Asunto(s)

Antineoplásicos Inmunológicos , Hematopoyesis Clonal , Inmunoterapia Adoptiva , Linfoma de Células B , Linfoma de Células T , Neoplasias Primarias Secundarias , Humanos , Inmunoterapia Adoptiva/efectos adversos , Linfoma de Células T/diagnóstico , Linfoma de Células T/genética , Linfoma de Células T/inmunología , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/inmunología , Receptores Quiméricos de Antígenos/inmunología , Riesgo , Hematopoyesis Clonal/genética , Hematopoyesis Clonal/inmunología , Linfoma de Células B/genética , Linfoma de Células B/inmunología , Linfoma de Células B/terapia , Linfoma de Células B/virología , Herpesvirus Humano 4/aislamiento & purificación , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Productos Biológicos/administración & dosificación , Productos Biológicos/efectos adversos , Síndrome de Liberación de Citoquinas/genética , Síndrome de Liberación de Citoquinas/inmunología

RESUMEN

BACKGROUND: Colorectal cancer ranks among the most prevalent malignancies globally. Accurate prediction of metachronous liver metastasis is crucial for optimizing postoperative management. Tripartite motif-containing protein 27 (TRIM27), an E3 ubiquitin ligase, is implicated in diverse cellular functions and tumorigenesis. METHODS: This study aimed to develop and validate a TRIM27-based nomogram for prognostication in colorectal cancer patients. Transcriptome sequencing of five paired tumor and normal tissue samples identified TRIM27 as a potential prognostic biomarker. Immunohistochemistry was employed to assess TRIM27 expression in colorectal cancer cohorts from two institutions. RESULTS: TRIM27 expression correlated significantly with both the prognosis of colorectal cancer patients and the occurrence of metachronous liver metastasis. A nomogram incorporating TRIM27 and clinical factors was constructed and demonstrated robust predictive accuracy in an independent validation cohort. CONCLUSION: The TRIM27-based nomogram is a valuable prognostic tool for predicting prognosis and metachronous liver metastasis in colorectal cancer patients, aiding in personalized treatment decisions.

Asunto(s)

Biomarcadores de Tumor , Neoplasias Colorrectales , Neoplasias Hepáticas , Nomogramas , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Masculino , Femenino , Pronóstico , Persona de Mediana Edad , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Anciano , Periodo Posoperatorio , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Neoplasias Primarias Secundarias/patología , Neoplasias Primarias Secundarias/metabolismo , Neoplasias Primarias Secundarias/genética , Proteínas de Motivos Tripartitos , Proteínas de Unión al ADN , Proteínas Nucleares

RESUMEN

BACKGROUND: Pancreatic acinar cell carcinoma (PACC) is a rare pancreatic neoplasm. Recently, molecular analysis revealed that PACC shows a high frequency of the BRCA1/2 mutation and is likely to be considered a cancer associated with hereditary breast and ovarian cancer (HBOC). Hereditary cancers, including HBOC, are characterized by multifocal and/or metachronous tumors. However, no case reports exist of germline BRCA1-mutated synchronous and metachronous PACC. CASE: A 58-year-old man was diagnosed with synchronous and metachronous PACC at the age of 56 and underwent two surgeries. Ten months after the second surgery, the patient developed multiple liver metastases. Gemcitabine plus nab-paclitaxel therapy was administered as first-line chemotherapy. After seven cycles, computed tomography examination revealed progressive disease (PD). Therefore, modified FOLFIRINOX (mFFX) was administered as second- line chemotherapy. After 19 cycles of mFFX, comprehensive cancer genomic profiling (CGP) identified a BRCA1 pathogenic variant that was confirmed to be germline origin. Accordingly, we treated the patient with olaparib; however, he was diagnosed with PD after 4 months. He subsequently died 5 years and 9 months after the initial surgery, and 3 years and 10 months after chemotherapy. Based on the genetic data of the patients, his family members received genetic counseling followed by cascade testing. Consequently, the same gBRCA1 pathogenic variant was detected in the son and his surveillance for HBOC-related cancers was initiated. CONCLUSION: We diagnosed a 58-year-old man with a synchronous and metachronous PACC with germline BRCA1 pathogenic variant. Considering that PACC is likely to have BRCA1/2 mutations responsible for HBOC, we need to be aware of the possible presence of multifocal and/or metachronous tumors in patients with PACC. Additionally, patients with PACC should undergo genetic examinations, which would be beneficial in determining treatment strategies and health care for blood relatives.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Proteína BRCA1 , Carcinoma de Células Acinares , Mutación de Línea Germinal , Neoplasias Pancreáticas , Humanos , Persona de Mediana Edad , Masculino , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Proteína BRCA1/genética , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/patología , Carcinoma de Células Acinares/diagnóstico , Carcinoma de Células Acinares/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/patología , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Múltiples/terapia , Oxaliplatino/administración & dosificación , Leucovorina/administración & dosificación , Irinotecán/administración & dosificación , Paclitaxel/administración & dosificación , Fluorouracilo/administración & dosificación

Asunto(s)

Antineoplásicos , Epigénesis Genética , Neoplasias Primarias Secundarias , Neoplasias Ováricas , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Enfermedades Raras , Adulto , Femenino , Humanos , ADN Helicasas/genética , Metilación de ADN , Epigénesis Genética/efectos de los fármacos , Proteínas Nucleares/genética , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Neoplasias Ováricas/terapia , Ovariectomía , Ovario/patología , Ovario/cirugía , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , Enfermedades Raras/terapia , Factores de Transcripción/genética , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Mutaciones Letales Sintéticas/efectos de los fármacos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias Primarias Secundarias/genética

RESUMEN

BACKGROUND: Early gastric cancer is treated endoscopically, but patients require surveillance due to the risk of metachronous gastric lesions (MGLs). Epigenetic alterations, particularly aberrant DNA methylation in genes, such as MIR124-3, MIR34b/c, NKX6-1, EMX1, MOS and CDO1, have been identified as promising biomarkers for MGL in Asian populations. We aimed to determine whether these changes could predict MGL risk in intermediate-risk Caucasian patients. METHODS: This case-cohort study included 36 patients who developed MGL matched to 48 patients without evidence of MGL in the same time frame (controls). Multiplex quantitative methylation-specific PCR was performed using DNA extracted from the normal mucosa adjacent to the primary lesion. The overall risk of progression to MGL was assessed using Kaplan-Meier and Cox proportional hazards model analyses. RESULTS: MIR124-3, MIR34b/c and NKX6-1 were successfully analyzed in 77 samples. MIR124-3 hypermethylation was detected in individuals who developed MGL (relative quantification 78.8 vs 50.5 in controls, p = 0.014), particularly in females and Helicobacter pylori-negative patients (p = 0.021 and p = 0.0079, respectively). This finding was further associated with a significantly greater risk for MGL development (aHR = 2.31, 95% CI 1.03-5.17, p = 0.042). Similarly, NKX6-1 was found to be hypermethylated in patients with synchronous lesions (relative quantification 7.9 vs 0.0 in controls, p = 0.0026). A molecular-based methylation model incorporating both genes was significantly associated with a threefold increased risk for MGL development (aHR = 3.10, 95% CI 1.07-8.95, p = 0.037). CONCLUSIONS: This preliminary study revealed an association between MIR124-3 and NKX6-1 hypermethylation and the development of MGL in a Western population. These findings may represent a burden reduction and a greener approach to patient care.

Asunto(s)

Metilación de ADN , Proteínas de Homeodominio , MicroARNs , Neoplasias Gástricas , Humanos , Femenino , Masculino , MicroARNs/genética , Neoplasias Gástricas/genética , Metilación de ADN/genética , Persona de Mediana Edad , Anciano , Proteínas de Homeodominio/genética , Población Blanca/genética , Estudios de Casos y Controles , Neoplasias Primarias Secundarias/genética , Epigénesis Genética/genética , Biomarcadores de Tumor/genética

RESUMEN

OBJECTIVES: We aimed to identify predictive markers for metachronous gastric cancer (MGC) in early gastric cancer (EGC) patients curatively treated with endoscopic submucosal dissection (ESD). MATERIALS AND METHODS: From EGC patients who underwent ESD, bulk RNA sequencing was performed on non-cancerous gastric mucosa samples at the time of initial EGC diagnosis. This included 23 patients who developed MGC, and 23 control patients without additional gastric neoplasms for over 3 years (1:1 matched by age, sex, and Helicobacter pylori infection state). Candidate differentially-expressed genes were identified, from which biomarkers were selected using real-time quantitative polymerase chain reaction and cell viability assays using gastric cell lines. An independent validation cohort of 55 MGC patients and 125 controls was used for marker validation. We also examined the severity of gastric intestinal metaplasia, a known premalignant condition, at initial diagnosis. RESULTS: From the discovery cohort, 86 candidate genes were identified of which KDF1 and CDK1 were selected as markers for MGC, which were confirmed in the validation cohort. CERB5 and AKT2 isoform were identified as markers related to intestinal metaplasia and were also highly expressed in MGC patients compared to controls (p < 0.01). Combining these markers with clinical data (age, sex, H. pylori and severity of intestinal metaplasia) yielded an area under the curve (AUC) of 0.91 (95% CI, 0.85-0.97) for MGC prediction. CONCLUSION: Assessing biomarkers in non-cancerous gastric mucosa may be a useful method for predicting MGC in EGC patients and identifying patients with a higher risk of developing MGC, who can benefit from rigorous surveillance.

Asunto(s)

Biomarcadores de Tumor , Neoplasias Primarias Secundarias , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/patología , Neoplasias Gástricas/genética , Masculino , Femenino , Biomarcadores de Tumor/genética , Persona de Mediana Edad , Anciano , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/patología , Resección Endoscópica de la Mucosa , Proteína Quinasa CDC2/genética , Proteína Quinasa CDC2/metabolismo , Mucosa Gástrica/patología , Mucosa Gástrica/cirugía , Mucosa Gástrica/microbiología , Mucosa Gástrica/metabolismo , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/genética , Gastroscopía , Regulación Neoplásica de la Expresión Génica , Metaplasia/genética , Metaplasia/patología , Helicobacter pylori/aislamiento & purificación , Estudios de Casos y Controles

RESUMEN

Therapy-related myeloid neoplasms (t-MN) are characterized by aggressive features and a dismal prognosis. Recent evidence suggests a higher incidence of t-MN in individuals harboring clonal hematopoiesis of indeterminate potential (CHIP). In order to gain insight into CHIP-driven malignant progression, we gathered data from ten published reports with available detailed patient characteristics at the time of primary malignancy and t-MN development. Detailed clinical and molecular information on primary malignancy and t-MN were available for 109 patients: 43% harbored at least one somatic mutation at the time of the primary malignancy. TET2 and TP53 mutations showed an increasing variant allele frequency from CHIP to t-MN. ASXL1-associated CHIP significantly correlated with the emergence of TET2 and CEBPA mutations at t-MN, as well as U2AF1-driven CHIP with EZH2 mutation and both IDH2 and SRSF2-driven CHIP with FLT3 mutation. DNMT3A-driven CHIP correlated with a lower incidence of TP53 mutation at t-MN. In contrast, TP53-driven CHIP correlated with a complex karyotype and a lower tendency to acquire new mutations at t-MN. Patients with multiple myeloma as their first malignancy presented a significantly higher rate of TP53 mutations at t-MN. The progression from CHIP to t-MN shows different scenarios depending on the genes involved. A deeper knowledge of CHIP progression mechanisms will allow a more reliable definition of t-MN risk.

Asunto(s)

Mutación , Neoplasias Primarias Secundarias , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Hematopoyesis Clonal/genética , Progresión de la Enfermedad , Trastornos Mieloproliferativos/genética , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/etiología

Asunto(s)

Leucemia Mielógena Crónica BCR-ABL Positiva , Linfohistiocitosis Hemofagocítica , Proteínas de la Membrana , Humanos , Linfohistiocitosis Hemofagocítica/genética , Linfohistiocitosis Hemofagocítica/patología , Linfohistiocitosis Hemofagocítica/complicaciones , Linfohistiocitosis Hemofagocítica/etiología , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/complicaciones , Proteínas de la Membrana/genética , Masculino , Niño , Proteínas Tirosina Quinasas/genética , Neoplasias Primarias Secundarias/patología , Neoplasias Primarias Secundarias/genética , Femenino , Pronóstico

RESUMEN

Children with acute lymphocytic leukemia rarely develop secondary hematological neoplasms. A 5-year-old boy was diagnosed with standard-risk precursor B-cell acute lymphocytic leukemia. The patient exhibited aberrant chromosomal changes in the bone marrow at 6 months postchemotherapy: 46,XY,der(6) t(1;6)(q12;p22) dup(6)(p22p12)[15]. Clinically, the patient has sustained complete remission and has not developed myeloid malignancy over the subsequent period (27 mo). The cytogenetic aberration was observed in 11% of CD34+ cells isolated from the bone marrow. We infer that the abnormal clone acquires self-renewal potency, differentiation, and growth advantage. Further long-term observation is needed to determine the nature of this cytogenetic aberration.

Asunto(s)

Hematopoyesis Clonal , Humanos , Masculino , Niño , Preescolar , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Aberraciones Cromosómicas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Neoplasias Primarias Secundarias/patología , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/tratamiento farmacológico

RESUMEN

The clinical impact of therapy-related acute leukemias is increasing with the extension of cancer-related survival; however, the origins remain largely unknown. Acute erythroleukemia (AEL), a rare unfavorable type of myeloid neoplasia, may also develop secondary to cytotoxic therapy. The disorder is featured by specific genetic alterations, most importantly multi-allelic mutations of the TP53 gene. While AEL might appear as a part of the therapy-related MDS/AML, spectrum information regarding the genetic complexity and progression is largely missing. We present two AEL cases arising after cytotoxic therapy and melphalan-based myeloablation/autologous peripheral stem cell transplantation due to multiple myeloma (MM). As stated, multiple pathogenic TP53 variants were present unrelated to preexisting MM, in parallel with uninvolved/wild-type hemopoiesis. Potential mechanisms of leukemic transformation are discussed, which include (1) preexisting preneoplastic hemopoietic stem cells (HSC) serving as the common origin for both MM and AEL, (2) the generation and intramedullary survival of p53-deficient post-chemotherapy HSCs, (3) reinoculation of mobilized autologous TP53 mutated HSCs, and (4) melphalan treatment-related late-onset myelodysplasia/leukemia with newly acquired TP53 mutations.

Asunto(s)

Leucemia Eritroblástica Aguda , Mieloma Múltiple , Trasplante Autólogo , Mieloma Múltiple/terapia , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Humanos , Persona de Mediana Edad , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/patología , Leucemia Eritroblástica Aguda/terapia , Masculino , Proteína p53 Supresora de Tumor/genética , Trasplante de Células Madre Hematopoyéticas/métodos , Transformación Celular Neoplásica/genética , Mutación , Femenino , Melfalán/uso terapéutico , Melfalán/administración & dosificación , Anciano , Quimioradioterapia/métodos , Neoplasias Primarias Secundarias/etiología , Neoplasias Primarias Secundarias/terapia , Neoplasias Primarias Secundarias/genética

RESUMEN

Therapy-related myeloid neoplasms (t-MN) arise as a complication of chemo- and/or radiotherapy. Although t-MN can occur both in adult and childhood cancer survivors, the mechanisms driving therapy-related leukemogenesis likely vary across different ages. Chemotherapy is thought to induce driver mutations in children, whereas in adults pre-existing mutant clones are selected by the exposure. However, selective pressures induced by chemotherapy early in life are less well studied. Here, we use single-cell whole genome sequencing and phylogenetic inference to show that the founding cell of t-MN in children starts expanding after cessation of platinum exposure. In patients with Li-Fraumeni syndrome, characterized by a germline TP53 mutation, we find that the t-MN already expands during treatment, suggesting that platinum-induced growth inhibition is TP53-dependent. Our results demonstrate that germline aberrations can interact with treatment exposures in inducing t-MN, which is important for the development of more targeted, patient-specific treatment regimens and follow-up.

Asunto(s)

Mutación de Línea Germinal , Síndrome de Li-Fraumeni , Neoplasias Primarias Secundarias , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/genética , Síndrome de Li-Fraumeni/genética , Niño , Neoplasias Primarias Secundarias/genética , Masculino , Femenino , Compuestos de Platino/uso terapéutico , Adulto , Adolescente , Secuenciación Completa del Genoma , Filogenia , Preescolar , Antineoplásicos/uso terapéutico , Análisis de la Célula Individual

RESUMEN

Objective: To investigate the clinicopathological features of children with metachronous or synchronous primary tumors and to identify related genetic tumor syndromes. Methods: The clinicopathological data of 4 children with multiple primary tumors diagnosed in the Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China from 2011 to 2023 were collected. The histological, immunophenotypic and molecular characteristics were examined using H&E staining, immunohistochemical staining, PCR, Sanger sequencing and next-generation sequencing (NGS). The patients were followed up. Results: Case 1 was an 8-year-old boy with the adrenal cortical carcinoma, and 5 years later a poorly differentiated gastric adenocarcinoma was detected. Case 2 was a 2-year-old boy, presented with a left ventricular choroid plexus carcinoma, and a hepatoblastoma was detected 8 months later. Case 3 was a 9-month-old girl, diagnosed with renal rhabdoid tumor first and intracranial atypical teratoid/rhabdoid tumor (AT/RT) 3 months later. Case 4 was a 7-year-old boy and had a sigmoid colon adenocarcinoma 3 years after the diagnosis of a glioblastoma. The morphology and immunohistochemical features of the metachronous or synchronous primary tumors in the 4 cases were similar to the corresponding symptom-presenting/first-diagnosed tumors. No characteristic germ line mutations were detected in cases 1 and 2 by relevant molecular detection, and the rhabdoid tumor predisposition syndrome was confirmed in case 3 using NGS. Case 4 was clearly related to constitutional mismatch repair deficiency as shown by the molecular testing and clinical features. Conclusions: Childhood multiple primary tumors are a rare disease with histological morphology and immunophenotype similar to the symptom-presenting tumors. They are either sporadic or associated with a genetic (tumor) syndrome. The development of both tumors can occur simultaneously (synchronously) or at different times (metachronously). Early identification of the children associated with genetic tumor syndromes can facilitate routine tumor screening and early treatment.

Asunto(s)

Hepatoblastoma , Neoplasias Renales , Neoplasias Hepáticas , Neoplasias Primarias Múltiples , Tumor Rabdoide , Neoplasias Gástricas , Humanos , Masculino , Niño , Femenino , Preescolar , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/patología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Neoplasias Renales/patología , Neoplasias Renales/genética , Lactante , Neoplasias Gástricas/patología , Neoplasias Gástricas/genética , Tumor Rabdoide/genética , Tumor Rabdoide/patología , Hepatoblastoma/genética , Hepatoblastoma/patología , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/diagnóstico , Neoplasias del Plexo Coroideo/genética , Neoplasias del Plexo Coroideo/patología , Neoplasias del Plexo Coroideo/diagnóstico , Carcinoma Corticosuprarrenal/genética , Carcinoma Corticosuprarrenal/patología , Neoplasias de la Corteza Suprarrenal/patología , Neoplasias de la Corteza Suprarrenal/genética , Teratoma/patología , Teratoma/genética , Teratoma/cirugía , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Proteína SMARCB1/genética , Homólogo 1 de la Proteína MutL/genética , Neoplasias Primarias Secundarias/patología , Neoplasias Primarias Secundarias/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/patología

RESUMEN

Historically, the increased incidence of myeloid neoplasms observed in individuals with breast and ovarian cancer has been attributed exclusively to prior exposure to cancer-directed therapies. However, as the association between deleterious germline variants and the development of hematopoietic malignancies (HMs) becomes better established, we propose the increased incidence of myeloid neoplasms in those with breast and ovarian cancer may be at least partially related to underlying germline cancer predisposition alleles. Deleterious germline variants in BRCA1/2, ATM, CHEK2, PALB2, and other related genes prevent normal homologous recombination DNA repair of double-strand breaks, leading to reliance on less effective repair mechanisms. This results in a high lifetime risk of breast and ovarian cancer, and likely also increases the risk of subsequent therapy-related myeloid neoplasms (t-MNs). These deleterious germline variants likely increase the risk for de novo HMs as well, as evidenced by the increased incidence of HMs observed in those with deleterious germline BRCA1/2 variants even in the absence of prior cancer-directed therapy. Thus, the association between poly(ADP-ribose) polymerase (PARP) inhibitors and other solid tumor directed therapies and the development of t-MNs may be confounded by the presence of deleterious germline variants which inherently increase the risk of both de novo and t-MNs, and additional data regarding the direct toxic effects of these drugs on bone marrow function are needed.

Asunto(s)

Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/genética , Neoplasias de la Mama/genética , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/epidemiología , Proteínas de la Ataxia Telangiectasia Mutada/genética , Quinasa de Punto de Control 2/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Neoplasias Hematológicas/genética , Genes BRCA2 , Proteína del Grupo de Complementación N de la Anemia de Fanconi

RESUMEN

BACKGROUND: The risk of second tumors after chimeric antigen receptor (CAR) T-cell therapy, especially the risk of T-cell neoplasms related to viral vector integration, is an emerging concern. METHODS: We reviewed our clinical experience with adoptive cellular CAR T-cell therapy at our institution since 2016 and ascertained the occurrence of second tumors. In one case of secondary T-cell lymphoma, a broad array of molecular, genetic, and cellular techniques were used to interrogate the tumor, the CAR T cells, and the normal hematopoietic cells in the patient. RESULTS: A total of 724 patients who had received T-cell therapies at our center were included in the study. A lethal T-cell lymphoma was identified in a patient who had received axicabtagene ciloleucel therapy for diffuse large B-cell lymphoma, and both lymphomas were deeply profiled. Each lymphoma had molecularly distinct immunophenotypes and genomic profiles, but both were positive for Epstein-Barr virus and were associated with DNMT3A and TET2 mutant clonal hematopoiesis. No evidence of oncogenic retroviral integration was found with the use of multiple techniques. CONCLUSIONS: Our results highlight the rarity of second tumors and provide a framework for defining clonal relationships and viral vector monitoring. (Funded by the National Cancer Institute and others.).

Asunto(s)

Antineoplásicos Inmunológicos , Inmunoterapia Adoptiva , Linfoma de Células B Grandes Difuso , Linfoma de Células T , Neoplasias Primarias Secundarias , Receptores Quiméricos de Antígenos , Femenino , Humanos , Persona de Mediana Edad , Productos Biológicos/efectos adversos , Productos Biológicos/uso terapéutico , Hematopoyesis Clonal , Herpesvirus Humano 4/inmunología , Herpesvirus Humano 4/genética , Inmunoterapia Adoptiva/efectos adversos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/terapia , Linfoma de Células T/etiología , Linfoma de Células T/genética , Linfoma de Células T/inmunología , Linfoma de Células T/terapia , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/etiología , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Integración Viral

RESUMEN

INTRODUCTION: Oncological outcomes in patients with nonclear cell renal cell carcinoma (non-ccRCC) treated with surgery for locoregional nodal disease (ND) remain incompletely characterized. The objective was to investigate the characteristics and outcomes of non-ccRCC patients treated with lymph node dissection (LND) and salvage-LND (S-LND). METHODS: A total of 1627 patients underwent nephrectomy for nonmetastatic non-ccRCC at Memorial Sloan Kettering Cancer Center between 2007 and 2023. Histology was grouped as papillary, chromophobe, unclassified, and rare subtypes. Retrospective evaluation identified 2.5% (n = 40) of patients with nodal disease at time of nephrectomy (synchronous-ND) and 1.1% (n = 18) with metachronous nodal disease limited to the retroperitoneum (metachronous-ND). Patients' demographics and tumor characteristics were recorded and evaluated by univariate and multivariate cox regression models. Recurrence-free survival (RFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Patients who underwent tumor DNA sequencing during their clinical course were considered for genomic analysis. RESULTS: OS trended toward longer in metachronous-ND (51 vs 105 months; P = .2), though 23% of patients with synchronous-ND were recurrence-free at 45 months median follow-up. In multivariate analysis, rare histologies were associated with decreased OS (P = .030) and metachronous-ND with improved OS (P = .036). RFS and OS after S-LND was 15 and 96 months, respectively. Late onset of metachronous-ND/recurrence was associated with improved OS (P = .008). Genetic alterations in SETD2, TP53, B2M, and FGFR3 were exclusively seen in synchronous-ND, and tumor mutation burden (TMB) was also higher in patients with synchronous-ND (P = .016). CONCLUSIONS: Patients with metachronous-ND tend to have prolonged OS compared to synchronous-ND, but a substantial portion of patients with synchronous-ND still enter a durable disease-free state following LND. S-LND can likewise provide long-term survival, particularly in patients with longer time to metachronous nodal recurrence. Synchronous-ND was associated with SETD2, TP53, and NF2 alteration as well as higher TMB.

Asunto(s)

Carcinoma de Células Renales , Neoplasias Renales , Escisión del Ganglio Linfático , Nefrectomía , Humanos , Masculino , Femenino , Neoplasias Renales/genética , Neoplasias Renales/cirugía , Neoplasias Renales/patología , Neoplasias Renales/mortalidad , Persona de Mediana Edad , Estudios Retrospectivos , Nefrectomía/métodos , Anciano , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/cirugía , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/mortalidad , Metástasis Linfática/genética , Metástasis Linfática/patología , Resultado del Tratamiento , Neoplasias Primarias Múltiples/genética , Neoplasias Primarias Múltiples/cirugía , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Múltiples/mortalidad , Genómica , Adulto , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/patología , Neoplasias Primarias Secundarias/cirugía , Neoplasias Primarias Secundarias/mortalidad

Asunto(s)

Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Neoplasias Primarias Secundarias/patología , Neoplasias Primarias Secundarias/genética , Niño , Masculino , Femenino

RESUMEN

BACKGROUND: Melanoma is rare as a secondary malignant neoplasm among childhood cancer survivors. CASE: We report a case of a 12-year-old boy who developed malignant melanoma with systemic metastases 17 months after completing treatment for hepatoblastoma. The diagnosis was made unexpectedly based on a bone marrow examination. The patient did not respond to immune checkpoint inhibitor therapy and died 6 weeks after being diagnosed with melanoma. Whole-exome sequencing to examine 103 genes associated with cancer predisposition did not identify any germ-line variants. CONCLUSION: This case study provides a unique example of melanoma in a childhood cancer survivor following hepatoblastoma treatment but does not identify any candidate variant to link hepatoblastoma and melanoma.

Asunto(s)

Hepatoblastoma , Neoplasias Hepáticas , Melanoma , Humanos , Masculino , Hepatoblastoma/genética , Hepatoblastoma/patología , Hepatoblastoma/terapia , Hepatoblastoma/diagnóstico , Niño , Melanoma/genética , Melanoma/patología , Melanoma/terapia , Melanoma/diagnóstico , Melanoma/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Resultado Fatal , Neoplasias Primarias Secundarias/patología , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/diagnóstico , Secuenciación del Exoma , Supervivientes de Cáncer

Asunto(s)

Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Neoplasias Primarias Secundarias , Adulto , Femenino , Humanos , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/terapia , Genes BRCA1 , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/epidemiología , Riesgo

RESUMEN

Extragonadal germ cell tumors (EGCTs) are rare, representing <5% of all germ cell tumors (GCTs). Whilst EGCTs share morphological and immunohistochemical features with their gonadal counterparts, they tend to be more aggressive and are frequently associated with secondary somatic malignancies. The aim of our study was to evaluate the clinical, morphological and immunohistochemical features, and to analyze tumors for chromosomal abnormalities of 12p, in addition to any novel genetic alterations, in a series of EGCTs. Seventy-seven EGCTs were included. Anterior mediastinum was the most common anatomic site, followed by central nervous system, retroperitoneum, sacroccygeal area, and neck. Whole genome SNP array identified isochromosome 12p in 26% of tumors. Additional cytogenetic abnormalities included the presence of gain of chr 21 in 37% of tumors. Somatic-type malignancies were identified in 8% of patients. Disease progression (metastasis and/or recurrence) was documented in 8 patients, most of whom died from their relapse. Three patients who died of disease had somatic-type malignancies. Mediastinal seminomas had a significantly better overall survival when compared to mediastinal non-seminomatous GCTs. Our study demonstrates that EGCTs share similar histologic features, but diverse clinical outcomes compared to their gonadal counterparts. Outcomes vary according to anatomic location and histologic subtypes. Our data corroborate that somatic-type malignancies are frequently encountered in mediastinal EGCTs and that their presence portends a poorer prognosis.

Asunto(s)

Neoplasias de Células Germinales y Embrionarias , Humanos , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias de Células Germinales y Embrionarias/genética , Masculino , Adulto , Femenino , Adulto Joven , Adolescente , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Niño , Neoplasias Primarias Secundarias/patología , Neoplasias Primarias Secundarias/genética , Neoplasias del Mediastino/patología , Neoplasias del Mediastino/genética , Neoplasias del Mediastino/mortalidad , Inmunohistoquímica , Cromosomas Humanos Par 12/genética , Anciano , Recurrencia Local de Neoplasia/patología , Progresión de la Enfermedad , Polimorfismo de Nucleótido Simple , Aberraciones Cromosómicas , Predisposición Genética a la Enfermedad , Neoplasias Testiculares

RESUMEN

Second malignant neoplasm (SMN) is one of the most severe long-term risks for childhood cancer survivors (CCS), significantly impacting long-term patient survival. While radiotherapy and chemotherapy are known risk factors, the observed inter-individual variability suggests a genetic component contributing to the risk of SMN. This article aims to conduct a systematic review of genetic factors implicated in the SMN risk among CCS. Searches were performed in PubMed, Scopus, and Web of Sciences. Eighteen studies were included (eleven candidate gene studies, three genome-wide association studies, and four whole exome/genome sequencing studies). The included studies were based on different types of first cancers, investigated any or specific types of SMN, and focused mainly on genes involved in drug metabolism and DNA repair pathways. These differences in study design and methods used to characterize genetic variants limit the scope of the results and highlight the need for further extensive and standardized investigations. However, this review provides a valuable compilation of SMN risk-associated variants and genes, facilitating efficient replication and advancing our understanding of the genetic basis for this major risk for CCS.

Asunto(s)

Neoplasias Primarias Secundarias , Humanos , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/epidemiología , Niño , Predisposición Genética a la Enfermedad , Factores de Riesgo , Neoplasias/genética , Supervivientes de Cáncer/estadística & datos numéricos , Estudio de Asociación del Genoma Completo