Somatic variants as a cause of drug-resistant epilepsy including mesial temporal lobe epilepsy with hippocampal sclerosis.

OBJECTIVE: The contribution of somatic variants to epilepsy has recently been demonstrated, particularly in the etiology of malformations of cortical development. The aim of this study was to determine the diagnostic yield of somatic variants in genes that have been previously associated with a somatic or germline epilepsy model, ascertained from resected brain tissue from patients with multidrug-resistant focal epilepsy. METHODS: Forty-two patients were recruited across three categories: (1) malformations of cortical development, (2) mesial temporal lobe epilepsy with hippocampal sclerosis, and (3) nonlesional focal epilepsy. Participants were subdivided based on histopathology of the resected brain. Paired blood- and brain-derived DNA samples were sequenced using high-coverage targeted next generation sequencing to high depth (585× and 1360×, respectively). Variants were identified using Genome Analysis ToolKit (GATK4) MuTect-2 and confirmed using high-coverage Amplicon-EZ sequencing. RESULTS: Sequence data on 41 patients passed quality control. Four somatic variants were validated following amplicon sequencing: within CBL, ALG13, MTOR, and FLNA. The diagnostic yield across 41 patients was 10%, 9% in mesial temporal lobe epilepsy with hippocampal sclerosis and 20% in malformations of cortical development. SIGNIFICANCE: This study provides novel insights into the etiology of mesial temporal lobe epilepsy with hippocampal sclerosis, highlighting a potential pathogenic role of somatic variants in CBL and ALG13. We also report candidate diagnostic somatic variants in FLNA in focal cortical dysplasia, while providing further insight into the importance of MTOR and related genes in focal cortical dysplasia. This work demonstrates the potential molecular diagnostic value of variants in both germline and somatic epilepsy genes.

HE4 and CA125 as preoperative risk stratifiers for lymph node metastasis in endometrioid carcinoma of the endometrium: A retrospective study in a cohort with histological proof of lymph node status.

OBJECTIVES: To investigate whether HE4 and CA125 could identify endometrioid adenocarcinoma patients who might most benefit from full staging surgery with lymphadenectomy. METHODS: Sequential patients with a preoperative banked serum and histology of endometrioid adenocarcinoma of endometrium who had undergone surgical staging with lymph node dissection over a 5-year period between 2011 and 2016 were included from a tertiary Gynaecological Cancer Centre, Dublin, Ireland. Preoperative serum HE4 and CA125 were measured using ELISA, with the cut-offs HE4 81 pmol/L and CA125 35 U/ml. Predictive values were estimated using AUC, sensitivity, specificity and odds ratios. RESULTS: 9.5% of the cohort had lymph node metastases. A HE4 cut-off of 81 pmol/L yielded a sensitivity of 78.6% and specificity of 53.4% for predicting lymph node metastases. Sensitivity of CA125 at 35 U/ml was 57% and specificity 91.4%. The AUC was 0.66 (0.52-0.80) for HE4 and 0.74 (0.58-0.91) for CA125. Sensitivity was 92.8% and specificity 51.1% when an elevation of either HE4 or CA125 was included, AUC was 0.72 (0.61-0.83), this combination yielded the highest NPV of 98.6%. Sensitivity was 42.9% and specificity 93.8% if both markers were elevated simultaneously, AUC was 0.68 (0.51-0.86). Preoperative clinical predictors of high-grade preoperative histology and radiology had sensitivities of 21.4% and 41.7%, respectively. Patients with a HE4 above 81 pmol/L had an odds ratio of 4.2 (1.12-15.74), p < 0.05, of lymph node metastases and CA125 had an odds ratio of 14.2 (4.16-48.31), p < 0.001. CONCLUSIONS: Serum HE4 and CA125 improved on existing methods for risk stratification of endometrioid carcinomas and warrant further investigation.