Abstract:Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare, highly lethal malignancy predominantly affecting young adult females. We report a patient with widely metastatic SCCOHT and concurrent uterine cervical pleomorphic liposarcoma. Clinical targeted next-generation sequencing was performed on both neoplasms and demonstrated hemizygous stop-gain TP53 mutations (p.R196*), and wild-type SMARCA4 in both tumors. Microarray analyses of both tumors revealed similar but not identical widespread los… Show more
“…Accumulation of p53 proteins was occasionally reported in SCCOHT 34, 66, but TP53 mutations, the hallmark of high grade serous carcinoma, were extremely rare in SCCOHT. To date, only two patients harbored TP53 mutations: one was a woman with Li-Fraumeni syndrome (germline TP53 mutation) 67; another was a recurrent SCCOHT case showing TP53 (I254N) and POLE (D287A) mutations 68. The additional mutations in the recurrent SCCOHT might reflect the molecular evolution in the process of tumor progression.…”
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a highly aggressive cancer in young women. The histogenesis remains unclear although a potential origin of germ cells has been suggested recently. The high throughput next generation sequencing techniques have facilitated the identification of inactivating SMARCA4 mutations as the driver of SCCOHT. These findings may greatly impact on the prevention, diagnosis, molecular classification and treatment of SCCOHTs. The SMARCA4 mutations, typically associated with dual loss of BRG1 and BRM expression, are highly sensitive and specific for the diagnosis of SCCOHT. Germline mutations of SMARCA4 support familial SCCOHT with a critical requirement of genetic counseling and possible prophylactic surgery for carriers. SCCOHT, malignant atypical teratoid/rhabdoid tumors, thoracic sarcomas and some undifferentiated carcinomas harbor rhabdoid morphology and mutations in the SMARC genes, generating an emerging molecular classification of SMARC-mutated tumors. A multi-modality treatment approach consisting of surgery and high dose multi-agent chemotherapy in atypical teratoid/rhabdoid tumors may have potential benefits for SCCOHT patients. Preliminary studies have implicated that the inhibitors targeting EZH2 and the receptor tyrosine kinase, and anti-PD-L1 immunotherapy might be potentially effective for SCCOHT patients. These recent advances on molecular genetics, diagnosis and treatment of SCCOHT address the necessity of multiple institutional collaboration work among oncologist, pathologist, genomic scientist, geneticist, molecular biologist, and pharmacologist.
“…Accumulation of p53 proteins was occasionally reported in SCCOHT 34, 66, but TP53 mutations, the hallmark of high grade serous carcinoma, were extremely rare in SCCOHT. To date, only two patients harbored TP53 mutations: one was a woman with Li-Fraumeni syndrome (germline TP53 mutation) 67; another was a recurrent SCCOHT case showing TP53 (I254N) and POLE (D287A) mutations 68. The additional mutations in the recurrent SCCOHT might reflect the molecular evolution in the process of tumor progression.…”
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a highly aggressive cancer in young women. The histogenesis remains unclear although a potential origin of germ cells has been suggested recently. The high throughput next generation sequencing techniques have facilitated the identification of inactivating SMARCA4 mutations as the driver of SCCOHT. These findings may greatly impact on the prevention, diagnosis, molecular classification and treatment of SCCOHTs. The SMARCA4 mutations, typically associated with dual loss of BRG1 and BRM expression, are highly sensitive and specific for the diagnosis of SCCOHT. Germline mutations of SMARCA4 support familial SCCOHT with a critical requirement of genetic counseling and possible prophylactic surgery for carriers. SCCOHT, malignant atypical teratoid/rhabdoid tumors, thoracic sarcomas and some undifferentiated carcinomas harbor rhabdoid morphology and mutations in the SMARC genes, generating an emerging molecular classification of SMARC-mutated tumors. A multi-modality treatment approach consisting of surgery and high dose multi-agent chemotherapy in atypical teratoid/rhabdoid tumors may have potential benefits for SCCOHT patients. Preliminary studies have implicated that the inhibitors targeting EZH2 and the receptor tyrosine kinase, and anti-PD-L1 immunotherapy might be potentially effective for SCCOHT patients. These recent advances on molecular genetics, diagnosis and treatment of SCCOHT address the necessity of multiple institutional collaboration work among oncologist, pathologist, genomic scientist, geneticist, molecular biologist, and pharmacologist.
“…Recurrences occur in the majority of patients within 2 years of diagnosis. 77 In Figure 5 is shown lobular endocervical glandular hyperplasia. Figure 5 Histology of lobular endocervical glandular hyperplasia.…”
Section: Hereditary Gynecologic Cancer Syndromesmentioning
confidence: 98%
“… 76 A case of small cell carcinoma of the ovary, hypercalcemic type and concurrent pleomorphic liposarcoma of the cervix associated with LFS has been described in medical literature. 77 …”
Section: Hereditary Gynecologic Cancer Syndromesmentioning
confidence: 99%
“…Gonadal dysgenesis (GD) comprises a variety of sexual differentiation disorders with different somatic or genetic features. 77 , 78 The syndrome includes the following subtypes – 46, XY pure (complete) GD (Swyer syndrome); 46, XX complete GD; 45, X complete GD (Turner syndrome), partial GD and mixed GD (asymmetric or atypical GD – 45, X/46, XY mosaicism). 23 , 77 , 78 The syndrome affects one in 4500–5000 births.…”
Section: Hereditary Gynecologic Cancer Syndromesmentioning
“…DNA was isolated from two engineered cell lines, one with a knock-in BRAF p.V600E variant (HD 200-002; Horizon Diagnostics, Cambridge, UK) and another with knock-in KRAS p.G13D and PIK3CA p.H1047R variants (HD 200-003; Horizon Diagnostics) as previously described. 16 DNA from the two cell lines was mixed to generate variants with VAFs ranging from approximately 1% to 25% (Supplemental Tables S1 and S2). 1 Modeling theoretical limits of variant detection based on depth of coverage using binomial sampling statistics.…”
PCR amplification, a key step in next-generation sequencing (NGS) library construction, can generate an unlimited amount of product from limited input; however, it cannot create more information than was present in the original template. Thus, NGS libraries can be made from very little DNA, but reducing the input may compromise assay sensitivity in ways that are difficult to ascertain unless library complexity (ie, the number of unique DNA molecules represented in the library) and depth of coverage with unique sequence reads (those derived from input DNA molecules) versus duplicate sequence reads (those resulting from overamplification of particular molecules) are discretely measured. A series of experiments was performed to explore the impact of low DNA input on an amplicon-based NGS assay using unique molecular identifiers to track unique versus duplicate reads. At high sequencing depths, unique and total (unique plus duplicate) read coverage are not well correlated, so increasing the number of sequenced reads does not necessarily improve sensitivity. Unique coverage depth tends to improve with more input, but improvements are not consistent. Fluctuations in library complexity complicated variant detection using both standardized and clinical specimens, often resulting in technical replicates with vastly different estimates of variant allelic fraction. In conclusion, depth of coverage with unique reads must be tracked in clinical NGS to ensure that sensitivity and accuracy are maintained.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
