23 research outputs found
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Biallelic somatic SMARCA4 mutations in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive tumor that primarily affects young women. SCCOHT has recently been identified as a monogenic disorder caused by germline and/or somatic SMARCA4 mutations. We describe a 15-year-old Caucasian female with a SCCOHT harboring a previously unreported somatic mutation in the SMARCA4 gene (c.1757delA; p.K586.fs) with loss of heterozygosity. No germline mutation was identified. Subsequent immunohistochemical staining confirmed loss of SMARCA4 protein. These molecular findings will aid with SCCOHT diagnosis through immunohistochemical staining for SMARCA4 and in the future may have implications for the management of this disease.This is the accepted manuscript. The final version is available at http://onlinelibrary.wiley.com/doi/10.1002/pbc.25279/abstract
The influence of clinical and genetic factors on patient outcome in small cell carcinoma of the ovary, hypercalcemic type.
Prophylactic oophorectomy for hereditary small cell carcinoma of the ovary, hypercalcemic type
âą Prophylactic oophorectomy can prevent small cell carcinoma of the ovary, hypercalcemic type in carriers of germline SMARCA4 mutations. âą Unaffected SMARCA4 mutation carriers who desire children may be best served by oocyte cryopreservation prior to prophylactic oophorectomy
Expanding the Noonan spectrum/RASopathy NGS panel: Benefits of adding NF1 and SPRED1
Abstract Background RASopathies are a group of disorders caused by disruptions to the RASâMAPK pathway. Despite being in the same pathway, Neurofibromatosis Type 1 (NF1) and Legius syndrome (LS) typically present with phenotypes distinct from Noonan spectrum disorders (NSDs). However, some NF1/LS individuals also exhibit NSD phenotypes, often referred to as NeurofibromatosisâNoonan syndrome (NFNS), and may be mistakenly evaluated for NSDs, delaying diagnosis, and affecting patient management. Methods A derivation cohort of 28 patients with a prior negative NSD panel and either NFNS or a suspicion of NSD and cafĂ©âauâlait spots underwent NF1 and SPRED1 sequencing. To further determine the utility and burden of adding these genes, a validation cohort of 505 patients with a suspected RASopathy were tested on a 14âgene RASopathyâassociated panel. Results In the derivation cohort, six (21%) patients had diseaseâcausing NF1 or SPRED1 variants. In the validation cohort, 11 (2%) patients had diseaseâcausing variants and 15 (3%) had variants of uncertain significance in NF1 or SPRED1. Of those with diseaseâcausing variants, 5/17 only had an NSD diagnosis. Conclusions Adding NF1 and SPRED1 to RASopathy panels can speed diagnosis and improve patient management, without significantly increasing the burden of inconclusive results
Primary rhabdoid tumor of the ovary: When large cells become small cells
âą The third case of pure primary malignant rhabdoid tumor of the ovary (MRTO) is described; âą SMARCA4 and SMARCB1 genetic analysis and immunohistochemistry are necessary for correct diagnosis of MRTO; âą MRTO and small cell carcinoma of the ovary, hypercalcemic type are essentially the same and should be treated as such
The hereditary nature of small cell carcinoma of the ovary, hypercalcemic type: two new familial cases
Malignant teratoid tumor of the thyroid gland: an aggressive primitive multiphenotypic malignancy showing organotypical elements and frequent DICER1 alterationsâis the term âthyroblastomaâ more appropriate?
Primary thyroid teratomas are exceedingly rare. Mature and immature variants recapitulate their gonadal counterparts (predilection for infants/children, triphasic germ layer differentiation, and favorable outcome). On the other hand, the so-called malignant teratomas affect predominantly adults and elderly, are highly aggressive, and, according to a few published cases, harbor DICER1 mutations. We describe three highly aggressive sporadic malignant teratoid thyroid tumors in 2 females (17 and 45Â years) and one male (17Â years). Histology showed triphasic neoplasms composed of solid nests of small primitive monomorphic cells embedded in a cellular stroma with primitive immature rhabdomyosarcoma-like (2) or pleomorphic sarcoma-like (1) phenotype. The third component was represented by TTF1+/PAX8+ primitive teratoid epithelial tubules reminiscent of primitive thyroid follicles and/or Wilms tumor, admixed with scattered respiratory- or enteric-type tubules, neuroepithelial rosettes, and fetal-type squamoid nests. Foci of cartilage were seen in two cases, but none contained mature organoid adult-type tissue or skin adnexa. SALL4 was expressed in the small cell (2) and stromal (1) component. Other germ cell markers were negative. Molecular testing revealed a known 'hotspot' pathogenic DICER1 mutation in two cases. In addition, case 1 had a missense TP53 variant. This type of thyroid malignancy is distinct from genuine teratomas. The immunoprofile suggests primitive thyroid- or branchial cleft-like differentiation. Given that 'blastoma' is a well-accepted terminology in the spectrum of DICER1-associated malignancies, the term 'thyroblastoma' might be more convenient for these malignant teratoid tumors of the thyroid gland. Relationship of thyroblastoma to the DICER1 syndrome remains to be addressed
Next-generation sequencing of non-small cell lung cancer at a Quebec health care cancer centre
Background: Lung cancer is the leading cause of cancer death in both men and women. Quebec has the highest lung cancer mortality out of all provinces in Canada, believed to be caused by higher smoking rates. Molecular testing for lung cancer is standard of care due to the discovery of actionable driver mutations that can be targeted with tyrosine kinase inhibitors. To date, no detailed molecular testing characterization of Quebec patients with lung cancer using next generation sequencing (NGS) has been performed. Materials and methods: The aim of this study was to describe the genomic landscape of patients with lung cancer (n = 997) who underwent NGS molecular testing at a tertiary care center in Quebec and to correlate it with clinical and pathology variables. Results: Compared to 10 other NGS studies found through a structured search strategy, our cohort had a higher prevalence of KRAS mutations (39.2%) compared to most geographical locations. Additionally, we observed a significant positive association between decreasing age and a higher proportion of KRAS G12C mutations. Conclusion: Overall, it remains important to assess institutional rates of actionable driver mutations to help guide governing bodies, fuel clinical trials and create benchmarks for expected rates as quality metrics
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Small-Cell Carcinoma of the Ovary, Hypercalcemic Type-Genetics, New Treatment Targets, and Current Management Guidelines.
Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and highly aggressive ovarian malignancy. In almost all cases, it is associated with somatic and often germline pathogenic variants in SMARCA4, which encodes for the SMARCA4 protein (BRG1), a subunit of the SWI/SNF chromatin remodeling complex. Approximately 20% of human cancers possess pathogenic variants in at least one SWI/SNF subunit. Because of their role in regulating many important cellular processes including transcriptional control, DNA repair, differentiation, cell division, and DNA replication, SWI/SNF complexes with mutant subunits are thought to contribute to cancer initiation and progression. Fewer than 500 cases of SCCOHT have been reported in the literature and approximately 60% are associated with hypercalcemia. SCCOHT primarily affects females under 40 years of age who usually present with symptoms related to a pelvic mass. SCCOHT is an aggressive cancer, with long-term survival rates of 30% in early-stage cases. Although various treatment approaches have been proposed, there is no consensus on surveillance and therapeutic strategy. An international group of multidisciplinary clinicians and researchers recently formed the International SCCOHT Consortium to evaluate current knowledge and propose consensus surveillance and therapeutic recommendations, with the aim of improving outcomes. Here, we present an overview of the genetics of this cancer, provide updates on new treatment targets, and propose management guidelines for this challenging cancer.Eve Appeal research charit