Characterization of greater middle eastern genetic variation for enhanced disease gene discovery

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia1-3, has resulted in an elevated burden of recessive disease4. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics

Circulating Soluble Fas and Fas Ligand Levels Are Elevated in Children with Nonalcoholic Steatohepatitis

BACKGROUND: There is an urgent need to develop alternatives to liver biopsy in children to diagnose nonalcoholic steatohepatitis (NASH), the aggressive form of nonalcoholic fatty liver disease (NAFLD). Increased hepatocyte apoptosis plays a central role in the development of NASH. AIMS: To evaluate the plasma levels of two markers of apoptosis, soluble Fas (sFas) and soluble Fas ligand (sFasL), in children with NAFLD and assess their utility as biomarkers of disease severity. METHODS: Children with biopsy-proven NAFLD were included, and blood samples were collected. Patients were divided into NASH and "not NASH." We measured plasma sFas and sFasL using specific ELISA immunoassays. RESULTS: One hundred and seventeen children with NAFLD were recruited. Average age was 12.2 ± 2.9 years, 67 % were male, and 58 % had NASH. Patients with NASH had significantly higher levels of sFas and sFasL than patients in the "not NASH" group (686.0 ± 186.5 pg/mL versus 594.2 ± 244.9, p = 0.023 for sFas and 324.9 ± 146.5 pg/mL versus 221.4 ± 134.0, p < 0.001 for sFasL). sFasL was found to have higher accuracy for predicting the presence of NASH on liver biopsy with an AUC (95 % CI) of 0.714 (0.618, 0.810). A prediction model, the NASH apoptosis score, was generated consisting of plasma sFasL, age, ferritin, transferrin, and triglyceride levels. The area under receiver operating characteristic curve was 0.78 (95 % CI 0.0.69, 0.87). CONCLUSIONS: Markers of the extrinsic pathway of hepatocyte apoptosis are elevated in children with NASH. sFasL and the NASH apoptosis score are potential novel biomarkers for NASH

Tall cell variant papillary thyroid carcinoma impacts disease-free survival at the 10 % cut-point on multivariate analysis

INTRODUCTION: The diagnosis of tall cell variant papillary thyroid carcinoma (TCV-PTC) corresponds to the feature of aggressive histology within the framework of the American Thyroid Association (ATA) Risk of Recurrence (ROR) guidelines. Using the current World Health Organization (WHO) definition for TCV-PTC (tall cells with height at least twice the width, distribution ≥ 30 %), we examined the impact of this diagnosis on disease-free survival (DFS). METHODS: The study cohort consisted of 347 patients treated for primary papillary thyroid carcinoma (PTC). Current ATA guidelines were followed for the extent of surgery and the administration of adjuvant radioiodine therapy. Clinical surveillance included ultrasound examination and biochemical parameters according to ATA standards. The outcome was measured as time from surgery to first disease recurrence (DR) versus time from surgery until the last documented disease-free encounter (no evidence of disease, NED). Disease-free patients with fewer than 6 months of follow-up were excluded from this cohort. Structural recurrences are documented by histology or cytology whereas biochemical recurrences are documented by rising serum thyroglobulin in the absence of structural disease. All slides on all patients were examined by two pathologists with the substantial interobserver agreement (Kappa = 73 %). The primary tumors are categorically classified either as (1) TCV-PTC (definition above), (2) Papillary thyroid carcinoma with tall cell features (PTC-TCF) (≥ 10 % \u3c 30 % tall cells), or (3) Control (\u3c 10 % tall cells). Tumor size is categorized as either (1) ≤ 10 mm, (2) 11-29 mm, or (3) ≥ 30 mm. Degree of ETE is categorized as either intrathyroidal, microscopic ETE, histologic spread to strap muscles, or pT4 disease. RESULTS: 185 patients are classified as TCV-PTC (≥ 30 % tall cells), 62 as PTC-TCF (≥ 10 % \u3c 30 % tall cells), and 100 as control group (\u3c 10 % tall cells). TCV-PTC is associated with ≥ 30 mm size (p = .0246) and invasion of strap muscles and/or pT4 (p = .0325). There was no relationship between TCV-PTC and aggressive lymph node (ALN) status defined by ATA. Overall follow-up ranged from two months (one patient death) to 203 months (mean 40.8, median 33.0). DR occurred in 61 patients (mean 31.4 months, range 0 -184, 59 structural recurrences, 2 biochemical recurrences). Three models for TCV-PTC were examined: Model 1 - Tall cells ≥ 10% versus control, Model 2 - TCV-PTC versus TCF-PTC versus control, and Model 3 - TCV-PTC versus control. Kaplan Meier curves demonstrated decreased DFS with ALN status (p = .0001), ETE (p = .0295), and TCV-PTC (Model 1, p = .041). On multivariate analysis, TCV-PTC (Model 1) remained significantly predictive when adjusted for ALN (p = .0059). ETE dropped out of the model. CONCLUSION: TCV-PTC is significantly associated with larger tumors and a greater degree of ETE. The diagnosis of TCV-PTC significantly impacts DFS at the 10 % cut-point on multivariate analysis

Synchronous thyroid cancer and malignant struma ovarii: concordant mutations and microRNA profile, discordant loss of heterozygosity loci

Abstract Background Struma ovarii is an unusual ovarian teratoma containing predominantly thyroid tissue. Less than 10% of cases undergo malignant transformation in the thyroid tissue and are considered malignant struma ovarii (MSO). MSO have been reported with concurrent thyroid lesions, but molecular data is lacking. Case presentation A 42-year-old female developed MSO and synchronous multifocal subcentimeter papillary thyroid carcinoma (PTC). The patient underwent a salpingo-oophrectomy, thyroidectomy, and low-dose radioactive iodine ablation. Both the thyroid subcentimeter PTC and MSO were positive for BRAF V600E mutation, and microRNA expression profiles were similar across all tumor deposits. However, only the malignant component demonstrated extensive loss of heterozygosity (LOH) involving multiple tumor suppressor gene (TSG) chromosomal loci. Conclusions We present the first reported case of MSO with synchronous multifocal subcentimeter PTC in the thyroid containing concordant BRAF V600E mutations and resulting with discordant LOH findings. This data suggests that loss of expression in tumor suppressor gene(s) may be an important contributor to phenotypic expression of malignancy

WPOI-5: Accurately Identified at Intraoperative Consultation and Predictive of Occult Cervical Metastases

BACKGROUND: Frozen section analysis of oral cancer specimens is ideal for assessing margin distances and depth of invasion (DOI); the latter impacts intraoperative decisions regarding elective neck dissection (END). Here, we show that intraoperative determination of worst pattern of invasion (WPOI), specifically WPOI-5, has a high level of accuracy. This relates to our demonstration herein that WPOI-5 predicts occult cervical metastases (OCM) for pT1 oral squamous carcinoma (OSC). METHODS: The presence of OCM was correlated with WPOI in 228 patients with primary T1/T2/cN0 OSC undergoing resection and END. Concordance between intraoperative and final pathology WPOI determination was assessed on 51 cases of OSC. RESULTS: WPOI-5 predicts OCM in pT1 patients, compared with WPOI-4/WPOI-3 (p \u3c 0.0001). Most pT1 WPOI-5 tumors had DOI of 4-5 mm (24/59 or 40.7%). Only two pT1 WPOI-5 tumors had DOI \u3c 4 mm (3.0 and 3.5 mm). If END were performed in this pT1 cohort for all WPOI-5 OSC patients regardless of DOI, OR all OSC patients with DOI ≥ 4 mm regardless of WPOI, then no OCM would be missed (p = 0.017, 100% sensitivity, 29% specificity, 77% positive predictive value, 23% negative predictive value). With respect to intraoperative WPOI-5 determination, the accuracy, sensitivity, and specificity was 92.16, 73.33, and 100.0%, respectively. CONCLUSIONS: DOI ≥ 4 mm is the dominant predictor of OCM. For the rare WPOI-5 OSC with DOI \u3c 4 mm, it is reasonable to suggest that surgeons perform END. WPOI-5 may be accurately determined intraoperatively. As microscopic instruction is needed to accurately assess WPOI-5, a teaching link is included in this manuscript