RESUMO
Chimeric antigen receptor T-cell (CAR-T) therapy is a recent advancement in precision medicine with promising results for patients with relapsed or refractory B-cell malignancies. However, rare post-therapy morphologic, immunophenotypic, and genomic alterations can occur. This study is to present a case of a patient with diffuse large B-cell lymphoma (DLBCL) who underwent anti-CD19 CAR-T therapy with disease in the uterus that showed transdifferentiation to a poorly differentiated malignant neoplasm that failed to express any lineage specific markers. In immunohistochemistry, fluorescence in situ hybridization (FISH) and targeted next-generation sequencing (NGS) were utilized to fully characterize the diagnostic DLBCL sample in comparison to the poorly differentiated neoplasm of the uterus. Analysis of the diagnostic DLBCL and the poorly differentiated neoplasm demonstrated evidence of a clonal relationship as well as revealing acquisition of mutations associated with CAR-T resistance. Furthermore, downregulation of B-cell associated antigens was observed, underscoring a mechanistic link to CAR-T evasion as well as demonstrating diagnostic confusion. This case illustrates the utility of employing multiple diagnostic modalities in elucidating a pathologic link between a B-cell lymphoma and poorly differentiated neoplasm following targeted therapy.
Assuntos
Transdiferenciação Celular , Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/genética , Feminino , Imunoterapia Adotiva/métodos , Pessoa de Meia-Idade , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Neoplasias Uterinas/patologia , Neoplasias Uterinas/terapia , Neoplasias Uterinas/genética , Neoplasias Uterinas/diagnósticoRESUMO
Pediatric cardiomyopathies (CM) are rare and challenging to diagnose due to the complex and mixed phenotypes. With the advent of next-generation sequencing (NGS), variants in several genes associated with CM have been identified, such as Troponin C (TnC), encoded by the TNNC1 gene. De novo variants in TNNC1 have been associated with different types of CM, including dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). The American College of Medical Genetics and Genomics recently added TNNC1 to their recommended list of genes for reporting secondary findings. In this study, we report a de novo variant, c.100G>C (p.Gly34Arg) in the TNNC1 gene identified in three siblings with a diagnosis of severe DCM causing infant death for one of the siblings and stillbirth in the other two pregnancies. The identification of the same de novo variant in all affected siblings is suggestive of germline mosaicism in this family.
Assuntos
Cardiomiopatia Dilatada , Troponina C , Feminino , Humanos , Recém-Nascido , Gravidez , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/mortalidade , Mortalidade Infantil , Mosaicismo , Mutação , Natimorto/genética , Troponina C/genéticaRESUMO
We report a 4-month-old male proband with a history of prominent forehead, hypertelorism, ear abnormalities, micrognathia, hypospadias, and multiple cardiac abnormalities. Initial microarray analysis detected a concurrent 7p21.3-p22.3 duplication and 13q33.2-q34 deletion indicating an unbalanced rearrangement. However, subsequent conventional cytogenetic studies only revealed what appeared to be a balanced t(12;20)(q24.33;p12.2). Fluorescence in situ hybridization (FISH) using chromosome-specific subtelomere probes confirmed the presence of an unbalanced der(13)t(7;13)(p21.3;q33.2) and balanced t(12;20)(q24.33;p12.2), both of maternal origin. In addition to our unique clinical findings, this case highlights the benefits and limitations of both conventional cytogenetic studies and microarray analysis and how FISH complements each methodology.
RESUMO
We report a 19-year-old female patient with a history of short stature, primary ovarian insufficiency, sensorineural hearing loss, sacral teratoma, neurogenic bladder, and intellectual disability with underlying mosaicism for der(X)t(X;3)(q13.2;q25.33), a ring X chromosome, and monosomy X. Derivative X chromosomes from unbalanced X-autosomal translocations are preferentially silenced by the XIST gene (Xq13.2) located within the X-inactivation center. The unbalanced X-autosomal translocation in our case resulted in loss of the XIST gene thus precluding the inactivation of the derivative X chromosome. As a result, clinical features of functional disomy Xp, Turner's syndrome, and duplication 3q syndrome were observed. Importantly, indications of the derivative X chromosome were revealed by microarray analysis following an initial diagnosis of Turner's syndrome made by conventional cytogenetic studies approximately 18 months earlier. This case demonstrates the importance of utilizing microarray analysis as a first-line test in patients with clinical features beyond the scope of a well-defined genetic syndrome.
RESUMO
While the mutagenic and carcinogenic properties of longwave UV light (UVA) are well established, mechanisms of UVA mutagenesis remain a matter of debate. To elucidate the mechanisms of mutation formation with UVA in human skin, we determined the spectra of UVA- and UVB-induced mutations in primary human fibroblasts. As with UVB, we found the majority of mutations to be C-to-T transitions also with UVA. For both UVA and UVB, these transitions were found within runs of pyrimidines, at identical hotspots, and with the same predilection for the nontranscribed strand. They also included CC-to-TT tandem mutations. Therefore, these mutations point to a major role of pyrimidine dimers not only in UVB but also in UVA mutagenesis. While some differences were noted, the similarity between the spectra of UVA- and UVB-induced mutations further supports similar mechanisms of mutation formation. A non-dimer type of DNA damage does not appear to play a major role in either UVA or UVB mutagenesis. Therefore, the previously reported increasing mutagenicity per dimer with increasing wavelengths cannot be due to non-dimer DNA damage. Differences in the cellular response to UVA and UVB, such as the less prominent activation of p53 by UVA, might determine a different mutagenic outcome of UVA- and UVB-induced dimers.
Assuntos
Mutação , Pele/efeitos da radiação , Raios Ultravioleta , Sequência de Bases , Linhagem Celular , Dano ao DNA , Genes p53 , Humanos , Dados de Sequência Molecular , Dímeros de Pirimidina/metabolismoRESUMO
Oxidative DNA damage, in particular 7,8-dihydro-8-oxoguanine (8-oxoG), has been suggested to mediate mutation formation and malignant transformation after exposure of the skin to long-wave ultraviolet (UVA) light. It is processed primarily by the base excision repair (BER) pathway. The initial step of BER is the removal of the damaged base by a damage-specific DNA-glycosylase, which is 8-oxoG DNA glycosylase (OGG1) for 8-oxoG. To study the contribution of 8-oxoG to UVA-light mutagenesis, we compared UVA- and UVB-light-induced mutation frequencies in mouse embryonal fibroblasts from OGG1 knockout mice and their OGG1-intact littermates using the ouabain mutagenesis assay. After irradiation with various doses of UVA or UVB radiation, mutations in the Na,K-ATPase gene of single cells were detected by testing for colony-forming ability in a selective medium. OGG1-/- cells did not exhibit an increased frequency of UV-light-induced mutations compared to OGG1+/+ cells after exposure to either UVA or UVB radiation. This indicates that 8-oxoG, which is processed by OGG1, does not contribute significantly to either UVA- or UVB-light-induced mutagenesis.
Assuntos
DNA Glicosilases/fisiologia , Guanina/análogos & derivados , Mutação , Raios Ultravioleta , Animais , Linhagem Celular , Dano ao DNA , Guanina/metabolismo , CamundongosRESUMO
Long-wave ultraviolet (UV) A light is able to damage DNA, to cause mutations, and to induce skin cancer, but the exact mechanisms of UVA-induced mutation formation remain a matter of debate. While pyrimidine dimers are well established to mediate mutation formation with shortwave UVB, other types of DNA damage, such as oxidative base damage, have long been thought to be the premutagenic lesions for UVA mutagenesis. However, pyrimidine dimers can also be generated by UVA, and there are several lines of evidence that these are the most important premutagenic lesions not only for UVB- but also for UVA-induced mutation formation. C-->T transition mutations, which are generated by pyrimidine dimers, are called UV-signature mutations. They cannot be interpreted to be solely UVB-induced, as they are induced by UVA as well. Furthermore, there is no consistent evidence for a separate UVA-signature mutation that is only generated with UVA. We hypothesize that a weaker anti-mutagenic cellular response, but not a different type of DNA damage, may be responsible for a higher mutation rate per DNA photoproduct with UVA, as compared with UVB.
Assuntos
Dano ao DNA , Mutação , Pele/efeitos da radiação , Raios Ultravioleta , Humanos , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/genéticaRESUMO
A female patient with progressive systemic sclerosis and pulmonary fibrosis had a dermatofibrosarcoma protuberans on the right thigh. After resection of the tumor, new lesions occurred in the scar, and wide excision was repeated. Two years later, a lung metastasis was discovered, and segmental resection was done. After 1 year of follow-up, no local recurrences or metastases were found.