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Aims: Ovarian Wilms tumour (WT)/nephroblastoma is an extremely rare neoplasm that has been reported to occur in pure form or as a component of a teratomatous neoplasm. We hypothesized that teratoma‐associated and pure ovarian WT may represent different tumour types with diverging molecular backgrounds. To test this hypothesis, we comprehensively characterized a series of five tumours originally diagnosed as ovarian WT. Methods and Results: The five cases comprised three teratoma‐associated (two mature and one immature) and two pure WTs. Two of the teratoma‐associated WTs consisted of small nodular arrangements of "glandular"/epithelial structures, while the third consisted of both an epithelial and a diffuse spindle cell/blastemal component. The pure WTs consisted of "glandular" structures, which were positive for sex cord markers (including inhibin and SF1) together with a rhabdomyosarcomatous component. The two pure WTs harboured DICER1 pathogenic variants (PVs), while the three associated with teratomas were DICER1 wildtype. Panel‐based DNA sequencing of four of the cases did not identify PVs in the other genes investigated. Analysis of the HA19/IGF2 imprinting region showed retention of imprinting in the pure WTs but loss of heterozygosity with hypomethylation of the ICR1 region in two of three teratoma‐associated WTs. Furthermore, copy number variation and clustering‐based whole‐genome DNA methylation analyses identified divergent molecular profiles for pure and teratoma‐associated WTs. Conclusion: Based on the morphological features, immunophenotype, and molecular findings (DICER1 PVs, copy number, and DNA methylation profiles), we suggest that the two cases diagnosed as pure primary ovarian WT represent moderately to poorly differentiated Sertoli Leydig cell tumours (SLCTs), while the tumours arising in teratomas represent true WTs. It is possible that at least some prior cases reported as pure primary ovarian WT represent SLCTs. [ABSTRACT FROM AUTHOR]

It is considered a pathognomonic feature of the DICER1 syndrome [[6], [28]], an uncommon tumor predisposition syndrome characterized by germline heterozygous loss-of-function variants in the I DICER1 i gene [[28]]. Pituitary blastoma (pitB) is a rare tumor of the anterior pituitary that was added to the WHO Classification of Pituitary Tumors in 2017 [[25]]. 8484187 2 Brenneman M, Field A, Yang J, Williams G, Doros L, Rossi C. Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in pleuropulmonary blastoma/DICER1 syndrome: a unique variant of the two-hit tumor suppression model. The rationale for no surveillance is based on the rarity of these tumors [[1], [39]], even within DICER1 syndrome, whereas yearly MRI has been recommended because of the poor disease outcome of DICER1-related CNS tumors [[43]]. [Extracted from the article]

Following this pattern, most of the I LZTR1/SMARCB1 i -schwannomas acquire a somatic loss of Chrm22 (thus, deleting the three genes) and a somatic mutation affecting the remaining wild-type I NF2 i copy on the GPV allele. As described for I LZTR1 i [[2]], in the I DGCR8 i path to schwannomatosis, the required loss of I NF2 i and the structure of Chrm22 would result in a complete loss of both I DGCR8 i alleles, which is likely incompatible with tumor formation in this cell type. In total, while all tumors had at least one alteration of I NF2 i , four tumors had no somatic mutations on the retained (not deleted) allele (30.8%). [Extracted from the article]

Aims: To expand the morphological spectrum of ovarian microcystic stromal tumour, a rare neoplasm considered to have a relatively constant morphology with microcysts, solid cellular regions and hyalinised fibrous stroma. Methods and results: We report four ovarian neoplasms in patients aged 45, 56, 61 and 71 years with the characteristic immunophenotype of microcystic stromal tumour (diffuse nuclear positivity with betacatenin, cyclin D1 and WT1; diffuse cytoplasmic positivity with CD10; negative inhibin, calretinin, oestrogen receptor and progesterone receptor). The tumours had variant morphology (diffuse, nested and corded arrangements in three cases, including one with spindle cell elements; nested, corded and tubular in the other). A CTNNB1 point mutation in exon 3 (c.98C>G,p.S33C; c.100G>A,p.G34R; c.97T>G, p.S33A) was present in the three cases with material available for testing. Conclusions: We feel that the cases we report are related to microcystic stromal tumour but with variant morphology; as such, the morphological spectrum of ovarian microcystic stromal tumour is broader than hitherto reported. [ABSTRACT FROM AUTHOR]

This would be analogous to cases where a I SMARCB1 i germline variant was reported to lead to malignant rhabdoid tumours and schwannomas within the same family or in the same person [[8]] and to a case where a nonsense I SMARCA4 i germline variant caused SCCOHT and CSS simultaneously in a young girl [[4]]. Biallelic I SMARCA4 i inactivation is known to cause small cell carcinoma of the ovary (hypercalcemic type) (SCCOHT) and more rarely, atypical teratoid/rhabdoid tumours (ATRT) [[1]]. Keywords: Schwannomatosis; SMARCA4; SWI/SNF; BRG1; Chromosome 22q EN Schwannomatosis SMARCA4 SWI/SNF BRG1 Chromosome 22q 505 507 3 03/21/23 20230401 NES 230401 Supplementary Information The online version contains supplementary material available at https://doi.org/10.1007/s00401-023-02546-4. (i-iii) show BRG1, INI1 and double staining with both BRG1 and INI1 of the same field in the daughter's schwannoma (400X), respectively; in (iii) (double stain), cells appear to be either INI1 + and BRG1- (brown) or INI1- and BRG1 + (red), (iv-vii) show mosaic loss of BRG1 (in 80-90% of tumour) and mosaic retention of INI1 (in 10-20% of tumour) in the daughter's schwannoma (200X) (iv-v) and in one of the mother's schwannomas (200X) (vi-vii). b LOH analysis of Chr19 and Chr22 in all tumour samples via ExomeAI. [Extracted from the article]

Pituitary blastoma (PitB) has recently been identified as a rare and potentially lethal pediatric intracranial tumor. All cases that have been studied molecularly possess at least one DICER1 pathogenic variant. Here, we characterized nine pituitary samples, including three fresh frozen PitBs, three normal fetal pituitary glands and three normal postnatal pituitary glands using small-RNA-Seq, RNA-Seq, methylation profiling, whole genome sequencing and Nanostring® miRNA analyses; an extended series of 21 pituitary samples was used for validation purposes. These analyses demonstrated that DICER1 RNase IIIb hotspot mutations in PitBs induced improper processing of miRNA precursors, resulting in aberrant 5p-derived miRNA products and a skewed distribution of miRNAs favoring mature 3p over 5p miRNAs. This led to dysregulation of hundreds of 5p and 3p miRNAs and concomitant dysregulation of numerous mRNA targets. Gene expression analysis revealed PRAME as the most significantly upregulated gene (500-fold increase). PRAME is a member of the Retinoic Acid Receptor (RAR) signaling pathway and in PitBs, the RAR, WNT and NOTCH pathways are dysregulated. Cancer Hallmarks analysis showed that PI3K pathway is activated in the tumors. Whole genome sequencing demonstrated a quiet genome with very few somatic alterations. The comparison of methylation profiles to publicly available data from ~ 3000 other central nervous system tumors revealed that PitBs have a distinct methylation profile compared to all other tumors, including pituitary adenomas. In conclusion, this comprehensive characterization of DICER1-related PitB revealed key molecular underpinnings of PitB and identified pathways that could potentially be exploited in the treatment of this tumor. [ABSTRACT FROM AUTHOR]

BACKGROUNDDICER1 is the only miRNA biogenesis component associated with an inherited tumor syndrome, featuring multinodular goiter (MNG) and rare pediatric-onset lesions. Other susceptibility genes for familial forms of MNG likely exist.METHODSWhole-exome sequencing of a kindred with early-onset MNG and schwannomatosis was followed by investigation of germline pathogenic variants that fully segregated with the disease. Genome-wide analyses were performed on 13 tissue samples from familial and nonfamilial DGCR8-E518K-positive tumors, including MNG, schwannomas, papillary thyroid cancers (PTCs), and Wilms tumors. miRNA profiles of 4 tissue types were compared, and sequencing of miRNA, pre-miRNA, and mRNA was performed in a subset of 9 schwannomas, 4 of which harbor DGCR8-E518K.RESULTSWe identified c.1552G>A;p.E518K in DGCR8, a microprocessor component located in 22q, in the kindred. The variant identified is a somatic hotspot in Wilms tumors and has been identified in 2 PTCs. Copy number loss of chromosome 22q, leading to loss of heterozygosity at the DGCR8 locus, was found in all 13 samples harboring c.1552G>A;p.E518K. miRNA profiling of PTCs, MNG, schwannomas, and Wilms tumors revealed a common profile among E518K hemizygous tumors. In vitro cleavage demonstrated improper processing of pre-miRNA by DGCR8-E518K. MicroRNA and RNA profiling show that this variant disrupts precursor microRNA production, impacting populations of canonical microRNAs and mirtrons.CONCLUSIONWe identified DGCR8 as the cause of an unreported autosomal dominant mendelian tumor susceptibility syndrome: familial multinodular goiter with schwannomatosis.FUNDINGCanadian Institutes of Health Research, Compute Canada, Alex's Lemonade Stand Foundation, the Mia Neri Foundation for Childhood Cancer, Cassa di Sovvenzioni e Risparmio fra il Personale della Banca d'Italia, and the KinderKrebsInitiative Buchholz/Holm-Seppensen. [ABSTRACT FROM AUTHOR]