Bi-allelic genetic variants in the translational GTPases GTPBP1 and GTPBP2 cause a distinct identical neurodevelopmental syndrome.

The homologous genes GTPBP1 and GTPBP2 encode GTP-binding proteins 1 and 2, which are involved in ribosomal homeostasis. Pathogenic variants in GTPBP2 were recently shown to be an ultra-rare cause of neurodegenerative or neurodevelopmental disorders (NDDs). Until now, no human phenotype has been linked to GTPBP1. Here, we describe individuals carrying bi-allelic GTPBP1 variants that display an identical phenotype with GTPBP2 and characterize the overall spectrum of GTP-binding protein (1/2)-related disorders. In this study, 20 individuals from 16 families with distinct NDDs and syndromic facial features were investigated by whole-exome (WES) or whole-genome (WGS) sequencing. To assess the functional impact of the identified genetic variants, semi-quantitative PCR, western blot, and ribosome profiling assays were performed in fibroblasts from affected individuals. We also investigated the effect of reducing expression of CG2017, an ortholog of human GTPBP1/2, in the fruit fly Drosophila melanogaster. Individuals with bi-allelic GTPBP1 or GTPBP2 variants presented with microcephaly, profound neurodevelopmental impairment, pathognomonic craniofacial features, and ectodermal defects. Abnormal vision and/or hearing, progressive spasticity, choreoathetoid movements, refractory epilepsy, and brain atrophy were part of the core phenotype of this syndrome. Cell line studies identified a loss-of-function (LoF) impact of the disease-associated variants but no significant abnormalities on ribosome profiling. Reduced expression of CG2017 isoforms was associated with locomotor impairment in Drosophila. In conclusion, bi-allelic GTPBP1 and GTPBP2 LoF variants cause an identical, distinct neurodevelopmental syndrome. Mutant CG2017 knockout flies display motor impairment, highlighting the conserved role for GTP-binding proteins in CNS development across species.

Microbial contamination and composition of oral samples subjected to clinical whole genome sequencing.

Biological material from the oral cavity is an excellent source of samples for genetic diagnostics. This is because collection is quick, easy-to-access, and non-invasive. We have set-up clinical whole genome sequence testing for patients with suspected hereditary disease. Beside the excellent quality of human DNA that can be isolated from such samples, we observed the presence of non-human DNA sequences at varying percentages. We investigated the proportion of non-human mapped reads (NHMR) sequenced from buccal swabs and saliva, the type of microbial genomes from which they were derived, and impact on molecular classification. Read sequences that did not map to the human reference genome were aligned to complete reference microbial reference sequences from the National Center for Biotechnology Information's (NCBI) RefSeq database using Kraken2. Out of 765 analyzed samples over 80% demonstrated more than 5% NHMRs. The majority of NHMRs were from bacterial genomes (average 69%, buccal swabs and 54% saliva), while the proportion of viruses was low, averaging 0.32% (buccal swabs) and 0.07% (saliva). We identified more than 30 different bacterial families of which Streptococcus mitis and Rothia mucilaginosa were the most common species. Importantly, the level of contamination did not impact the diagnostic yield.

Secondary findings in a large Pakistani cohort tested with whole genome sequencing.

Studies on genomic secondary findings (SFs) are diverse in participants' characteristics, sequencing methods, and versions of the ACMG SF list. Based on whole genome sequencing and the version 3.1 of the ACMG SF list, we studied SFs in 863 individuals from five different regions in Pakistan. We identified 24 ACMG SFs in 23 (2.7%) of 863 individuals: 18 of 24 were related to cardiovascular disease and four to cancer syndromes. In addition to ACMG SFs, we identified 16 (1.9%) participants with pathogenic and likely pathogenic variants in genes that were not related to the participants' clinical conditions but with clear medical actionability (non-ACMG SFs): 4 of 16 were related to eye diseases, two to metabolic disorders, and two to urinary system disorders. By testing a large Pakistani cohort with whole genome sequencing, we concluded that in countries such as Pakistan, the ACMG SF list could be expanded, and our non-ACMG SF list is one example.

Potential Refinement of Recurrence Score by pSTAT3 Status.

The likelihood of recurrence in breast cancer patients with hormone receptor-positive (HR-positive) tumors is influenced by clinical, histopathological, and molecular features. Recent studies suggested that activated STAT3 (pSTAT3) might serve as a biomarker of outcome in breast cancer patients. In the present work, we have analyzed the added value of pSTAT3 to OncotypeDx Recurrence Score (RS) in patient prognostication. We have found that patients with low RS (<26) and low pSTAT3 might represent a population at a higher risk for cancer recurrence. Furthermore, we have observed that a positive pSTAT3 score alone can be a favorable marker for patients with HR-positive breast cancer under the age of 50. In an era of personalized medicine, these findings warrant further appraisal of chemotherapy benefit in this population.

Assessment and Efficacy of Low-Dose CT Screening and Primary Care Providers Perspective on Lung Cancer Screening: An Institutional Review.

Lung cancer is the most common cause of death in both men and women. The United States Preventive Services Task Force (USPSTF) recommends annual lung screening with low-dose computed tomography (LDCT) chest for individuals aged 55-80 who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years. We reviewed the electronic medical records of patients visiting our outpatient clinic over a period of one year. We included all eligible individuals according to USPSTF guidelines for LDCT to identify screening rates at our institution. All primary care physicians, including residents and attendings, were given a prepared questionnaire to understand their beliefs and concerns with the implementation of this program. A total of 13,500 patients visited the outpatient clinic and 1178 were eligible for LDCT. Forty-five percent (45%) of patients received LDCT screening, which was higher than the national average of 2%-5%. A total of 50 primary care providers were included in the survey. The majority of the providers were aware of the USPSTF guidelines and believed that patients with multiple comorbidities and insurance issues were barriers in initiating LDCT screening. Lung cancer screening is an important component in cancer preventive strategies. Widespread awareness among the primary care providers and the public is extremely necessary for improving the use of LDCT.

Do High Rates of Atypical Glandular Cells Correlate With Higher Incidence of Disease in a Large Safety Net Hospital.

OBJECTIVE: The aim of the study was to describe the incidence and correlates of atypical glandular cell (AGC) Pap tests in a low socioeconomic status, underserved population. MATERIALS AND METHODS: Medical records of patients with AGC Pap tests at a single institution were reviewed from January 2013 to August 2019. Baseline characteristics were extracted including age, body mass index, birth control, abnormal uterine bleeding, and human papillomavirus (HPV). All colposcopy and endometrial biopsies were classified into negative/low-risk (polyps, tubular metaplasia, microglandular hyperplasia, cervical intraepithelial neoplasia 1) and high-risk (HR) lesions (cervical intraepithelial neoplasia 2/3, adenocarcinoma in situ, endometrial hyperplasia, cervical cancer, endometrial cancer). Logistic regression identified significant associations. Sixty-eight randomly selected AGC cytology slides from the cohort and 32 non-AGC slides outside the cohort were blindly reviewed by 6 pathologists. Fleiss κ interrater agreement was assessed. RESULTS: Seven hundred forty patients with AGC Pap tests were identified (0.8% of all Pap tests performed during this time). After excluding for incomplete data, 478 patients were included. Sixty-three patients had HR lesions (13.3%). Patients with HR lesions had increased odds of abnormal uterine bleeding (odds ratio = 4.32, p < .001) and HPV positivity (odds ratio = 10.89, p < .001) when compared with patients with low-risk lesions. The κ agreement was 0.21 for all cases and 0.18 for AGC alone. CONCLUSIONS: This population falls within the national averages for AGC Pap tests. There was an increased risk of HR lesions in patients with abnormal uterine bleeding and HPV positivity. The rate of HR lesions among AGC Pap tests was at the lower end of values in the literature. After blinded pathologist review, interobserver κ agreement was low for AGC Pap tests.

Diagnosing Anal Squamous Intraepithelial Lesions With and Without p16: An Interobserver Variability Study.

OBJECTIVE: Morphologic diagnosis and grading of anal squamous intraepithelial lesions (ASILs) are challenging. In this study, we investigated interobserver variability and p16 utility in accurately grading anal SIL. MATERIALS AND METHODS: Six pathologists evaluated the degree of SIL on hematoxylin and eosin slides from 146 anal biopsies, followed by the review of both p16 and hematoxylin and eosin slides in cases where p16 was previously performed. κ was calculated in the following 4 ways: (A) 4-tiered diagnosis (negative for SIL [NSIL], anal intraepithelial neoplasia [AIN 1, AIN 2, AIN 3]); (B) 3-tiered diagnosis (NSIL and AIN 1 [pooled], AIN 2, AIN 3); (A) 3-tiered diagnosis (NSIL, low-grade SIL, high-grade SIL [HSIL]); and (D) 2-tiered diagnosis (no HSIL, HSIL). RESULTS: There is only moderate agreement with a 4-tiered diagnosis with or without p16 (κ = 0.48-0.57). There is substantial agreement when AIN 2 and AIN 3 are pooled as HSIL in cases with or without p16 review (κ = 0.71-0.78). There is almost perfect agreement with a 2-tiered diagnosis of negative for HSIL and HSIL both in cases where p16 was used and where p16 was not required, with the best agreement for a 2-tiered diagnosis with concurrent p16 review. CONCLUSIONS: This study highlights the importance of a judicious use of p16 for diagnosis. When there is no need for p16 by the Lower Anogenital Squamous Terminology guidelines, interobserver agreement was substantial to almost perfect with a 2-tiered diagnosis. However, when its use is indicated but it is not performed or reviewed, the agreement is much lower even with a 2-tiered diagnosis. Rational use of p16 will ensure diagnostic accuracy and the best possible patient care.

Spleen Stiffness as Predictor of Esophageal Varices in Cirrhosis of Different Etiologies.

The purpose of this study is to determine whether esophageal varices (EV) can be identified through the evaluation of spleen stiffness (SSM) via acoustic radiation force impulse (ARFI). A total of 135 patients suffering from cirrhosis underwent a clinical exam, laboratory tests, abdominal ultrasound, liver stiffness (LSM) measurement, SSM evaluation and upper gastrointestinal endoscopy. Based on the endoscopy results, the patients were classified into three groups: those with no evident EV, those with small EV and those with varices needing treatment (VNT). Patients with EV of any grade had significantly higher average SSM values over those with no EV (3.37 m/s versus 2.79 m/s, p-value < 0.001), while patients with VNT showed an even greater difference (3.96 m/s versus 2.93 m/s, p-value < 0.001). SSM proved to be an excellent method of predicting patients with VNT.

De Novo Variants in TAOK1 Cause Neurodevelopmental Disorders.

De novo variants represent a significant cause of neurodevelopmental delay and intellectual disability. A genetic basis can be identified in only half of individuals who have neurodevelopmental disorders (NDDs); this indicates that additional causes need to be elucidated. We compared the frequency of de novo variants in patient-parent trios with (n = 2,030) versus without (n = 2,755) NDDs. We identified de novo variants in TAOK1 (thousand and one [TAO] amino acid kinase 1), which encodes the serine/threonine-protein kinase TAO1, in three individuals with NDDs but not in persons who did not have NDDs. Through further screening and the use of GeneMatcher, five additional individuals with NDDs were found to have de novo variants. All eight variants were absent from gnomAD (Genome Aggregation Database). The variant carriers shared a non-specific phenotype of developmental delay, and six individuals had additional muscular hypotonia. We established a fibroblast line of one mutation carrier, and we demonstrated that reduced mRNA levels of TAOK1 could be increased upon cycloheximide treatment. These results indicate nonsense-mediated mRNA decay. Further, there was neither detectable phosphorylated TAO1 kinase nor phosphorylated tau in these cells, and mitochondrial morphology was altered. Knockdown of the ortholog gene Tao1 (Tao, CG14217) in Drosophila resulted in delayed early development. The majority of the Tao1-knockdown flies did not survive beyond the third instar larval stage. When compared to control flies, Tao1 knockdown flies revealed changed morphology of the ventral nerve cord and the neuromuscular junctions as well as a decreased number of endings (boutons). Furthermore, mitochondria in mutant flies showed altered distribution and decreased size in axons of motor neurons. Thus, we provide compelling evidence that de novo variants in TAOK1 cause NDDs.

Novel pathogenic variants and multiple molecular diagnoses in neurodevelopmental disorders.

BACKGROUND: Rare denovo variants represent a significant cause of neurodevelopmental delay and intellectual disability (ID). METHODS: Exome sequencing was performed on 4351 patients with global developmental delay, seizures, microcephaly, macrocephaly, motor delay, delayed speech and language development, or ID according to Human Phenotype Ontology (HPO) terms. All patients had previously undergone whole exome sequencing as part of diagnostic genetic testing with a focus on variants in genes implicated in neurodevelopmental disorders up to January 2017. This resulted in a genetic diagnosis in 1336 of the patients. In this study, we specifically searched for variants in 14 recently implicated novel neurodevelopmental disorder (NDD) genes. RESULTS: We identified 65 rare, protein-changing variants in 11 of these 14 novel candidate genes. Fourteen variants in CDK13, CHD4, KCNQ3, KMT5B, TCF20, and ZBTB18 were scored pathogenic or likely pathogenic. Of note, two of these patients had a previously identified cause of their disease, and thus, multiple molecular diagnoses were made including pathogenic/likely pathogenic variants in FOXG1 and CDK13 or in TMEM237 and KMT5B. CONCLUSIONS: Looking for pathogenic variants in newly identified NDD genes enabled us to provide a molecular diagnosis to 14 patients and their close relatives and caregivers. This underlines the relevance of re-evaluation of existing exome data on a regular basis to improve the diagnostic yield and serve the needs of our patients.

Development of an evidence-based algorithm that optimizes sensitivity and specificity in ES-based diagnostics of a clinically heterogeneous patient population.

PURPOSE: Next-generation sequencing (NGS) is rapidly replacing Sanger sequencing in genetic diagnostics. Sensitivity and specificity of NGS approaches are not well-defined, but can be estimated from applying NGS and Sanger sequencing in parallel. Utilizing this strategy, we aimed at optimizing exome sequencing (ES)-based diagnostics of a clinically diverse patient population. METHODS: Consecutive DNA samples from unrelated patients with suspected genetic disease were exome-sequenced; comparatively nonstringent criteria were applied in variant calling. One thousand forty-eight variants in genes compatible with the clinical diagnosis were followed up by Sanger sequencing. Based on a set of variant-specific features, predictors for true positives and true negatives were developed. RESULTS: Sanger sequencing confirmed 81.9% of ES-derived variants. Calls from the lower end of stringency accounted for the majority of the false positives, but also contained ~5% of the true positives. A predictor incorporating three variant-specific features classified 91.7% of variants with 100% specificity and 99.75% sensitivity. Confirmation status of the remaining variants (8.3%) was not predictable. CONCLUSIONS: Criteria for variant calling in ES-based diagnostics impact on specificity and sensitivity. Confirmatory sequencing for a proportion of variants, therefore, remains a necessity. Our study exemplifies how these variants can be defined on an empirical basis.

A Provocative Molecular Link between Mammographic Density and BRCA1-loss associated TNBC.

Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that has a high mortality rate and disproportionately affects young African American (AA) women who carry mutations in the BRCA1 gene. Approximately 80% of breast cancers which develop in BRCA1-mutant carriers will have TNBC and the molecular mechanism facilitating tumor development is unclear. Our earlier work suggested Ubc9 to play a critical role in BRCA1 loss mediated TNBC cell migration and metastasis. Collagen is one of the major components of the stromal extracellular matrix (ECM) network that influences tissue density. Its re-organization act as a scaffold aiding cancer cells to migrate causing metastasis. Ubc9 is known to increase the production of collagen, a key component of fibroglandular breast tissue, as well as tumorigenesis. Our work is based on the hypothesis that loss of BRCA1 in women with high breast density causes abnormal Ubc9 levels which upregulates collagen, fibronectin and inhibits SIRT1, ß-catenin expression facilitating TNBC. We tested this hypothesis by studying the expression of total collagen, fibronectin, Ubc9, SIRT1, ß-catenin in BRCA1 mutant TNBC cells and tumor sample derived from patient with dense breasts using immunofluorescence, immunohistochemistry, and collagen assay. Our results suggest for the first time that mutation or loss of BRCA1 function in women with fibrocystic breasts can lead to over expression of Ubc9, induction of collagen and; fibronectin, inhibition of SIRT1 and nuclear accumulation of ß-catenin which could contribute to TNBC development. This network will aid not only in the identification of potential mechanism-based biomarkers that could detect disease early, but also enforce preventive measures that could reduce the risk for TNBC in women with high MD thus reducing the mortality associated with these cancers to achieve health equity.

A comprehensive global genotype-phenotype database for rare diseases.

BACKGROUND: The ability to discover genetic variants in a patient runs far ahead of the ability to interpret them. Databases with accurate descriptions of the causal relationship between the variants and the phenotype are valuable since these are critical tools in clinical genetic diagnostics. Here, we introduce a comprehensive and global genotype-phenotype database focusing on rare diseases. METHODS: This database (CentoMD ®) is a browser-based tool that enables access to a comprehensive, independently curated system utilizing stringent high-quality criteria and a quickly growing repository of genetic and human phenotype ontology (HPO)-based clinical information. Its main goals are to aid the evaluation of genetic variants, to enhance the validity of the genetic analytical workflow, to increase the quality of genetic diagnoses, and to improve evaluation of treatment options for patients with hereditary diseases. The database software correlates clinical information from consented patients and probands of different geographical backgrounds with a large dataset of genetic variants and, when available, biomarker information. An automated follow-up tool is incorporated that informs all users whenever a variant classification has changed. These unique features fully embedded in a CLIA/CAP-accredited quality management system allow appropriate data quality and enhanced patient safety. RESULTS: More than 100,000 genetically screened individuals are documented in the database, resulting in more than 470 million variant detections. Approximately, 57% of the clinically relevant and uncertain variants in the database are novel. Notably, 3% of the genetic variants identified and previously reported in the literature as being associated with a particular rare disease were reclassified, based on internal evidence, as clinically irrelevant. CONCLUSIONS: The database offers a comprehensive summary of the clinical validity and causality of detected gene variants with their associated phenotypes, and is a valuable tool for identifying new disease genes through the correlation of novel genetic variants with specific, well-defined phenotypes.

Novel GNB1 mutations disrupt assembly and function of G protein heterotrimers and cause global developmental delay in humans.

Global developmental delay (GDD), often accompanied by intellectual disability, seizures and other features is a severe, clinically and genetically highly heterogeneous childhood-onset disorder. In cases where genetic causes have been identified, de novo mutations in neuronally expressed genes are a common scenario. These mutations can be best identified by exome sequencing of parent-offspring trios. De novo mutations in the guanine nucleotide-binding protein, beta 1 (GNB1) gene, encoding the Gß1 subunit of heterotrimeric G proteins, have recently been identified as a novel genetic cause of GDD. Using exome sequencing, we identified 14 different novel variants (2 splice site, 2 frameshift and 10 missense changes) in GNB1 in 16 pediatric patients. One mutation (R96L) was recurrently found in three ethnically diverse families with an autosomal dominant mode of inheritance. Ten variants occurred de novo in the patients. Missense changes were functionally tested for their pathogenicity by assaying the impact on complex formation with Gγ and resultant mutant Gßγ with Gα. Signaling properties of G protein complexes carrying mutant Gß1 subunits were further analyzed by their ability to couple to dopamine D1R receptors by real-time bioluminescence resonance energy transfer (BRET) assays. These studies revealed altered functionality of the missense mutations R52G, G64V, A92T, P94S, P96L, A106T and D118G but not for L30F, H91R and K337Q. In conclusion, we demonstrate a pathogenic role of de novo and autosomal dominant mutations in GNB1 as a cause of GDD and provide insights how perturbation in heterotrimeric G protein function contributes to the disease.

Metastatic colorectal cancer in a cirrhotic liver with synchronous hepatocellular carcinoma.

We are reporting a case of a patient with a previous history of colorectal cancer (CRC) and cirrhosis, who developed concurrent liver lesions consistent with hepatocellular carcinoma (HCC); a case which is unique due to the low incidence of multiple cancers, particularly HCC in the setting of previous advanced colorectal carcinoma along, in a cirrhotic liver. We will review the known literature on multiple cancer rates found in patients with known colorectal carcinoma. We will then outline this particular patient's presentation, followed by a discussion as to why the particular concurrent development of HCC in the setting of previous CRC is of note.

The 21-gene recurrence score and locoregional recurrence in breast cancer patients.

PURPOSE: Although the 21-gene recurrence score (RS) assay has been validated to assess the risk of distant recurrence in hormone receptor-positive breast cancer patients, the relationship between RS and the risk of locoregional recurrence (LRR) remains unclear. The purpose of this study was to determine if RS is associated with LRR in breast cancer patients and whether this relationship varies based on the type of local treatment [mastectomy or breast-conserving therapy (BCT)]. METHODS: 163 consecutive estrogen receptor-positive breast cancer patients at our institution had an RS generated from the primary breast tumor between August 2006 and October 2009. Patients were treated with lumpectomy and radiation (BCT) (n = 110) or mastectomy alone (n = 53). Patients were stratified using a pre-determined RS of 25 and then grouped according to local therapy type. RESULTS: Median follow-up was 68.2 months. Patients who developed an LRR had stage I or IIA disease, >2 mm surgical margins, and received chemotherapy as directed by RS. While an RS > 25 did not predict for a higher rate of LRR, an RS > 24 was associated with LRR in our subjects. Among mastectomy patients, the 5-year LRR rate was 27.3 % in patients with an RS > 24 versus 10.7 % (p = 0.04) in those whose RS was ≤ 24. RS was not associated with LRR in patients who received BCT. CONCLUSIONS: Breast cancer patients treated with mastectomy for tumors that have an RS > 24 are at high risk of LRR and may benefit from post-mastectomy radiation.

A Novel Pathway that Links Caveolin-1 Down-Regulation to BRCA1 Dysfunction in Serous Epithelial Ovarian Cancer Cells.

Ovarian cancer is the second most common gynecological cancer and the five-year survival rate is only about 40%. High-grade serous carcinoma is the pre-dominant histotype associated with hereditary ovarian cancer and women with inherited mutations in BRCA1 have a lifetime risk of 40-60%. BRCA1 and its isoform BRCA1a are multifunctional proteins that are the most evolutionary conserved of all the other splice variants. Our group has previously reported that BRCA1/1a proteins, unlike K109R and C61G mutants, suppress growth of ovarian cancer cells by tethering Ubc9. In this study we found wild type BRCA1/1a proteins to induce expression of caveolin-1, a tumor suppressor in BRCA1-mutant serous epithelial ovarian cancer (SEOC) cells by immunofluorescence analysis. The K109R and C61G disease associated mutant BRCA1 proteins that do not bind Ubc9 were not as efficient in up-regulation of caveolin-1 expression in SEOC cells. Additionally, immunofluorescence analysis showed BRCA1/1a proteins to induce redistribution of Caveolin-1 from cytoplasm and nucleus to the cell membrane. This is the first study demonstrating the physiological link between loss of Ubc9 binding, loss of growth suppression and loss of Caveolin-1 induction of disease-associated mutant BRCA1 proteins in SEOC cells. Decreased Caveolin-1 expression combined with elevated Ubc9 expression can in the future be used as an early biomarker for BRCA1 mutant SEOC.

BRCA1 proteins regulate growth of ovarian cancer cells by tethering Ubc9.

Mutation in the BRCA1 gene is associated with increased risk for hereditary breast and ovarian cancers. In sporadic ovarian tumors, BRCA1 dysfunction is thought to be common. BRCA1 is a nuclear-cytoplasm shuttling protein. Our group has previously reported that BRCA1 proteins, unlike K109R and cancer-predisposing mutant C61G BRCA1 proteins, bind the sole SUMO E2-conjugating enzyme Ubc9. In this study, we examined the result of altered Ubc9 binding and knockdown on the sub-cellular localization and growth inhibitory function of BRCA1 proteins in ovarian cancer cells. Using live imaging of YFP, RFP-tagged BRCA1 and BRCA1a proteins, our results show enhanced cytoplasmic localization of K109R and C61G mutant BRCA1 proteins in ES-2, NIHOVCAR3 and UWB 1.289 ovarian cancer cells. Down-regulation of Ubc9 in ovarian cancer cells using Ubc9 siRNA resulted in cytoplasmic localization of BRCA1 and BRCA1a proteins. These mutant BRCA1a proteins were impaired in their capacity to inhibit growth of ES-2 ovarian cancer cells. Several ovarian cancer cells, including a BRCA1-null ovarian cancer cell line, showed higher levels of expression of Ubc9. This is the first study demonstrating the physiological link between loss of Ubc9 binding and loss of growth suppression of disease-associated mutant BRCA1a proteins in ovarian cancer cells. BRCA1, by turning off or on Ubc9 binding, regulates growth of ovarian cancers.

Pseudoangiomatous stromal hyperplasia (PASH) of the breast: a series of 24 patients.

Pseudoangiomatous stromal hyperplasia (PASH) is a benign mesenchymal proliferative lesion of the breast. In 2005, only 109 cases had been reported since its initial description in 1986 by Vuitch et al. Our 24 cases represent one of the largest series to be reported from a single institution. We retrospectively reviewed data from 2004 to 2010 of patients diagnosed with PASH by surgical excision or image-guided biopsy. All pathological specimens were reviewed by a single pathologist. The samples were stained for estrogen and progesterone receptors (ER and PR), CD34, and the lymphatic marker D2-40. All but one of 24 (96%) patients presented with breast masses either on imaging or clinically. Fourteen of the 24 patients (58%) were diagnosed on surgical excision, 10 (42%) diagnosed with core needle biopsy, and five (20%) were diagnosed using both techniques. The tumors ranged in size from 0.3 cm to 7.0 cm. All women except two were premenopausal or perimenopausal at diagnosis. Nineteen samples were available for hormonal receptor staining and of these 18 of 19 (95%) were ER or PR positive. PASH was diagnosed in two men, a transgender male on hormones and the other with gynecomastia. The patients' ages ranged from 18 to 86 years old. In addition to PASH other benign histopathological findings include stromal fibrosis and atypical ductal or lobular hyperplasia. Imaging revealed no distinguishing feature for PASH with benign histology. One patient had synchronous ductal carcinoma in-situ (DCIS). Patients were treated with local excision or observation. This study suggests that PASH is primarily a diagnosis of premenopausal and perimenopausal women. Our series supports a hormonal basis for its development due to the positive staining for hormonal receptors. Management is conservative surgery for larger masses with careful observation being an option in patients not at high risk for breast cancer.