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The American Journal of Surgical... Feb 2024Germline and somatic pathogenic variants (PVs) in DICER1 , encoding a miRNA biogenesis protein, are associated with a wide variety of highly specific pathologic...
Germline and somatic pathogenic variants (PVs) in DICER1 , encoding a miRNA biogenesis protein, are associated with a wide variety of highly specific pathologic entities. The lung tumors pleuropulmonary blastoma, pulmonary blastoma (PB), and well-differentiated fetal lung adenocarcinoma (WDFLAC) are all known to harbor DICER1 biallelic variants (loss of function and/or somatic hotspot missense mutations), and all share pathologic features reminiscent of the immature lung. However, the role of DICER1 PVs in non-small cell lung cancer (NSCLC) is relatively unknown. Here, we aimed to establish the spectrum of lung pathologies associated with DICER1 hotspot PVs and to compare the mutational landscape of DICER1 -mutated NSCLC with and without hotspots. We queried DNA sequencing data from 12,146 NSCLCs featuring somatic DICER1 variants. 235 (1.9%) cases harboring ≥ 1 DICER1 PV were found and 9/235 (3.8%) were DICER1 hotspot-positive cases. Histologic review of DICER1 hotspot-positive cases showed that all but one tumor were classified as within the histologic spectrum of PB/WDFLAC, whereas all the DICER1 non-hotspot double variants were classified as lung adenocarcinomas, not otherwise specified. Comparison between the mutational landscape of DICER1 hotspot-positive and hotspot-negative cases revealed a higher frequency of CTNNB1 mutations in the hotspot-positive cases (5/9 vs. 2/225; P <0.00001). We conclude that DICER1 somatic hotspots are not implicated in the most common forms of NSCLC but rather select for morphologic features of lung tumor types such as PB and WDFLAC. As a corollary, cases showing this tumor morphology should undergo testing for DICER1 variants, and if positive, genetic counseling should be considered.
Topics: Humans; Infant, Newborn; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Mutation; MicroRNAs; Pulmonary Blastoma; Ribonuclease III; Germ-Line Mutation; DEAD-box RNA Helicases
PubMed: 38050371
DOI: 10.1097/PAS.0000000000002162 -
Journal of Bronchology & Interventional... Jan 2024
Topics: Humans; Pulmonary Blastoma; Kidney Neoplasms; Neoplastic Syndromes, Hereditary; Ribonuclease III; DEAD-box RNA Helicases
PubMed: 38014858
DOI: 10.1097/LBR.0000000000000955 -
Journal of Pediatric Surgery Mar 2024Distinguishing congenital pulmonary airway malformations (CPAMs) from pleuropulmonary blastoma (PPB) can be challenging. Previously diagnosed patients with CPAM may have...
BACKGROUND
Distinguishing congenital pulmonary airway malformations (CPAMs) from pleuropulmonary blastoma (PPB) can be challenging. Previously diagnosed patients with CPAM may have been misdiagnosed and we may have missed DICER1-associated PPBs, a diagnosis with important clinical implications for patients and their families. To gain insight in potential misdiagnoses, we systematically assessed somatic DICER1 gene mutation status in an unselected, retrospective cohort of patients with a CPAM diagnosis.
METHODS
In the Amsterdam University Medical Center (the Netherlands), it has been standard policy to resect CPAM lesions. We included all consecutive cases of children (age 0-18 years) with a diagnosis of CPAM between 2007 and 2017 at this center. Clinical and radiographic features were reviewed, and DICER1 gene sequencing was performed on DNA retrieved from CPAM tissue samples.
RESULTS
Twenty-eight patients with a surgically removed CPAM were included. CPAM type 1 and type 2 were the most common subtypes (n = 12 and n = 13). For 21 patients a chest CT scan was available for reassessment by two pediatric radiologists. In 9 patients (9/21, 43%) the CPAM subtype scored by the radiologists did not correspond with the subtype given at pathology assessment. No pathogenic mutations and no copy number variations of the DICER1 gene were found in the DNA extracted from CPAM tissue (0/28).
CONCLUSIONS
Our findings suggest that the initial CPAM diagnoses were correct. These findings should be validated through larger studies to draw conclusions regarding whether systematic DICER1 genetic testing is required in children with a pathological confirmed diagnosis of CPAM or not.
LEVEL OF EVIDENCE
Level IV.
Topics: Child; Humans; Infant, Newborn; Infant; Child, Preschool; Adolescent; Cohort Studies; Retrospective Studies; Pulmonary Blastoma; Cystic Adenomatoid Malformation of Lung, Congenital; DNA; Ribonuclease III; DEAD-box RNA Helicases
PubMed: 37989646
DOI: 10.1016/j.jpedsurg.2023.10.031 -
Diagnostic Cytopathology Feb 2024Pleuropulmonary blastoma (PPB) is a rare, aggressive, primary intrathoracic malignancy typically seen in infancy and early childhood. Accurate distinction from... (Review)
Review
INTRODUCTION
Pleuropulmonary blastoma (PPB) is a rare, aggressive, primary intrathoracic malignancy typically seen in infancy and early childhood. Accurate distinction from congenital cystic lung lesions is crucial due to significant prognostic and therapeutic differences. Cytologic features have rarely been described. Establishing a cytodiagnosis is challenging owing to its rarity, lack of awareness, and multiple morphologic mimics.
MATERIALS AND METHODS
This was a retrospective study conducted over 8 years. The histopathology and cytopathology databases were searched for all pediatric PPB cases. The corresponding cytologic samples were reviewed to identify characteristic features that can help distinguish PPB from its mimics.
RESULTS
There was a total of six cases of pediatric PPB reported during the study period. Of these, four (66.7%) presented as intrathoracic, and two (33.3%) as pleural-based masses. Cytology smears showed discretely scattered and perivascular arrangements of round-oval tumor cells with background eosinophilic stromal material. The tumor cells were mildly pleomorphic (n = 3) with round nuclei, fine chromatin, inconspicuous nucleoli, and scanty cytoplasm; however, three cases showed marked anaplasia, and one each showed necrosis and rhabdoid differentiation. On immunocytochemistry (4/6), these were positive for vimentin and desmin and negative for WT1, chromogranin, SALL4, cytokeratin, CD45, and CD99. FISH (1/6) did not show N-Myc amplification.
CONCLUSIONS
Knowledge of the characteristic cytomorphological and immunocytochemical features of PPB is vital to establish a prompt and accurate cytodiagnosis with appropriate clinicoradiologic correlation.
Topics: Humans; Child; Child, Preschool; Lung Neoplasms; Retrospective Studies; Pleural Neoplasms; Pulmonary Blastoma
PubMed: 37964698
DOI: 10.1002/dc.25254 -
MedRxiv : the Preprint Server For... Nov 2023Current clinical variant analysis pipelines focus on coding variants and intronic variants within 10-20 bases of an exon-intron boundary that may affect splicing. The...
BACKGROUND
Current clinical variant analysis pipelines focus on coding variants and intronic variants within 10-20 bases of an exon-intron boundary that may affect splicing. The impact of newer splicing prediction algorithms combined with splicing assays on rare variants currently considered Benign/Likely Benign (B/LB) is unknown.
METHODS
Exome sequencing data from 576 pediatric cancer patients enrolled in the Texas KidsCanSeq study were filtered for intronic or synonymous variants absent from population databases, predicted to alter splicing via SpliceAI (>0.20), and scored as potentially deleterious by CADD (>10.0). Total cellular RNA was extracted from monocytes and RT-PCR products analyzed. Subsequently, rare synonymous or intronic B/LB variants in a subset of genes submitted to ClinVar were similarly evaluated. Variants predicted to lead to a frameshifted splicing product were functionally assessed using an splicing reporter assay in HEK-293T cells.
RESULTS
KidsCanSeq exome data analysis revealed a rare, heterozygous, intronic variant (NM_177438.3():c.574-26A>G) predicted by SpliceAI to result in gain of a secondary splice acceptor site. The proband had a personal and family history of pleuropulmonary blastoma consistent with syndrome but negative clinical sequencing reports. Proband RNA analysis revealed alternative transcripts including the SpliceAI-predicted transcript.Similar bioinformatic analysis of synonymous or intronic B/LB variants (n=31,715) in ClinVar from 61 Mendelian disease genes yielded 18 variants, none of which could be scored by MaxEntScan. Eight of these variants were assessed ( n=4, n=2, n=2) using splice reporter assay and demonstrated abnormal splice products (mean 66%; range 6% to 100%). Available phenotypic information from submitting laboratories demonstrated phenotypes in 2 families (1 variant) and breast cancer phenotypes for in 3 families (2 variants).
CONCLUSIONS
Our results demonstrate the power of newer predictive splicing algorithms to highlight rare variants previously considered B/LB in patients with features of hereditary conditions. Incorporation of SpliceAI annotation of existing variant data combined with either direct RNA analysis or assays has the potential to identify disease-associated variants in patients without a molecular diagnosis.
PubMed: 37961416
DOI: 10.1101/2023.10.30.23297632 -
Surgical Case Reports Nov 2023Pleuropulmonary blastoma (PPB) is an extremely rare and malignant pediatric lung tumor. Purely cystic PPB has a more favorable prognosis than solid PPB, but may be...
BACKGROUND
Pleuropulmonary blastoma (PPB) is an extremely rare and malignant pediatric lung tumor. Purely cystic PPB has a more favorable prognosis than solid PPB, but may be difficult to distinguish from a certain type of "benign" congenital pulmonary airway malformation before and during surgery. The influence of tumor rupture on long life prognosis has not been clarified in detail.
CASE PRESENTATION
A 5-month-old boy underwent emergency transfer from another hospital due to a left thoracic cystic lesion and left pneumothorax detected on chest radiography performed for persistent wheeze and cough. Contrast-enhanced computed tomography of the chest revealed marked deviation of the mediastinum to the right due to a giant cystic lesion and pneumothorax. Thoracotomy was performed on hospital day 2. A cystic lesion had developed from the distal alveolar region of lower lobe of the left lung and the tumor showed a tiny adhesion to the left diaphragm and a tiny rupture near the adhesion. Partial lung excision including the cyst and scraping of the adhesion were performed. Histopathological investigations revealed immature blast cell-like mesenchymal cells and differentiated striated muscle cells in a dense cambium layer were found under the epithelium of the cystic lesion. Type I PPB was diagnosed.
CONCLUSIONS
Surgery should be performed with the possibility of type I PPB in mind when an extrapulmonary cystic lung lesion is found. Since issues such as the pathogenesis and long-term prognosis of ruptured cases remain unclear, continued careful follow-up of this case will be required.
PubMed: 37930461
DOI: 10.1186/s40792-023-01777-7 -
Zhonghua Bing Li Xue Za Zhi = Chinese... Nov 2023
Topics: Humans; Child; Pulmonary Blastoma; Lung Neoplasms
PubMed: 37899323
DOI: 10.3760/cma.j.cn112151-20230413-00256 -
JCO Precision Oncology Sep 2023Germline pathogenic loss-of-function (pLOF) variants in are associated with a predisposition for a variety of solid neoplasms, including pleuropulmonary blastoma and...
Germline pathogenic loss-of-function (pLOF) variants in are associated with a predisposition for a variety of solid neoplasms, including pleuropulmonary blastoma and Sertoli-Leydig cell tumor (SLCT). The most common pLOF variants include small insertions or deletions leading to frameshifts, and base substitutions leading to nonsense codons or altered splice sites. Larger deletions and pathogenic missense variants occur less frequently. Identifying these variants can trigger surveillance algorithms with potential for early detection of -related cancers and cascade testing of family members. However, some patients with -associated tumors have no pLOF variants detected by germline or tumor testing. Here, we present two patients with SLCT whose tumor sequencing showed only a somatic missense RNase IIIb variant. Conventional exon-directed germline sequencing revealed no pLOF variants. Using a custom capture panel, we discovered novel intronic variants, ENST00000343455.7: c.1752+213A>G and c.1509+16A>G, that appear to interfere with normal splicing. We suggest that when no pLOF variants or large deletions are discovered in exonic regions despite strong clinical suspicion, intron sequencing and splicing analysis should be performed.
Topics: Male; Female; Humans; Sertoli-Leydig Cell Tumor; Ovarian Neoplasms; Introns; Germ-Line Mutation; Mutation; Ribonuclease III; DEAD-box RNA Helicases
PubMed: 37883719
DOI: 10.1200/PO.23.00189 -
EJC Paediatric Oncology Dec 2023While all childhood cancers are rare, tumors that are particularly infrequent or underrepresented within pediatrics are studied under the umbrella of the Children's...
While all childhood cancers are rare, tumors that are particularly infrequent or underrepresented within pediatrics are studied under the umbrella of the Children's Oncology Group Rare Tumor committee, divided into the Retinoblastoma and Infrequent Tumor subcommittees. The Infrequent Tumor subcommittee has traditionally included an emphasis on globally rare tumors such as adrenocortical carcinoma, nasopharyngeal carcinoma, or those tumors that are rare in young children, despite being common in adolescents and young adults, such as colorectal carcinoma, thyroid carcinoma, and melanoma. Pleuropulmonary blastoma, gonadal stromal tumors, pancreatic tumors including pancreatoblastoma, gastrointestinal stromal tumor, nonmelanoma skin cancers, neuroendocrine tumors, and desmoplastic small round cell tumors, as well as other carcinomas are also included under the heading of the Children's Oncology Group Rare Tumor committee. While substantial challenges exist in rare cancers, inclusion and global collaboration remain key priorities to ensure high quality research to advance care.
PubMed: 37829670
DOI: 10.1016/j.ejcped.2023.100024 -
Genes Aug 2023The identification of cancer predisposition syndromes (CPSs) plays a crucial role in understanding the etiology of pediatric cancers. CPSs are genetic mutations that...
The identification of cancer predisposition syndromes (CPSs) plays a crucial role in understanding the etiology of pediatric cancers. CPSs are genetic mutations that increase the risk of developing cancer at an earlier age compared to the risk for the general population. This article aims to provide a comprehensive analysis of three unique cases involving pediatric patients with CPS who were diagnosed with multiple simultaneous or metachronous cancers. The first case involves a child with embryonal rhabdomyosarcoma, nephroblastoma, glioma, and subsequent medulloblastoma. Genetic analysis identified two pathogenic variants in the gene. The second case involves a child with alveolar rhabdomyosarcoma, juvenile xanthogranuloma, gliomas, and subsequent JMML/MDS/MPS. A pathogenic variant in the gene was identified. The third case involves a child with pleuropulmonary blastoma and pediatric cystic nephroma/nephroblastoma, in whom a pathogenic variant in the gene was identified. Multiple simultaneous and metachronous cancers in pediatric patients with CPSs are a rare but significant phenomenon. Comprehensive analysis and genetic testing play significant roles in understanding the underlying mechanisms and guiding treatment strategies for these unique cases. Early detection and targeted interventions are important for improving outcomes in these individuals.
PubMed: 37761810
DOI: 10.3390/genes14091670