Citations

Polygenic scores (or genetic risk scores) quantify the aggregate of small effects from many common genetic loci that have been associated with a trait through genome-wide association. Polygenic scores were first used successfully in schizophrenia and have since been applied to multiple phenotypes including multiple sclerosis, rheumatoid arthritis, and height. Because human height is an easily-measured and complex polygenic trait, polygenic height scores provide exciting insights into the predictability of aggregate common variant effect on the phenotype. Shawn Bradley is an extremely tall former professional basketball player from Brigham Young University and the National Basketball Association (NBA), measuring 2.29 meters (7 ′ 6 ″ , 99.99999th percentile for height) tall, with no known medical conditions. Here, we present a case where a rare combination of common SNPs in one individual results in an extremely high polygenic height score that is correlated with an extreme phenotype. While polygenic scores are not clinically significant in the average case, our findings suggest that for extreme phenotypes, polygenic scores may be more successful for the prediction of individuals.

OBJECTIVES: Our aim was to characterize upper gastrointestinal (UGI) symptoms and associations in individuals with diabetes mellitus (DM) who had undergone evaluation of gastric emptying (GE) and accommodation (GA) at a referral center. METHODS: From the Mayo Clinic Rochester electronic medical records of adults with diabetes types 1 and 2 (DM1 and DM2) evaluated between January 1997 and December 2015, we extracted demographics, UGI symptoms, current medications, treatments for diabetes, GE solids by scintigraphy, GA by single photon emission computed tomography (SPECT), and diabetes complications. We compared subgroups with delayed (GE at 2 h <25% or GE at 4 h <75%), rapid (GE at 1 h > 35%), and normal GE, as well as reduced (<428 mL) and normal GA. RESULTS: We reviewed 108 patients (60.2% females, median age 49.0 years). Overall, 71.3% had DM2; one-third of these were insulin dependent and had fairly well-controlled diabetes (median HbA1c 6.7% (IQR 6.2; 7.9)). Manifestations of diabetic triopathy (peripheral neuropathy, nephropathy, and retinopathy) were uncommon at presentation with UGI symptoms. Nausea was the most common symptom (80.6%). There were single or combined GE (total 56%: rapid in 37%, slow in 19%) and GA (total 39%) abnormalities; there was normal GA and GE in 28%; 40.3% of the DM2 patients had accelerated GE at 1 h. GE at 1 h is associated with nausea/vomiting, and fasting gastric volume is associated with bloating. CONCLUSIONS: Among referred diabetic patients with UGI symptoms, GE and GA testing identifies potential targets for individualizing treatment and avoidance of empirical trials for the 28% with no disturbance of GE and GA.

AbstractBetween 1967 and 2017, 361 patients with myeloproliferative neoplasms (MPN), age ≤ 40 years, were seen at our institution, constituting 12% of all MPN patients (n = 3023) seen during the same time period; disease‐specific incidences were 12% in polycythemia vera (PV; n = 79), 20% in essential thrombocythemia (ET; n = 219) and 5% in primary myelofibrosis (PMF; n = 63). Compared to their older counterparts, younger patients were more likely to present with low risk disease (P < .001) and display female preponderance in ET (P = .04), lower incidence of arterial events overall (P < .001), and higher incidence of venous thrombosis in PV (P = .01). Younger patients were also more likely to express CALR mutations, in ET and PMF, normal karyotype, in PV and PMF, and lower incidence of high molecular risk mutations in PMF (P significant in all instances). Over median follow‐up of 11.3, 13, and 7.1 years for PV, ET, and PMF, leukemic transformations were respectively documented in 4%, 2%, and 10% (P values 0.1‐0.9) while incidences of fibrotic progression in PV (22%) and ET (16%) were expectedly higher in young patients, because of their longer survival (P < .001). Median survival in young patients was 37 years for PV, 35 for ET and 20 for PMF; the corresponding values were 22, 22, and 8 years for ages 41‐60 years and 10, 11, and 3 years for ages >60 years (P < .001). Young MPN patients comprise a unique disease subset defined by an attenuated‐risk cytogenetic and mutational backdrop and conspicuously longer survival compared to their older counterparts, which requires assertion during patient counseling.

AbstractBreast cancer is the most common cancer of adolescents and young adult (AYA) women aged 15 to 39 years, accounting for 5.6% of all invasive breast cancer in women. In comparison with older women, AYAs are more likely to have familial cancer predisposition genes, larger breast tumors, unfavorable biological characteristics, distant metastatic disease at diagnosis, and adverse outcome. Endocrine therapy and some chemotherapy recommendations differ between young and older women. AYAs require coordinated multidisciplinary care, treatment regimens that minimize late effects such as premature menopause and osteoporosis, and proactive management of psychological and sexual health during and after cancer treatment.

Abstract Ewing sarcoma is the second most common sarcoma of the bone, afflicting predominantly the pediatric population. Although patients with localized disease exhibit favorable survival rates, patients with metastatic disease suffer a dismal 5-year rate of approximately 25%. Thus, there is a great need to develop treatments to combat the disseminated disease. Ubiquitin-specific protease 6 (USP6/TRE17) has been implicated as the key etiologic factor in several benign mesenchymal tumors, including nodular fasciitis and aneurysmal bone cyst (ABC). However, the role of USP6 in the biology of malignant entities remains unexplored. Previously, it was observed that USP6 is sufficient to drive formation of tumors mimicking ABC and nodular fasciitis, and that it functions through JAK1/STAT3 signaling. However, in the context of Ewing sarcoma, USP6 does not enhance the transformation, but rather triggers an IFN response signature, both in cultured Ewing sarcoma cells in vitro and in clinical specimens in vivo. Not only does USP6 independently induce activation of the IFN signaling mediators, JAK1 and STAT1, but it also renders Ewing sarcoma cells exquisitely responsive to exogenous IFNs, potentiating activation of STAT1 and STAT3. Furthermore, IFNβ (a type I IFN) induces apoptosis specifically in USP6-positive but not USP6-negative Ewing sarcoma cells. Finally, apoptosis is mediated through the proapoptotic ligand TRAIL, which is synergistically induced by type I IFN and USP6. Implications: These findings provide the first insights into USP6 functions in a clinically relevant malignant entity, and raise the possibility of using IFN for targeting USP6-positive Ewing sarcoma.

Abstract The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here we show that c-MYC itself is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (~10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic c-MYC activation include focally amplified distal enhancers or translocation of highly active enhancers from other genes to within topologically associating domains containing the c-MYC gene locus. The clinical outcome for patients with high levels of c-MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish c-MYC as a bona fide oncogene in a clinically significant group of high risk childhood neuroblastomas. Citation Format: Mark W. Zimmerman, Yu Liu, Shuning He, Adam D. Durbin, Brian J. Abraham, John Easton, Ying Shao, Xu Beisi, Shizhen Zhu, Xiaoling Zhang, Zhaodong Li, Nina Weichert-Leahey, Richard A. Young, Jinghui Zhang, A. Thomas Look. c-MYC drives a subset of high-risk pediatric neuroblastoma and is activated through mechanisms including enhancer hijacking and focal enhancer amplification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4135.

Abstract Our goal is to identify novel targeted therapies for Ewing sarcoma (ES). ES is a devastating malignancy that predominantly affects children and young adults. It is the second most common cancer of the bone, yet in contrast to many other malignancies, survival rates have not improved for decades. For patients with localized disease, no biomarkers exist to predict recurrence or response to chemotherapy. For those with metastatic disease, chemotherapy is largely ineffective, and 5-year survival rates have stagnated at approximately 20%. Thus, there is an urgent need to identify biomarkers that can predict recurrence and response to therapy, as well as identify novel targeted therapies to combat this lethal disease. USP6 is the key etiologic agent in several benign bone and soft tissue tumors (BSTTs), where its chromosomal translocation results in overexpression. USP6 encodes a deubiquitylating enzyme, and our prior studies identified the tyrosine kinase Jak1 as an essential substrate of USP6 during BSTT development. Jak1 levels are dramatically elevated in USP6-overexpressing cells, leading to phosphorylation and activation of STAT transcription factors. We recently discovered that USP6 is also highly expressed in multiple sarcomas, including ES. Since Jak1-STATs play a central in mediating response to interferon (IFN), we hypothesized that USP6 might cause dysregulated IFN signaling in ES. Microarray and RNA-sequencing analysis revealed that USP6 by itself induced an IFN-response gene signature, both in immortalized, patient-derived ES cells and in primary human ES tumors. USP6+ ES cells were found to be exquisitely sensitive to exogenous IFN compared to USP6- ES cells, with both prolonged and heightened STAT1 and STAT3 activation observed. Furthermore, IFN selectively induced apoptosis of USP6+ but not USP6- ES cells. Gene expression analysis confirmed that in USP6+ ES cells, IFN synergistically induced expression of numerous IFN-stimulated genes (ISGs), including the pro-apoptotic ligand TRAIL. CRISPR-mediated depletion of TRAIL completely abrogated IFN-induced death of USP6+ ES cells. In sum, these results identify USP6 as a potential novel biomarker that may predict sensitivity of ES to targeted IFN therapy. This abstract is also being presented as Poster B11. Citation Format: Ian Henrich, Rob Young, Laura Quick, Xiaoke Wang, Andre Oliveira, Margaret Chou. Ubiquitin-specific protease 6 (USP6) oncogene confers sensitivity of Ewing sarcoma to interferon cytotoxicity [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr PR08.