Genetic analysis of a morphologically heterogeneous ovarian endometrioid carcinoma

Abstract

Aims Low-grade ovarian endometrioid carcinomas may be associated with high-grade components. Whether the latter are clonally-related to and originate from the low-grade endometrioid carcinoma remains unclear. Here we employed massively parallel sequencing to characterize the genomic landscape and clonal relatedness of an ovarian endometrioid carcinoma containing low- and high-grade components. Methods and Results DNA samples extracted from each tumor component (low-grade endometrioid, high-grade anaplastic and high-grade squamous) and matched normal tissue were subjected to targeted massively parallel sequencing using the 410 gene Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing assay. Somatic single nucleotide variants, small insertions and deletions, and copy number alterations were detected by state-of-the-art bioinformatics algorithms, and validated with orthogonal methods. The endometrioid carcinoma and the associated high-grade components shared copy number alterations and four clonal mutations, including SMARCA4 mutations, which resulted in loss of BRG1 protein expression. Subclonal mutations and mutations restricted to single components were also identified, such as distinct TP53 mutations restricted to each histologic component. Conclusions Histologically distinct components of ovarian endometrioid carcinomas may display intra-tumor genetic heterogeneity but be clonally related, harboring a complex clonal composition. In the present case, SMARCA4 mutations were likely early events, whereas TP53 somatic mutations were acquired later in evolution.

Clonal relationship and directionality of progression of synchronous endometrial and ovarian carcinomas in patients with DNA mismatch repair-deficiency associated syndromes

“…Combining our previously published synchronous EC/OC Lynch syndrome case, SV2 [ 12 ], with the analyses performed here, we report a 40% (2/5) rate of independent primary tumors versus metastatic lesions in patients with Lynch syndrome. This is in contrast to sporadic synchronous clinically independent ECs/OCs, which have been consistently shown to be clonally related and metastases from each other, as demonstrated by both our group and others [ 13 – 16 , 41 , 44 , 45 ].…”

“…Loss of DNA MMR protein expression was defined as the complete absence from all tumor cell nuclei in the presence of a positive internal control, including blood vessels, stromal cells and/or lymphocytes. Cases LS5 and LS6 were also subjected to PTEN immunohistochemistry (IHC) using the monoclonal 138G6 antibody (#9559; Cell Signaling), as previously described [ 41 ]. All assays were performed on a Leica Bond 3 (Leica) automated stainer platform.…”

An In-Depth Look at Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT): Clinical Implications from Recent Molecular Findings

“…In line with their proposal, gene profiling analyses demonstrated that SMARCA4- deficient thoracic sarcomas (“SMARCA4-deficient thoracic sarcomas”) were related to malignant rhabdoid tumors and SCCOHTs 78. SCCOHT and other tumors, such as thoracic sarcoma, undifferentiated/rhabdoid carcinomas of the gastrointestinal tract, and SMARCA4-deficient undifferentiated uterine sarcoma can be added to the list of this unique, highly lethal catalogue 43-45, 78, 91, 98, 99.…”

“…Recent studies have indicated that SCCOHT is characterized by germline or somatic mutations in SMARCA4 and other subunits in the SWI/SNF chromatin remodeling complex 6-8. These mutations are found in a variety of cancers including epithelial carcinoma and mesenchymal neoplasms 43-45. These mutations can not provide useful information on their histologic origin, either.…”

“…An estimated 20% of human cancers displayed mutations in one or more of the SWI/SNF subunits 84. These large set of “SWI/SNFomas” are particularly associated with pediatric cancers, such as brain tumors, medulloblastoma, AT/RT, and leukemia 86-88 as well as a small subset of adult cancers including non-small cell lung cancer, gastrointestinal or uterine undifferentiated carcinoma, and Burkitt lymphoma 43-45, 89-91. Given the substantial portion of “SWI/SNFomas” in human cancers, the identification of SMARCA4 mutations in virtually all SCCOHT tumors may confer a broader translational relevance covering tumor classification, diagnosis, prevention and intervention [ Figure 2 ].…”