RESUMO
Childhood melanoma is a rare and biologically heterogeneous pediatric malignancy. The differential diagnosis of pediatric melanoma is usually broad, including a wide variety of spindle cell or epithelioid neoplasms. Different molecular alterations affecting the MAPK and PI3K/AKT/mTOR pathways, tumor suppressor genes, and telomerase reactivation have been implicated in melanoma tumorigenesis and progression. Here, we report a novel MED15::ATF1 fusion in a pediatric melanoma with spitzoid features and an aggressive clinical course.
Assuntos
Glicina , Melanoma , Nevo de Células Epitelioides e Fusiformes , Proteínas de Fusão Oncogênica , Pirróis , Neoplasias Cutâneas , Criança , Humanos , Diagnóstico Diferencial , Glicina/análogos & derivados , Complexo Mediador , Melanoma/diagnóstico , Melanoma/genética , Melanoma/patologia , Nevo de Células Epitelioides e Fusiformes/diagnóstico , Fosfatidilinositol 3-Quinases , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Proteínas de Fusão Oncogênica/genéticaRESUMO
Rhabdoid Tumor Predisposition Syndrome 1 (RTPS1) confers an increased risk of developing rhabdoid tumors and is caused by germline mutations in SMARCB1. RTPS1 should be evaluated in all individuals with rhabdoid tumor and is more likely in those with a young age at presentation (occasionally congenital presentation), multiple primary tumors, or a family history of rhabdoid tumor or RTPS1. Proband genetic testing is the standard method for diagnosing RTPS1. Most known RTPS1-related SMARCB1 gene mutations are copy number variants (CNVs) or single nucleotide variants/indels, but structural variant analysis (SVA) is not usually included in the molecular evaluation. Here, we report two children with RTPS1 presenting with atypical teratoid/rhabdoid tumor (ATRT) who had constitutional testing showing balanced chromosome translocations involving SMARCB1. Patient 1 is a 23-year-old female diagnosed with pineal region ATRT at 7 months who was found to have a de novo, constitutional t(16;22)(p13.3;q11.2). Patient 2 is a 24-month-old male diagnosed with a posterior fossa ATRT at 14 months, with subsequent testing showing a constitutional t(5;22)(q14.1;q11.23). These structural rearrangements have not been previously reported in RTPS1. While rare, these cases suggest that structural variants should be considered in the evaluation of children with rhabdoid tumors to provide more accurate genetic counseling on the risks of developing tumors, the need for surveillance, and the risks of passing the disorder on to future children. Further research is needed to understand the prevalence, clinical features, and tumor risks associated with RTPS1-related constitutional balanced translocations.
Assuntos
Neoplasias Encefálicas , Transtornos Cromossômicos , Tumor Rabdoide , Teratoma , Criança , Feminino , Masculino , Humanos , Adulto Jovem , Adulto , Lactente , Tumor Rabdoide/genética , Tumor Rabdoide/patologia , Proteína SMARCB1/genética , Neoplasias Encefálicas/genética , Mutação em Linhagem Germinativa , Translocação Genética , Teratoma/genética , Teratoma/patologiaRESUMO
Small round cell neoplasms comprise a diverse group of tumors characterized by a primitive/undifferentiated appearance. Although several entities are associated with recurrent gene fusions, many of these neoplasms have not been fully characterized, and novel molecular alterations are being discovered. Here, we report an undifferentiated small round cell neoplasm arising in the anterior mediastinum of a 17-month-old female. The tumor harbored a novel HNRNPM::LEUTX fusion resulting from chromothripsis of chromosome 19, which was identified by whole transcriptome sequencing, but not by targeted sequencing. The structural variations caused by the chromothripsis event also challenged the interpretation of the targeted sequencing findings. This report expands the spectrum of gene partners involved in LEUTX fusions and underscores the value of whole transcriptome sequencing in the diagnostic workup of undifferentiated small round cell tumors. It also highlights the interpretive challenges associated with complex genomic alterations. A careful evidence-based analysis of sequencing data along with histopathologic correlation is essential to ensure correct categorization of fusions.
Assuntos
Cromotripsia , Sarcoma , Humanos , Criança , Feminino , Lactente , Cromossomos Humanos Par 19 , Sarcoma/genética , Fusão Gênica , Biomarcadores Tumorais/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo M/genética , Proteínas de Homeodomínio/genéticaRESUMO
The promyelocytic leukemia-retinoic acid receptor-α (PML::RARA) fusion is the hallmark of acute promyelocytic leukemia (APL) and is observed in over 95% of APL cases. RARA and homologous receptors RARB and RARG are occasionally fused to other gene partners, which differentially affect sensitivity to targeted therapies. Most APLs without RARA fusions have rearrangements involving RARG or RARB, both of which frequently show resistance to all-trans-retinoic acid (ATRA) and/or multiagent chemotherapy for acute myeloid leukemia (AML). We present a 13-year-old male diagnosed with variant APL with a novel FNDC3B::RARB in-frame fusion that showed no response to ATRA but responded well to conventional AML therapy. While FNDC3B has been identified as a rare RARA translocation partner in ATRA-sensitive variant APL, it has never been reported as a fusion partner with RARB and it is only the second known fusion partner with RARB in variant APL. We also show that this novel fusion confers an RNA expression signature that is similar to APL, despite clinical resistance to ATRA monotherapy.
Assuntos
Leucemia Mieloide Aguda , Leucemia Promielocítica Aguda , Masculino , Humanos , Adolescente , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Translocação Genética , Tretinoína/uso terapêutico , Leucemia Mieloide Aguda/genética , Receptor alfa de Ácido Retinoico/genética , Genômica , Proteínas de Fusão Oncogênica/genética , Fibronectinas/genéticaRESUMO
Recent advancements in molecular characterisation have identified four principal molecular groups of medulloblastoma: WNT, SHH, group 3 and group 4. Each has its characteristic clinical features, signature genetic alterations and distinct DNA methylome profiles. Thus far, CTNNB1 mutations have been considered pathognomonic of WNT-activated medulloblastoma. Furthermore, it has been shown that CTNNB1 mutations dominantly drive the WNT-activated phenotype in medulloblastoma, even in the presence of alterations in the SHH pathway. We herein report an illustrative case that challenges this belief-a medulloblastoma with a pathogenic CTNNB1 mutation that otherwise showed the histopathology, immunophenotype and methylation and transcriptomic profiles of an SHH-activated medulloblastoma. Detailed molecular analyses, including whole exome sequencing, transcriptome analysis and DNA methylation profiling with DKFZ brain tumour classifier and St. Jude MLPnet neural network classifier analyses, have been performed on the tumour. Our example emphasises the diagnostic value of the immunohistochemistry panel with YAP1, GAB1 and ß-catenin and DNA methylation profiling, combined with exome sequencing, in the characterisation of medulloblastoma. CTNNB1 mutations are not specific for WNT-activated medulloblastoma, and different CTNNB1 mutations have diverse oncogenic potential.
Assuntos
Neoplasias Cerebelares , Meduloblastoma , beta Catenina , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Metilação de DNA , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Meduloblastoma/genética , Meduloblastoma/patologia , Mutação , Transcriptoma , beta Catenina/genéticaRESUMO
Female adnexal tumors of probable Wolffian origin are rare and present a diagnostic challenge due to their morphological and immunohistochemical overlap with more common ovarian and broad ligament entities. We evaluated the morphological, immunohistochemical, and molecular features of 15 tumors of probable Wolffian origin. Patients ranged from 32 to 69 (mean 47) years and tumors from 1.8 to 30 (mean 10) cm. All except one arose in para-adnexal soft tissues. Follow-up was available for six patients, five of whom were alive and well, while the sixth, who had extra-adnexal disease at diagnosis, died from unrelated causes. The following patterns were noted: tubular (all tumors), solid 11/15 (73%), sieve-like 7/15 (47%), and reticular 1/15 (7%). A myxoid background was present in 3/15 (20%) of tumors and eosinophilic luminal secretions in 11/15 (73%). Most tumors (12/15, 80%) had low-grade nuclear atypia, while three showed foci with scattered high-grade atypia. Mitotic index ranged from 0 to 17 (mean 4) per ten high-power fields. Tumors were positive for pankeratin and negative for TTF-1. EMA, GATA3, and PAX8 were positive in 2/10 (20%; focal), 3/15 (20%; focal), and 1/15 (7%; focal) of tumors, respectively. CD10, SF-1, calretinin, inhibin, ER, PR, cytokeratin 7, and WT1 were variably expressed. Pathogenic mutations were rare and included STK11 (n = 3), APC (n = 1), and MBD4 (n = 1). Copy number variations were detected in the three tumors with STK11 mutations and a myxoid background. These data demonstrate that female adnexal tumors of probable Wolffian origin are morphologically and immunohistochemically diverse, but infrequently harbor pathogenic mutations. However, their lack of mutations in contrast to their mimickers may be a valuable tool in diagnostically difficult cases.
Assuntos
Adenoma , Anexos Uterinos , Doenças dos Anexos , Biomarcadores Tumorais , Neoplasias dos Genitais Femininos , Imuno-Histoquímica , Técnicas de Diagnóstico Molecular , Adenoma/genética , Adenoma/metabolismo , Adenoma/patologia , Anexos Uterinos/química , Anexos Uterinos/patologia , Doenças dos Anexos/genética , Doenças dos Anexos/metabolismo , Doenças dos Anexos/patologia , Adulto , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Biópsia , Feminino , Dosagem de Genes , Predisposição Genética para Doença , Neoplasias dos Genitais Femininos/química , Neoplasias dos Genitais Femininos/genética , Neoplasias dos Genitais Femininos/patologia , Humanos , Pessoa de Meia-Idade , Mutação , Fenótipo , Valor Preditivo dos TestesRESUMO
Epithelioid trophoblastic tumor is a malignancy derived from the chorionic laeve-type intermediate trophoblast with sufficient rarity that the vast majority of literature on the topic exists in the form of case reports and small series. Classically, it is regarded as a well-circumscribed tumor with an expansile growth pattern that occurs in reproductive-aged women, usually after a normal pregnancy. However, we recently encountered a case of epithelioid trophoblastic tumor with aggressive spread throughout the abdomen and pelvis in a 68-yr-old female presenting 30 yr after her last delivery. Although to our knowledge this is the first report in a postmenopausal patient to be confirmed by molecular analysis of short tandem repeats, there are multiple similar case reports spanning a variety of clinical settings that deviate from the original description. We therefore sought to synthesize the clinicopathologic data among the available reports in the English literature, with emphasis on pathologic findings. While the overarching themes are largely unchanged, this series of 77 patients reveals a broader spectrum of disease and highlights frequent misdiagnosis. Here we present a clinicopathologic update on this rare entity, with emphasis on a practical approach to diagnosis.
Assuntos
Células Epitelioides/patologia , Neoplasias Trofoblásticas/diagnóstico , Neoplasias Trofoblásticas/patologia , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/patologia , Adolescente , Adulto , Idoso , Feminino , Técnicas de Genotipagem , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Pós-Menopausa , Gravidez , Doenças Raras/diagnóstico , Doenças Raras/genética , Doenças Raras/patologia , Fatores de Tempo , Neoplasias Trofoblásticas/genética , Neoplasias Uterinas/genética , Adulto JovemAssuntos
Neoplasias , Coativador 3 de Receptor Nuclear , beta Catenina , Criança , Humanos , beta Catenina/imunologia , beta Catenina/metabolismo , Biomarcadores Tumorais/genética , Núcleo Celular/genética , Núcleo Celular/metabolismo , Coativador 3 de Receptor Nuclear/genética , Fibroblastos/patologiaAssuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Lactamas Macrocíclicas/uso terapêutico , Aminopiridinas , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/cirurgia , Pré-Escolar , Terapia Combinada , Glioma/diagnóstico por imagem , Glioma/patologia , Glioma/cirurgia , Humanos , Lactamas , Imageamento por Ressonância Magnética , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Pirazóis , Indução de RemissãoAssuntos
Neoplasias do Sistema Nervoso Central , Neoplasias Meníngeas , Neoplasias Neuroepiteliomatosas , Humanos , Neoplasias do Sistema Nervoso Central/genética , Cromossomos , Cromossomos Humanos Par 1/genética , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/patologia , Metilação , Neoplasias Neuroepiteliomatosas/genética , Neoplasias Neuroepiteliomatosas/patologia , PrognósticoRESUMO
AIMS: The diagnosis of undifferentiated pleomorphic sarcoma (UPS) may be challenging, as other lesions with undifferentiated spindle cell morphology must be excluded, including melanoma. Microphthalmia-associated transcription factor (MiTF) stains naevi and epithelioid melanomas, as well as some mesenchymal neoplasms. The aim of this study was to evaluate the prevalence of MiTF and melanocytic markers in UPS and a subset of atypical fibroxanthoma (AFX). METHODS AND RESULTS: MiTF, SOX10, Melan-A, HMB45 and S100 immunostaining was performed on resection specimens from 19 UPSs and five AFXs. Next-generation sequencing of 50 genes was performed in UPSs to exclude dedifferentiated melanoma. In 17 of 19 UPSs (89%), tumour cells showed nuclear positivity for MiTF that was not eliminated by casein block. Three showed focal nuclear staining for HMB45, which was eliminated by casein block. One showed focal nuclear vacuole staining for S100 with red but not brown chromogen. None expressed SOX10 or Melan-A. Mutational analysis of 15 UPSs with adequate DNA showed no mutations within hotspot regions of BRAF, KIT, or NRAS. Four of five AFXs (80%) stained with MiTF; other markers were negative. CONCLUSION: There is a high prevalence of nuclear MiTF expression in UPSs (89%) and AFXs (80%). Rare UPSs showed non-specific nuclear HMB45 or S100 staining. These findings argue against using MiTF in isolation to differentiate between UPS or AFX and melanoma, and caution in interpreting focal staining for a single additional melanocytic marker. Casein block may eliminate non-specific staining. MiTF should be used to support a diagnosis of melanoma only if multiple melanocytic markers are positive.
Assuntos
Biomarcadores Tumorais/análise , Melanoma/diagnóstico , Fator de Transcrição Associado à Microftalmia/análise , Sarcoma/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Masculino , Melanócitos/metabolismo , Pessoa de Meia-Idade , Reação em Cadeia da PolimeraseRESUMO
Langerhans cell histiocytosis (LCH) represents a clonal proliferation of Langerhans cells. BRAF V600E mutations have been identified in approximately 50% of cases. To discover other genetic mechanisms underlying LCH pathogenesis, we studied 8 cases of LCH using a targeted next-generation sequencing platform. An E102_I103del mutation in MAP2K1 was identified in one BRAF wild-type case and confirmed by Sanger sequencing. Analysis of 32 additional cases using BRAF V600E allele-specific polymerase chain reaction and Sanger sequencing of MAP2K1 exons 2 and 3 revealed somatic, mutually exclusive BRAF and MAP2K1 mutations in 18 of 40 (45.0%) and 11 of 40 (27.5%) cases, respectively. This is the first report of MAP2K1 mutations in LCH that occur in 50% of BRAF wild-type cases. The mutually exclusive nature of MAP2K1 and BRAF mutations implicates a critical role of oncogenic MAPK signaling in LCH. This finding may also have implications in the use of BRAF and MEK inhibitor therapy.
Assuntos
Histiocitose de Células de Langerhans/genética , MAP Quinase Quinase 1/genética , Proteínas Proto-Oncogênicas B-raf/genética , Substituição de Aminoácidos , Feminino , Frequência do Gene , Predisposição Genética para Doença , Ácido Glutâmico/genética , Histiocitose de Células de Langerhans/epidemiologia , Humanos , Masculino , Mutação de Sentido Incorreto , Prevalência , Estudos Retrospectivos , Valina/genéticaRESUMO
INTRODUCTION: Adult polyglucosan body disease (APBD) is associated with formation of polyglucosan bodies in peripheral nerve branches. Some muscle biopsies show these inclusions in intramuscular nerve branches. It has not been established whether the presence of multiple polyglucosan bodies in intramuscular peripheral nerve branches could or should suggest testing for APBD. METHODS: Fifteen muscle biopsies from adults between the ages of 36 and 84 years, all showing polyglucosan bodies in intramuscular peripheral nerve twigs, were tested by sequencing of the GBE1 gene. RESULTS: In 4 patients, testing identified heterozygous missense mutations not previously described. No homozygous or compound heterozygous mutations were identified. CONCLUSIONS: The presence of polyglucosan bodies in intramuscular nerve twigs by itself, even if they are multiple, is not an indication of APBD. Further testing may only be indicated in patients with clinical disease manifestations.
Assuntos
Sistema da Enzima Desramificadora do Glicogênio/genética , Doença de Depósito de Glicogênio/genética , Mutação/genética , Doenças do Sistema Nervoso/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fosfofrutoquinases/metabolismo , Estudos RetrospectivosRESUMO
Tumor mutational burden (TMB) has been recognized as a predictive biomarker for immunotherapy response in several tumor types. Several laboratories offer TMB testing, but there is significant variation in how TMB is calculated, reported, and interpreted among laboratories. TMB standardization efforts are underway, but no published guidance for TMB validation and reporting is currently available. Recognizing the current challenges of clinical TMB testing, the Association for Molecular Pathology convened a multidisciplinary collaborative working group with representation from the American Society of Clinical Oncology, the College of American Pathologists, and the Society for the Immunotherapy of Cancer to review the laboratory practices surrounding TMB and develop recommendations for the analytical validation and reporting of TMB testing based on survey data, literature review, and expert consensus. These recommendations encompass pre-analytical, analytical, and postanalytical factors of TMB analysis, and they emphasize the relevance of comprehensive methodological descriptions to allow comparability between assays.
Assuntos
Biomarcadores Tumorais , Mutação , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/terapia , Neoplasias/imunologia , Biomarcadores Tumorais/genética , Imunoterapia/métodos , Patologia Molecular/métodos , Consenso , Sociedades Médicas , Estados Unidos , Patologistas , Reprodutibilidade dos Testes , Análise Mutacional de DNA/métodos , Análise Mutacional de DNA/normasRESUMO
CONTEXT.: The College of American Pathologists (CAP) accreditation requirements for clinical laboratory testing help ensure laboratories implement and maintain systems and processes that are associated with quality. Machine learning (ML)-based models share some features of conventional laboratory testing methods. Accreditation requirements that specifically address clinical laboratories' use of ML remain in the early stages of development. OBJECTIVE.: To identify relevant CAP accreditation requirements that may be applied to the clinical adoption of ML-based molecular oncology assays, and to provide examples of current and emerging ML applications in molecular oncology testing. DESIGN.: CAP accreditation checklists related to molecular pathology and general laboratory practices (Molecular Pathology, All Common and Laboratory General) were reviewed. Examples of checklist requirements that are generally applicable to validation, revalidation, quality management, infrastructure, and analytical procedures of ML-based molecular oncology assays were summarized. Instances of ML use in molecular oncology testing were assessed from literature review. RESULTS.: Components of the general CAP accreditation framework that exist for traditional molecular oncology assay validation and maintenance are also relevant for implementing ML-based tests in a clinical laboratory. Current and emerging applications of ML in molecular oncology testing include DNA methylation profiling for central nervous system tumor classification, variant calling, microsatellite instability testing, mutational signature analysis, and variant prediction from histopathology images. CONCLUSIONS.: Currently, much of the ML activity in molecular oncology is within early clinical implementation. Despite specific considerations that apply to the adoption of ML-based methods, existing CAP requirements can serve as general guidelines for the clinical implementation of ML-based assays in molecular oncology testing.
RESUMO
CONTEXT.: Rapid advancements in the understanding and manipulation of tumor-immune interactions have led to the approval of immune therapies for patients with non-small cell lung cancer. Certain immune checkpoint inhibitor therapies require the use of companion diagnostics, but methodologic variability has led to uncertainty around test selection and implementation in practice. OBJECTIVE.: To develop evidence-based guideline recommendations for the testing of immunotherapy/immunomodulatory biomarkers, including programmed death ligand-1 (PD-L1) and tumor mutation burden (TMB), in patients with lung cancer. DESIGN.: The College of American Pathologists convened a panel of experts in non-small cell lung cancer and biomarker testing to develop evidence-based recommendations in accordance with the standards for trustworthy clinical practice guidelines established by the National Academy of Medicine. A systematic literature review was conducted to address 8 key questions. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, recommendations were created from the available evidence, certainty of that evidence, and key judgments as defined in the GRADE Evidence to Decision framework. RESULTS.: Six recommendation statements were developed. CONCLUSIONS.: This guideline summarizes the current understanding and hurdles associated with the use of PD-L1 expression and TMB testing for immune checkpoint inhibitor therapy selection in patients with advanced non-small cell lung cancer and presents evidence-based recommendations for PD-L1 and TMB testing in the clinical setting.
Assuntos
Antígeno B7-H1 , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Mutação , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/diagnóstico , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , ImunoterapiaRESUMO
Autosomal trisomy is the most common genetic abnormality observed in pregnancy loss. We designed a panel of mini-short tandem repeats (mini-STRs) for aneuploidy detection in chromosomes 13, 16, 18 and 21 from fresh and formalin fixed, paraffin embedded (FFPE) samples from products of conception (POC). FFPE POCs with trisomy 13 (n = 6), trisomy 18 (n = 6), trisomy 21 (n = 12), 6 euploid for the chromosomes of interest and two trisomy 16 samples from fresh tissue were tested. Concordance between cytogenetics and genotyping was 100% for non-mosaic samples. Mini-STR genotyping is a viable method for targeted aneuploidy detection in low quality DNA samples.
Assuntos
Aneuploidia , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Técnicas de Genotipagem/métodos , Repetições de Microssatélites/genética , Aborto Espontâneo/genética , Feminino , Genótipo , Humanos , Masculino , Microdissecção , Inclusão em Parafina , Reação em Cadeia da Polimerase/métodos , GravidezRESUMO
Herein, we present a rare case of acute myeloid leukemia (AML) with CBFA2T3-rearrangement and the expression of megakaryocytic and lymphoid markers, highlighting the need for a high suspicion index in differential diagnosis and applying adequate workup to avoid misdiagnosing this entity. CBFA2T3::GLIS2-positive AML is primarily found in infants with non-down syndrome acute megakaryoblastic leukemia (non-DSAMKL). Flow cytometry immunophenotyping plays an important role in recognizing the unique immunophenotype of bright CD56 expression with dim/negative expression of HLA-DR, CD38, and CD45 termed the RAM immunophenotype in this entity. Still, CBFA2T3::GLIS2-positive acute leukemia with T/megakaryocytic markers could be misdiagnosed as T-lymphoblastic leukemia/lymphoma, early T-cell precursor acute lymphoblastic leukemia/lymphoma, NK lymphoblastic leukemia, AML with minimal differentiation, or AML with myelodysplasia-related changes.
RESUMO
PURPOSE: Clinical genomic sequencing of pediatric tumors is increasingly uncovering pathogenic variants in adult-onset cancer predisposition genes (aoCPG). Nevertheless, it remains poorly understood how often aoCPG variants are of germline origin and whether they influence tumor molecular profiles and/or clinical care. In this study, we examined the prevalence, spectrum, and impacts of aoCPG variants on tumor genomic features and patient management at our institution. EXPERIMENTAL DESIGN: This is a retrospective study of 1,018 children with cancer who underwent clinical genomic sequencing of their tumors. Tumor genomic data were queried for pathogenic variants affecting 24 preselected aoCPGs. Available tumor whole-genome sequencing (WGS) data were evaluated for second hit mutations, loss of heterozygosity (LOH), DNA mutational signatures, and homologous recombination deficiency (HRD). Patients whose tumors harbored one or more pathogenic aoCPG variants underwent subsequent germline testing based on hereditary cancer evaluation and family or provider preference. RESULTS: Thirty-three patients (3%) had tumors harboring pathogenic variants affecting one or more aoCPGs. Among 21 tumors with sufficient WGS sequencing data, six (29%) harbored a second hit or LOH affecting the remaining aoCPG allele with four of these six tumors (67%) also exhibiting a DNA mutational signature consistent with the altered aoCPG. Two additional tumors demonstrated HRD, of uncertain relation to the identified aoCPG variant. Twenty-one of 26 patients (81%) completing germline testing were positive for the aoCPG variant in the germline. All germline-positive patients were counseled regarding future cancer risks, surveillance, and risk-reducing measures. No patients had immediate cancer therapy changed due to aoCPG data. CONCLUSIONS: AoCPG variants are rare in pediatric tumors; however, many originate in the germline. Almost one third of tumor aoCPG variants examined exhibited a second hit and/or conferred an abnormal DNA mutational profile suggesting a role in tumor formation. aoCPG information aids in cancer risk prediction but is not commonly used to alter the treatment of pediatric cancers.