RESUMEN

INTRODUCTION: The inactivation of both alleles of the ATM gene leads to ataxia-telangiectasia syndrome, whereas carriers of monoallelic mutations in the ATM gene are associated with increased risk of different types of cancer. Three substitutions in the ATM gene (c.6095G>A, c.7630-2A>C, c.5932G>T) are the most common mutations causing ataxia-telangiectasia among Polish patients. The aim of this study was to determine whether these ATM mutations are associated with increased risk of tobacco-related cancers. MATERIAL AND METHODS: 783 Polish patients with tobacco-related cancers were included in the study (468 with lung cancer, 153 with a single laryngeal cancer, 86 with multiple primary tumors localized in the larynx and 76 multiple primary tumors localized in the head or neck). The control group consisted of 464 healthy subjects from the Polish population. Three ATM mutations - c.5932G>T, c.6095G>A, c.7630-2A>C - were tested among selected patients. Molecular analyses were performed using high resolution melting analysis and restriction fragment length polymorphism. RESULTS: In the present study, we detected only one mutation, c.7630-2A>C, and no carriers of c.5932G>T, c.6095G>A mutations in the ATM gene among Polish patients with tobacco-related cancers. A patient with c.7630-2A>C mutation was diagnosed with lung adenocarcinoma, the most common type of lung cancer. One carrier of c.6095G>A mutation was found in the control group. CONCLUSIONS: The results indicate that the studied ATM variants do not seem to be associated with tobacco-related cancers in Poland.

RESUMEN

BACKGROUND: Ibrutinib, an inhibitor of the Bruton's kinase (BTK), is characterized by high efficacy in the therapy of patients with relapsed and refractory chronic lymphocytic leukemia (RR-CLL). AIMS: To analyze the potential significance of the mutational status of selected 30 genes on the disease outcome in 45 patients with RR-CLL using custom-made gene panel and sequencing on Illumina MiSeq FGx platform. RESULTS: The highest rate of mutations was observed in TP53 (n = 18; 40.0%), NOTCH1 (n = 13; 28.8%), SF3B1 (n = 11; 24.4%), ATM (n = 7; 15.6%), MED12 (n = 6, 13.3%), CHD2 (n = 5; 11.1%), XPO1 (n = 5; 11.1%), NFKBIE (n = 5; 11.1%), BIRC3 (n = 4; 8.9%), SPEN (n = 4; 8.9%), POT1 (n = 4; 8.9%), EGR2 (n = 3; 6.7%), and RPS15 (n = 3; 6.7%). With a median observation time of 45.9 months, the median progression-free survival (PFS) and overall survival (OS) were not reached. The 36-month estimated rate of PFS and OS were 64% and 68.2%, respectively. The overall response rate was noted in 23 patients (51.1%), while twenty (44.4%) patients achieved stability. Progression was noted in 2 (4.5%) cases. Analyzed molecular factors had no impact on PFS and OS. CONCLUSION: Despite accumulation of several poor prognostic factors in our real-life cohort of heavily pretreated patients with CLL, ibrutinib treatment showed long-term clinical benefit.

Asunto(s)

Adenina/análogos & derivados , Biomarcadores de Tumor/genética , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adenina/administración & dosificación , Adenina/efectos adversos , Adenina/uso terapéutico , Resistencia a Antineoplásicos , Pruebas Genéticas , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/mortalidad , Terapia Molecular Dirigida , Piperidinas/administración & dosificación , Piperidinas/efectos adversos , Pronóstico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Recurrencia , Resultado del Tratamiento

RESUMEN

The morbidity and mortality of endometrial cancer has been increasing over years. Ataxia telangiectasia mutated (ATM) gene, encoding a protein kinase participated in the response to DNA damage, is frequently mutated in endometrial cancer patients. However, the potential relationship between ATM mutations and the progression of endometrial cancer remains unclear. We performed an integrative bioinformatics analysis to investigate the relationship between ATM mutational status with clinical outcomes and tumor microenvironment in endometrial cancer patients. The whole exome sequencing data, RNA sequencing data and clinical information were collected from The Cancer Genome Atlas (TCGA) dataset. We found that mutation in the ATM gene was an independent prognostic factor for endometrial cancer. Antitumor immune pathways were enriched in endometrial tumors with ATM mutations. The tumor-infiltrating T lymphocytes, especially cytotoxic lymphocytes, were generally more abundant in tumors with ATM mutations. Furthermore, patients with ATM mutations exhibited higher tumor mutational burden, higher neoantigen load and increased expression levels of some immune checkpoints. In conclusion, the present study indicated that ATM mutations were linked to longer overall survival of endometrial cancer. Our findings may add better understanding for potential immunotherapy of endometrial cancer.

Asunto(s)

Proteínas de la Ataxia Telangiectasia Mutada/genética , Biomarcadores de Tumor/genética , Neoplasias Endometriales/genética , Microambiente Tumoral/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/inmunología , Biología Computacional , Análisis Mutacional de ADN , Neoplasias Endometriales/inmunología , Neoplasias Endometriales/patología , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico , Linfocitos Infiltrantes de Tumor , Persona de Mediana Edad , Mutación , Pronóstico

RESUMEN

INTRODUCTION: Mantle cell lymphoma (MCL) is an aggressive B cell non-Hodgkin lymphoma (NHL) that is characterized by the translocation t(11;14)(q13;q32) and a poor response to rituximab-anthracycline-based chemotherapy. Intensive regimens offer durable response, but a subgroup of MCL patients will not be eligible for those regimens and hence are candidates for less toxic, novel therapies based on a more tailored personalized approach. AREAS COVERED: This article examines the molecular landscape of MCL, drug resistance mechanisms, and the data on emerging targeted therapies. EXPERT OPINION: DNA damage pathway, ATM mutation, TP53, and epigenetic abnormalities are key drivers of MCL. sBCL2, PARP, ATR, CDK inhibitors or epigenetic modifiers are among the most promising drugs under investigation in clinical trials. The genomic landscape of MCL suggests two types of disease based on the presence of ATM or TP53 alterations which should be the framework of future molecular driven strategies. Among novel drugs, those interacting with the DNA damage response pathway offer the most effective rational for their use in MCL.

Asunto(s)

Antineoplásicos/farmacología , Daño del ADN/efectos de los fármacos , Linfoma de Células del Manto/tratamiento farmacológico , Terapia Molecular Dirigida , Animales , Desarrollo de Medicamentos , Resistencia a Antineoplásicos , Epigénesis Genética , Humanos , Linfoma de Células del Manto/genética , Linfoma de Células del Manto/patología , Mutación

RESUMEN

The authors present an unique familial case of ataxia-telangiectasia (AT) mimicking autosomal dominant inheritance with different phenotypes in a 3-year-old boy (ataxia and moderate dyskinesia since 1.5 years) and his 31-year-old mother (mild dystonia, predominantly torticollis, since 10 years). Exome sequencing of the boy detected two heterozygous ATM mutations c.1564_1565delGA (p.Glu522fs) and c.6154G>A (p.Glu2052Lys) reported earlier. Sanger sequencing found both mutations in the child, the father was heterozygous for c.1564_1565delGA, the mother for 6154G>A earlier reported in the rare A-T phenotype of 'pure' local dystonia. Exome sequencing of the mother, who considered herself healthy, detected the allelic ATM mutation c.7630-2A>C in intron 51.

Asunto(s)

Ataxia Telangiectasia , Trastornos Distónicos , Ataxia Telangiectasia/complicaciones , Ataxia Telangiectasia/genética , Niño , Preescolar , Heterocigoto , Humanos , Masculino , Linaje , Fenotipo

RESUMEN

Colorectal cancer (CRC) heritability has been estimated to be around 30%. However, mutations in the known CRC-susceptibility genes explain CRC risk in fewer than 10% of affected individuals. Germline mutations in DNA-repair genes (DRGs) have recently been reported in CRC, but their contribution to CRC risk is largely unknown. We evaluated the gene-level germline mutation enrichment of 40 DRGs in 680 unselected CRC individuals and 27,728 ancestry-matched cancer-free adults. Significant findings were then examined in independent cohorts of 1,661 unselected CRC individuals and 1,456 individuals with early-onset CRC. Of the 680 individuals in the discovery set, 31 (4.56%) individuals harbored germline pathogenic mutations in known CRC-susceptibility genes, and another 33 (4.85%) individuals had DRG mutations that have not been previously associated with CRC risk. Germline pathogenic mutations in ATM and PALB2 were enriched in both the discovery (OR = 2.81 and p = 0.035 for ATM and OR = 4.91 and p = 0.024 for PALB2) and validation (OR = 2.97 and adjusted p = 0.0013 for ATM and OR = 3.42 and adjusted p = 0.034 for PALB2) sets. Biallelic loss of ATM was evident in all individuals with matched tumor profiling. CRC individuals also had higher rates of actionable mutations in the HR pathway, which can substantially increase the risk of developing cancers other than CRC. Our analysis provides evidence for ATM and PALB2 as CRC-risk genes, underscoring the importance of the homologous recombination pathway in CRC. In addition, we identified frequent complete homologous recombination deficiency in CRC tumors, representing a unique opportunity to explore targeted therapeutic interventions such as poly-ADP ribose polymerase inhibitor (PARPi).

Asunto(s)

Neoplasias Colorrectales/genética , Reparación del ADN/genética , Patrón de Herencia/genética , Adulto , Anciano , Estudios de Cohortes , Femenino , Regulación Neoplásica de la Expresión Génica , Genes Relacionados con las Neoplasias , Predisposición Genética a la Enfermedad , Mutación de Línea Germinal/genética , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo

RESUMEN

Radiation therapy is a mainstay of cancer treatment, yet the molecular determinants of clinical response are poorly understood. We identified exceptional responders to radiotherapy based on clinical response, and investigated the associated tumor sequencing data in order to identify additional patients with similar mutations. Among head and neck squamous cell cancer patients receiving palliative radiotherapy at our institution, we identified one patient with documented complete metabolic response. Targeted sequencing analysis of the tumor identified a somatic frame-shift mutation in ATM, a gene known to be associated with radio-sensitivity in the germline. To validate the association of somatic ATM mutation with radiotherapy response, we identified eight patients with ATM truncating mutations who received radiotherapy, all of whom demonstrated excellent responses with a median local control period of 4.62 years. Analysis of 22 DNA repair genes in The Cancer Genome Atlas (TCGA) data revealed mutations in 15.9% of 9064 tumors across 24 cancer types, with ATM mutations being the most prevalent. This is the first study to suggest that exceptional responses to radiotherapy may be determined by mutations in DNA repair genes. Sequencing of DNA repair genes merits attention in larger cohorts and may have significant implications for the personalization of radiotherapy.

Asunto(s)

Proteínas de la Ataxia Telangiectasia Mutada/genética , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Carcinoma de Células Escamosas/radioterapia , Neoplasias Endometriales/radioterapia , Neoplasias de Cabeza y Cuello/radioterapia , Neoplasias Pulmonares/radioterapia , Mutación , Tolerancia a Radiación/genética , Dosificación Radioterapéutica , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Biología Computacional , Análisis Mutacional de ADN , Bases de Datos Genéticas , Neoplasias Endometriales/diagnóstico por imagen , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Femenino , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Persona de Mediana Edad , Cuidados Paliativos , Selección de Paciente , Medicina de Precisión , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello , Resultado del Tratamiento

RESUMEN

Ataxia-telangiectasia is a multisystemic disease with severe neurological affectation, immunodeficiency and telangiectasia. The disorder is caused by alterations in the ATM gene, whose size and complexity make molecular diagnosis difficult. We designed a target-enrichment next-generation sequencing strategy to characterize 28 patients from several regions of Spain. This approach allowed us to identify gene variants affecting function in 54 out of the 56 alleles analyzed, although the two unresolved alleles belong to brothers. We found 28 ATM gene mutations, of which 10 have not been reported. A total of 171 gene variants not affecting function were also found, of which 22 are reported to predispose to disease. Interestingly, all Roma (Spanish Gypsies) patients are homozygous for the same mutation and share the H3 ATM haplotype, which is strong evidence of a founder effect in this population. In addition, we generated a panel of 27 primary T cell lines from A-T patients, which revealed significant expression of ATM in two patients and traces of the protein in nine more. None of them retained residual ATM activity, and almost all T cell lines show increased or intermediate radiosensitivity.

Asunto(s)

Proteínas de la Ataxia Telangiectasia Mutada/genética , Ataxia Telangiectasia/genética , Ataxia Telangiectasia/etnología , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Secuencia de Bases , Línea Celular , Codón sin Sentido , Ensayo de Unidades Formadoras de Colonias , Análisis Mutacional de ADN , Efecto Fundador , Mutación del Sistema de Lectura , Haplotipos/genética , Humanos , Fosforilación , Polimorfismo de Nucleótido Simple , Procesamiento Proteico-Postraduccional , Romaní/genética , Alineación de Secuencia , Análisis de Secuencia de ADN/métodos , Eliminación de Secuencia , España/epidemiología , Linfocitos T/metabolismo , Linfocitos T/patología

RESUMEN

Abstract ATM gene alteration is a frequent event in pathogenesis of chronic lymphocytic leukemia (CLL) and occurs as monoallelic loss in the form of 11q23 deletion, with and without mutation in the remaining ATM allele. ATM is a principal DNA damage response gene and biallelic ATM alterations lead to ATM functional loss and chemoresistance. The introduction of new therapies, such as intensive chemoimmunotherapy and inhibition of B-cell receptor (BCR) signaling, has changed clinical responses for the majority of CLL tumors including those with 11q deletion, but it remains to be determined whether these strategies can prevent clonal evolution of tumors with biallelic ATM alterations. In this review we discuss ATM function and the consequences of its loss during CLL pathogenesis, differences in clinical behavior of tumors with monoallelic and biallelic ATM alterations, and we outline possible approaches for targeting the ATM null CLL phenotype.

Asunto(s)

Proteínas de la Ataxia Telangiectasia Mutada/genética , Síndrome de Deleción Distal 11q de Jacobsen/genética , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Biomarcadores de Tumor , Deleción Cromosómica , Cromosomas Humanos Par 11 , Evolución Clonal , Progresión de la Enfermedad , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/terapia , Terapia Molecular Dirigida , Fenotipo , Pronóstico