Somatic DICER1 mutations in adult-onset pulmonary blastoma

Xiang

et al. 2019

Preprint

Background: This study was designed to investigate the clinicopathologic features of pulmonary blastomatoid carcinosarcoma and explore the genomic profiles of epithelial and mesenchymal components in this tumor. Methods: Three cases of pulmonary blastomatoid carcinosarcoma were enrolled in this study. Clinic-pathologic information and prognostic data were retrospectively reviewed. Diagnostic immunohistochemistry was performed. The epithelial and mesenchymal components were microdissected to investigate the genomic profiles by performing capture-based targeted next generation sequencing. Results: The epithelial component in patient one was consistent of low-grade and high-grade fetal lung adenocarcinoma and displayed aberrant nuclear expression of β-catenin and missense mutation of CTNNB1 in its low-grade epithelial. The epithelial component in another two patients were consistent of high-grade fetal lung adenocarcinoma/enteric adenocarcinoma and harbored no mutation of CTNNB1. The mesenchymal components in all three tumors were primitive round/spindle cells in morphology without definite differentiation and showed cytoplasmic dot positive of β-catenin and no corresponding mutation. Within a tumor, both components exhibited relatively comparable molecular profile. In patient one, 4 mutations: RB1, FAT3, PTCH1 and LRP1B were shared by both epithelial and mesenchymal components. Epithelial had additional mutations in BCOR, CTNNB1, CTCF, FAT1 and DICER1. In patient two, 12 mutations were shared. The epithelial had BRCA2 mutations and the mesenchymal had mutations in CREBBP, ALK, DNMT3A, ASXL2, MYCN andRICTOR. Patient three had 6 shared mutations. The epithelial had an additional mutation in KAT6A and the mesenchymal had an additional mutation in APC. Collectively, we observed heterogeneity between epithelial and mesenchymal components of the same tumor. Conclusions: Parallel detection of genetic abnormalities in epithelial and mesenchymal components of blastomatoid carcinosarcoma could provide evidence for tumor differentiation, molecular targeting and further distinguish them from conventional pulmonary blastoma and carcinosarcoma.

Section: Genetic Sequencing Resultssupporting

confidence: 89%

Clinicopathologic features and genomic analysis of pulmonary blastomatoid carcinosarcoma

Xiang

et al. 2019

Preprint

“…Pleuropulmonary blastoma is a manifestation of DICER1 syndrome [ 29 ]. Primarily observed in children, it is a rare cancer that originates in the pleural cavity or the lungs [ 30 ].…”

Section: Manifestations Of Dicer1 Gene Mutationmentioning

confidence: 99%

DICER1 Syndrome: DICER1 Mutations in Rare Cancers

Robertson

Jorcyk

Oxford

2018

Cancers

128

DICER1 syndrome is a rare genetic disorder that predisposes individuals to multiple cancer types. Through mutations of the gene encoding the endoribonuclease, Dicer, DICER1 syndrome disrupts the biogenesis and processing of miRNAs with subsequent disruption in control of gene expression. Since the first description of DICER1 syndrome, case reports have documented novel germline mutations of the DICER1 gene in patients with cancers as well as second site mutations that alter the function of the Dicer protein expressed. Here, we present a review of mutations in the DICER1 gene, the respective protein sequence changes, and clinical manifestations of DICER1 syndrome. Directions for future research are discussed.

“…Previous studies demonstrate that CTNNB1 mutation and subsequent activation of the Wnt signaling pathway play an important role in tumorigenesis of L-FLAC and PB tumors, but not in carcinosarcoma [1,3,4]. Besides, few cases of PB were found to harbor somatic DICER1 missense mutation and indicated that DICER1 may be closely related to these tumors presenting later in life [24]. Our results demonstrated that aberrant nuclear expression of β-catenin and missense mutation of CTNNB1 and DICER1 were found only in L-FLAC component but not in both H-FLAC and mesenchymal components which was further supported by previous studies [25].…”

Section: Discussionmentioning

confidence: 99%

Clinicopathologic features and genomic analysis of pulmonary blastomatoid carcinosarcoma

et al. 2020

Background: This study was designed to investigate the clinicopathologic features of pulmonary blastomatoid carcinosarcoma and explore the genomic profiles of epithelial and mesenchymal components in this tumor. Methods: Three cases of pulmonary blastomatoid carcinosarcoma were enrolled in this study. Clinicopathologic information and prognostic data were retrospectively reviewed. Diagnostic immunohistochemistry was performed. The epithelial and mesenchymal components were microdissected to investigate the genomic profiles by performing capture-based targeted next generation sequencing. Results: The epithelial components in patient one consisted of low-grade and high-grade fetal lung adenocarcinoma. Low-grade epithelial cells showed nuclear expression of β-catenin and missense mutation of CTNNB1. The epithelial components in another two patients consisted of high-grade fetal lung adenocarcinoma/ enteric adenocarcinoma. The epithelial cells showed membrane staining of β-catenin and harbored no mutation of CTNNB1. The mesenchymal components in all three tumors were composed of primitive round/spindle cells without definite differentiation and showed cytoplasmic dot positive of β-catenin and no corresponding mutation. Within a tumor, both components exhibited relatively comparable molecular profile. In patient one, 4 mutations: RB1, FAT3, PTCH1 and LRP1B were shared by both epithelial and mesenchymal components. Epithelial component had additional mutations in BCOR, CTNNB1, CTCF, FAT1 and DICER1. In patient two, 12 mutations were shared. The epithelial component had BRCA2 mutation and the mesenchymal had mutations in CREBBP, ALK, DNMT3A, ASXL2, MYCN and RICTOR. Patient three had 6 shared mutations. The epithelial component had an additional mutation in KAT6A and the mesenchymal had an additional mutation in APC. Collectively, we observed heterogeneity between epithelial and mesenchymal components of the same tumor. Conclusions: Blastomatoid carcinosarcoma showed characteristic morphology and immunophenotype. Parallel detection of genetic abnormalities in epithelial and mesenchymal components could provide further evidence for tumor differentiation, molecular targeting and differential diagnosis.