amplification. These sequences are useful for filtering out low frequency artefacts. The utility of ctDNA as a cancer biomarker depends on accurate detection of cancer variants. RESULTS: In this study, we benchmarked six variant calling tools, including two UMI-aware callers for their ability to call ctDNA variants. The standard variant callers tested included Mutect2, bcftools, LoFreq and FreeBayes. The UMI-aware variant callers benchmarked were UMI-VarCal and UMIErrorCorrect. We used both datasets with known variants spiked in at low frequencies, and datasets containing ctDNA, and generated synthetic UMI sequences for these datasets. Variant callers displayed different preferences for sensitivity and specificity. Mutect2 showed high sensitivity, while returning more privately called variants than any other caller in data without synthetic UMIs - an indicator of false positive variant discovery. In data encoded with synthetic UMIs, UMI-VarCal detected fewer putative false positive variants than all other callers in synthetic datasets. Mutect2 showed a balance between high sensitivity and specificity in data encoded with synthetic UMIs. CONCLUSIONS: Our results indicate UMI-aware variant callers have potential to improve sensitivity and specificity in calling low frequency ctDNA variants over standard variant calling tools. There is a growing need for further development of UMI-aware variant calling tools if effective early detection methods for cancer using ctDNA samples are to be realised.


Asunto(s)
Benchmarking , ADN Tumoral Circulante , Secuenciación de Nucleótidos de Alto Rendimiento , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Humanos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , Variación Genética , Neoplasias/genética , Neoplasias/sangre , Análisis de Secuencia de ADN/métodos , Programas Informáticos , Sensibilidad y Especificidad
20.
Am J Physiol Lung Cell Mol Physiol ; 326(5): L646-L650, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38529551

RESUMEN

Novel screening techniques for early detection of lung cancer are urgently needed. Profiling circulating tumor cell-free DNA (ctDNA) has emerged as a promising tool for biopsy-free tumor genotyping. However, both the scarcity and short half-life of ctDNA substantially limit the sensitivity and clinical utility of ctDNA detection methodologies. Our discovery that red blood cells (RBCs) sequester mitochondrial DNA opens a new avenue for detecting circulating nucleic acids, as RBCs represent an unrecognized reservoir of circulating nucleic acid. Here, we show that RBCs acquire tumor DNA following coculture with lung cancer cell lines harboring Kirsten rat sarcoma viral oncogene homolog (KRAS) and epidermal growth factor receptor (EGFR) mutations. RBC-bound tumor DNA is detectable in patients with early-stage non-small cell lung cancer (NSCLC) but not in healthy controls by qPCR. Our results collectively uncover a previously unrecognized yet easily accessible reservoir of tumor DNA, offering a promising foundation for future RBC-based tumor diagnostics.NEW & NOTEWORTHY We present a novel method for lung cancer detection by revealing RBCs as a reservoir for tumor DNA, overcoming the limitations of current circulating tumor ctDNA methodologies. By demonstrating that RBCs can capture tumor DNA, including critical mutations found in lung cancer, we provide a promising, biopsy-free avenue for early cancer diagnostics. This discovery opens up exciting possibilities for developing RBC-based diagnostic tools, significantly enhancing the sensitivity and clinical utility of noninvasive cancer detection.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Eritrocitos , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/diagnóstico , Eritrocitos/metabolismo , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Mutación , Línea Celular Tumoral , Receptores ErbB/genética , Receptores ErbB/metabolismo , ADN Mitocondrial/genética , ADN Mitocondrial/sangre , Proteínas Proto-Oncogénicas p21(ras)/genética , Masculino , Femenino , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/sangre , ADN de Neoplasias/sangre , ADN de Neoplasias/genética
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