Polycystic ovary syndrome is the most common endocrine disorder affecting women of reproductive age. A number of criteria have been developed for clinical diagnosis of polycystic ovary syndrome, with the Rotterdam criteria being the most inclusive. Evidence suggests that polycystic ovary syndrome is significantly heritable, and previous studies have identified genetic variants associated with polycystic ovary syndrome diagnosed using different criteria. The widely adopted electronic health record system provides an opportunity to identify patients with polycystic ovary syndrome using the Rotterdam criteria for genetic studies.
To identify novel associated genetic variants under the same phenotype definition, we extracted polycystic ovary syndrome cases and unaffected controls based on the Rotterdam criteria from the electronic health records and performed a discovery-validation genome-wide association study.
We developed a polycystic ovary syndrome phenotyping algorithm on the basis of the Rotterdam criteria and applied it to 3 electronic health record-linked biobanks to identify cases and controls for genetic study. In the discovery phase, we performed an individual genome-wide association study using the Geisinger MyCode and the Electronic Medical Records and Genomics cohorts, which were then meta-analyzed. We attempted validation of the significant association loci (P<1×10-6) in the BioVU cohort. All association analyses used logistic regression, assuming an additive genetic model, and adjusted for principal components to control for population stratification. An inverse-variance fixed-effect model was adopted for meta-analysis. In addition, we examined the top variants to evaluate their associations with each criterion in the phenotyping algorithm. We used the STRING database to characterize protein-protein interaction network.
Using the same algorithm based on the Rotterdam criteria, we identified 2995 patients with polycystic ovary syndrome and 53,599 population controls in total (2742 cases and 51,438 controls from the discovery phase; 253 cases and 2161 controls in the validation phase). We identified 1 novel genome-wide significant variant rs17186366 (odds ratio [OR]=1.37 [1.23, 1.54], P=2.8×10-8) located near SOD2. In addition, 2 loci with suggestive association were also identified: rs113168128 (OR=1.72 [1.42, 2.10], P=5.2×10-8), an intronic variant of ERBB4 that is independent from the previously published variants, and rs144248326 (OR=2.13 [1.52, 2.86], P=8.45×10-7), a novel intronic variant in WWTR1. In the further association tests of the top 3 single-nucleotide polymorphisms with each criterion in the polycystic ovary syndrome algorithm, we found that rs17186366 (SOD2) was associated with polycystic ovaries and hyperandrogenism, whereas rs11316812 (ERBB4) and rs144248326 (WWTR1) were mainly associated with oligomenorrhea or infertility. We also validated the previously reported association with DENND1A1. Using the STRING database to characterize protein-protein interactions, we found both ERBB4 and WWTR1 can interact with YAP1, which has been previously associated with polycystic ovary syndrome.
Through a discovery-validation genome-wide association study on polycystic ovary syndrome identified from electronic health records using an algorithm based on Rotterdam criteria, we identified and validated a novel genome-wide significant association with a variant near SOD2. We also identified a novel independent variant within ERBB4 and a suggestive association with WWTR1. With previously identified polycystic ovary syndrome gene YAP1, the ERBB4-YAP1-WWTR1 network suggests involvement of the epidermal growth factor receptor and the Hippo pathway in the multifactorial etiology of polycystic ovary syndrome.

A recurrent YAP1-TFE3 gene fusion has been identified in WWTR1-CAMTA1-negative epithelioid hemangioendotheliomas arising in soft tissue, bone, and lung, but not in liver. We present the first case of TFE3-rearranged hepatic epithelioid hemangioendothelioma in a 39-year-old Taiwanese woman. Computed tomography scan revealed multifocal, ill-defined nodules involving both hepatic lobes. She then underwent deceased donor liver transplantation. Histologically, the tumors in the liver explant showed a biphasic growth pattern. One component was composed of dilated and well-formed blood vessels lined by epithelioid cells with abundant eosinophilic cytoplasm, mimicking an alveolar pattern, whereas the other component was composed of cords and single cells, featuring intracytoplasmic vacuoles, separated by a myxoid stroma. The tumor cells showed vesicular nuclei and small indistinct nucleoli with mild to moderate cytologic atypia. Most tumor cells showed factor VIII, CD34, CD31, and TFE3 positivity in immunohistochemical study. Fluorescence in situ hybridization analysis for the tumor cells exhibited TFE3 gene rearrangement. The patient is currently alive, and no post-operative tumor recurrence developed during a 13-year follow-up. Awareness of this rare vasoformative variant and identification of the gene rearrangement would be helpful on differential diagnosis with other high-grade carcinoma and angiosarcoma of liver.

Malignant thoracic epithelioid vascular tumors are an uncommon and heterogenous group of tumors that include low-grade to intermediate-grade epithelioid hemangioendothelioma (EHE) and high-grade epithelioid angiosarcoma (EAS). We examine the morphologic and immunohistochemical features of 52 malignant epithelioid vascular tumors (10 low-grade EHE, 29 intermediate-grade EHE, and 13 EAS) involving the thorax (lung, pleura, mediastinum, heart, great vessels) including cases with exclusively thoracic disease (35) and with multiorgan disease including the thorax (17). Intermediate-grade EHE differs from low-grade EHE by the presence of necrosis, increased mitotic activity, and increased atypia. Morphologic features such as intranuclear inclusions, intracytoplasmic vacuoles, and stromal changes (chondroid, myxoid, or hyalinized stroma) are seen more frequently in EHE, whereas blood lakes, proliferation of slit-like vessels, and prominent nucleoli favor EAS. Fluorescence in situ hybridization analysis showed CAMTA1-WWTR1 fusions in 4/7 low-grade and 23/23 intermediate-grade EHE (P<0.001). In EAS, CAMTA1 rearrangement was negative in all cases, whereas a WWTR1 complex abnormality was found in 1/5 cases (P<0.001). This offers an objective means of differentiating intermediate-grade EHE from EAS, especially on limited biopsies. All cases show expression of at least 1 vascular marker, which allows differentiation from primary thoracic epithelial malignancies, although keratin expression is a potential pitfall with 29% of EHE and 25% of EAS showing keratin expression. Survival analysis shows that higher tumor grade for all tumors (P=0.026) as well as lung and pleural tumors only (P=0.010) and the presence of pleural involvement in lung and/or pleural tumors (P=0.042) correlate with poor prognosis.