tbuckley/cabot-search huggingface dataset:
Monosomic Loss of MIR15A/MIR16-1 Is a Driver of Multiple Myeloma Proliferation and Disease Progression
Authors: Marta Chesi, Caleb K. Stein, Victoria M. Garbitt, Meaghen E. Sharik, Yan W. Asmann, Matteo Bergsagel, Daniel L. Riggs, Seth J. Welsh, Erin W. Meermeier, Shaji K. Kumar, Esteban Braggio, P. Leif Bergsagel
Journal: Blood Cancer Discovery (2020)

Abstract The most common genetic abnormality in multiple myeloma is the deletion of chromosome 13, seen in almost half of newly diagnosed patients. Unlike chronic lymphocytic leukemia, where a recurrent minimally deleted region including MIR15A/MIR16-1 has been mapped, the deletions in multiple myeloma predominantly involve the entire chromosome and no specific driver gene has been identified. Additional candidate loci include RB1 and DIS3, but while biallelic deletion of RB1 is associated with disease progression, DIS3 is a common essential gene and complete inactivation is not observed. The Vk*MYC transgenic mouse model of multiple myeloma spontaneously acquires del(14), syntenic to human chromosome 13, and Rb1 complete inactivation, but not Dis3 mutations. Taking advantage of this model, we explored the role in multiple myeloma initiation and progression of two candidate loci on chromosome 13: RB1 and MIR15A/MIR16-1. Monoallelic deletion of Mir15a/Mir16-1, but not Rb1, was sufficient to accelerate the development of monoclonal gammopathy in wild-type mice and the progression of multiple myeloma in Vk*MYC mice, resulting in increased expression of Mir15a/Mir16-1 target genes and plasma cell proliferation, which was similarly observed in patients with multiple myeloma. Significance: In the absence of a defined, minimally deleted region the significance of del(13) in multiple myeloma has remained controversial. Here we show that haploinsufficiency of Mir15a/Mir16-1, but not Rb1, upregulates the cell cycle–regulatory network, inducing monoclonal gammopathy in mice and promoting multiple myeloma progression in both mice and men. See related commentary by Walker, p. 16. This article is highlighted in the In This Issue feature, p. 5
Lysosomal enzyme cathepsin L mediates resveratrol - induced autophagy and apoptotic cell death in cervical cancer
Authors: Keng-Fu Hsu, Chao-Liang Wu, Yi-Te Yo, Jenn-Ren Hsiao, Ai-Li Shiau, Cheng-Yang Chou
Journal: Cancer Research (2008)

3363  Cathepsins were considered as housekeeping molecules. However, specific functions have been attributed to each one of these lysosomal proteases, i.e. cathepsin L (Cat L) was implicated in many key cellular functions. In this study, we investigate whether the lysosomal pathway and autophagy involved in resveratrol (RSV) -induced cytotoxicity in cervical cancer cells. RSV induced GFP-LC3 aggregation, increased LC3-II expression and autophagosomes by electro-microscopy in cervical cancer cells. RSV also induced cytosolic translocation of cytochrome c, caspase 3 activation and apoptotic cell death in cervical cancer cells. This apoptotic effect was prevented by trans-epoxysuccinyl- L-leucylamido -(4-guanidino)butane, an inhibitor of cathepsins B and L, but not prevented by pepstatin A, an inhibitor of lysosomal cathepsin D. Since cervical cancer cells express little or no cathepsin B immunoreactivity, we further studied the role of Cat L. RSV induced lysosomal membrane permeability, leakage and increased cytosolic immunoreactivity of Cat L. Inhibition of Cat L by small interference RNA, protected cells from RSV cytotoxicity. On the contrary, inhibition of squamous cell carcinoma antigen 1, an endogenous Cat L inhibitor, by siRNA promoted RSV cytotoxicity in cervical cancer cells. Inhibit autophagy response by 3-MA, reduced Cat L activities. In conclusion, we have identified a new cytotoxic mechanism in which the lysosomal enzyme cathepsin L acts as a death signal integrator in cervical cancer cells. In the mean time, SCCA, known as useful tumor marker clinically, may play an anti-apoptotic role through anti-Cat L activity in cervical cancer.
The Mechanisms of Atopic Dermatitis to Asthma in Children (MPAACH) Cohort: Novel Atopic Dermatitis Endotypes
Authors: Jocelyn Biagini Myers, Michael Sherenian, Asel Baatyrbek Kyzy, Rosario Alarcon, Amen An, Zachary Flege, David Morgan, Tammy Gonzalez, Mariana Stevens, Hua He, John Kroner, Daniel Spagna, Brittany Grashel, Lisa Martin, Andrew Herr, Gurjit Khurana Hershey
Journal: Journal of Allergy and Clinical Immunology (2020)
Disulfiram (DSF) pharmacokinetics (PK) and copper PET imaging in a phase Ib study of intravenous (IV) copper loading with oral DSF for patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Tian Zhang, Julie Kephart, Elizabeth Bronson, Monika Anand, Christine Daly, Ivan Spasojevic, Hannah Berg, Olga G. James, Patrick Healy, Susan Halabi, Michael Roger Harrison, Andrew J. Armstrong, Daniel J. George
Journal: Journal of Clinical Oncology (2020)

96 Background: In preclinical models of prostate cancer (PC), DSF reduced tumor growth when co-administered with copper (Cu). Further, intracellular Cu uptake is partially regulated by androgen-receptor signaling. Given these data, we conducted a phase Ib clinical trial of mCRPC patients (pts) receiving Cu with DSF. Methods: Pts with mCRPC were assigned to 1 of 3 cohorts: neuroendocrine PC (NEPC) (A), adenocarcinoma (adenoCA) mCRPC with non-liver/peritoneal metastases (B), and adenoCA mCRPC with liver and/or peritoneal metastases (C). IV CuCl 2 was given weekly for 3 doses with oral daily DSF. After CuCl 2 dosing, daily oral Cu gluconate was started and DSF continued until disease progression as defined by Prostate Cancer Working Group Three (PCWG3). DSF and metabolite MeDDC levels in plasma were sampled at 0, 2, 4, 6 and 8 hours after the first dose and on Cycle 2 Day 1, and measured by HPLC. DSF and MeDDC were evaluated for cytotoxicity in 3 PC cell lines (22Rv1, LnCAP, and PC3) and a prostate epithelial cell line (PWR-1E). mCRPC Cu avidity was measured by 64 Cu PET scan at baseline for all pts. Results: We treated 9 pts with mCRPC, 6 on cohort B and 3 on cohort C. No confirmed PSA declines or radiographic responses were observed in either cohort. Common adverse events included fatigue and psychomotor depression; no grade 4/5 AEs were observed. PK analysis: No DSF was detected in plasma (LOQ = 0.032 ng/mL, LOD = 0.01 ng/mL), whereas MeDDC was measurable in all study samples (LOQ = 0.512 ng/mL). MeDDC exhibited no cytotoxicity activity in PC cell lines. On 64 Cu PET scans, bone metastases showed differential and heterogeneous Cu uptake. Lymph node and pulmonary metastases were evaluable, but not liver metastases due to significant Cu uptake in the liver. Conclusions: Oral DSF is not an effective treatment for mCRPC because it is quickly metabolized into the non-cytotoxic inactive metabolite, MeDDC. As such, this trial has stopped enrollment. Further work is needed to identify a stable DSF formulation so that the conditional lethality of Cu and DSF may be evaluated for treatment of mCRPC. Clinical trial information: NCT02963051.
Inferring the Demographic History of Inbred Species from Genome-Wide SNP Frequency Data
Authors: Paul D Blischak, Michael S Barker, Ryan N Gutenkunst
Journal: Molecular Biology and Evolution (2020)

Demographic inference using the site frequency spectrum (SFS) is a common way to understand historical events affecting genetic variation. However, most methods for estimating demography from the SFS assume random mating within populations, precluding these types of analyses in inbred populations. To address this issue, we developed a model for the expected SFS that includes inbreeding by parameterizing individual genotypes using beta-binomial distributions. We then take the convolution of these genotype probabilities to calculate the expected frequency of biallelic variants in the population. Using simulations, we evaluated the model's ability to coestimate demography and inbreeding using one- and two-population models across a range of inbreeding levels. We also applied our method to two empirical examples, American pumas (Puma concolor) and domesticated cabbage (Brassica oleracea var. capitata), inferring models both with and without inbreeding to compare parameter estimates and model fit. Our simulations showed that we are able to accurately coestimate demographic parameters and inbreeding even for highly inbred populations (F = 0.9). In contrast, failing to include inbreeding generally resulted in inaccurate parameter estimates in simulated data and led to poor model fit in our empirical analyses. These results show that inbreeding can have a strong effect on demographic inference, a pattern that was especially noticeable for parameters involving changes in population size. Given the importance of these estimates for informing practices in conservation, agriculture, and elsewhere, our method provides an important advancement for accurately estimating the demographic histories of these species.
FDG Uptake in the Basal Forebrain as Measured by Digital High-Resolution PET Is a Promising Marker of Basal Forebrain Degeneration in the Lewy Body Disease Spectrum
Authors: Cansu Özden, Lars Frings, Ivayla Apostolova, Catharina Lange, Susanne Klutmann, Gerhard Adam, Peter Bannas, Philipp T. Meyer, Michel J. Grothe, Ralph Buchert
Journal: Clinical Nuclear Medicine (2020)

Cognitive decline in diseases of the Lewy body spectrum (LBS) is linked to dysfunction/degeneration of the basal forebrain (BF). Assessment of glucose metabolism in the BF by FDG PET is hampered by the small size of the BF and limited spatial resolution of conventional PET. This pilot study tested the feasibility of assessing BF glucose metabolism by high-resolution digital PET (dPET).The retrospective study included 12 LBS patients (61-86 years, 5 demented). Whole-brain stereotactic normalization to anatomical standard space was followed by local stereotactic normalization of a 7 × 7 × 7-cm box around the BF to a custom-made 1 × 1 × 1-mm FDG dPET template. FDG uptake was scaled voxelwise to mean FDG uptake in the pons. Scaled FDG uptake in the BF was compared between demented and nondemented LBS patients and tested for correlation with cortical FDG uptake.Scaled FDG uptake in the BF was significantly lower in demented compared with nondemented patients (1.14 ± 0.09 vs 1.25 ± 0.06, P = 0.031). Brain-wide voxel-based testing for correlations with scaled FDG uptake in the BF revealed a large cluster comprising medial and ventrolateral frontal cortex, anterior cingulate cortex, insular cortex, and striatum as well as smaller clusters in motor cortex and occipital cortex (P < 0.001, uncorrected).These results suggest that dementia-associated BF degeneration in LBS can be sensitively measured as reduced BF FDG uptake on dPET. More accurate delineation of the BF based on individual high-resolution MRI might be useful to make optimal use of improved spatial resolution of dPET and to correct for possible disease- and age-dependent partial volume effects.
Non-rising PSA disease progression on C-11 choline PET/CT imaging in patients receiving second generation hormone therapies (2nd-HT).
Authors: Mohamed E. Ahmed, Jack R. Andrews, Ayca Dundar, Masaya Jimbo, Vidhu B. Joshi, Giovanni Motterle, Jeffrey Karnes, Eugene D. Kwon, Alan Haruo Bryce, Ayse T. Kendi, Michael S. Bold
Journal: Journal of Clinical Oncology (2020)

144 Background: Despite having well-recognized limitations, urologists often rely on serial PSA testing as a marker for treatment response or disease progression. To determine if PSA was indeed a reliable marker for treatment response or disease progression, we compared PSA levels against C-11 choline PET/CT in the evaluation of patients with advanced prostate cancer treated with second generation hormonal therapy (2nd-HT). Methods: We retrospectively identified 239 patients who were undergoing treatment with 2nd-HT (enzalutamide or abiraterone) for advanced prostate cancer. While on treatment, patients underwent serial PSA testing and C-11 choline PET/ CTs every 3 – 6 months. Paradoxical response was defined as increasing blood pool-corrected SUVmax of known choline-avid lesions and/or identification of new choline-avid lesions, despite stable or down-trending PSA. Results: Median (IQR) age was 70.4(64.3 – 75.7) years and median (IQR) primary Gleason Score was 8 (7 – 9). In our study, 19% of patients (n = 46/239) who were receiving 2nd-HT exhibited paradoxical response. Median (IQR) PSA and corrected SUVmax at baseline evaluation were 1.3 ng/mL (0.3 – 12.8 ng/mL) and 3.5 (1.8 – 5.8), respectively. Median (IQR) PSA and corrected SUVmax at the time of paradoxical response were 0.4 ng/mL (0.1 – 5.4 ng/mL) and 4.5 (2.8 – 6.8), respectively. The median duration of 2nd-HT treatment prior to detection of paradoxical response was 4.8 months (2.9 – 10.1 months). No significant difference was noted between patients receiving enzalutamide versus abiraterone (p = 0.35). Independent predictors of paradoxical response were prior primary systemic treatment (i.e. hormonal/chemo-hormonal therapy versus local therapy) and patient’s age at time of 2nd-HT initiation on univariate and multivariate analysis. Conclusions: Our retrospective review demonstrated prostate cancer disease progression discordant with PSA down-trending in 19% of patients receiving 2nd-HT. We conclude that in this subset of patients with advanced prostate cancer, PSA may not be a reliable marker of treatment response of disease progression, and routine radiographic evaluation in these patients is warranted.
Outcomes after first-line therapy for immune/immune or immune/VEGF combinations.
Authors: Francesca Jackson-Spence, Agne Jovaisaite, Michael Grant, Wing-Kin Liu, Thomas Butters, Thomas Powles, Bernadett Szabados
Journal: Journal of Clinical Oncology (2020)

706 Background: The introduction of first line immune combination or immune/VEGF therapy in metastatic renal cancer has changed treatment landscape. Here we compare outcomes of these combinations with patients treated with first line sunitinib. The focus is on the impact of subsequent treatments. Methods: This retrospective analysis was performed at Barts Cancer Institute for consecutive patients from April 2015 when front line immune therapy was first used at our institution. Only patients enrolled on reported prospective trials were included to avoid selection bias. Patients were treated with VEGF targeted therapy (n=35) (group V), PD-1 + CTLA4 (n=15) (group I/I) or a combination of PD-L1 + VEGF TKI inhibitor (n=29) (group I/V). The primary analysis focused on the proportion of patients who received second line therapy and their outcome. Results: 79 patients received first line therapy for clear cell RCC. IMDC good, intermediate and poor risk occurred in 27.8%, 60.8% and 11.4% respectively. Front line response rates for V, I/I and I/V groups were 34.3%, 46.7% and 65.5% and PFS in V, I/I and I/V groups were 11mo (95%CI 6-16), 18mo (95% CI 0-41) and 36mo (95% CI 13-59), respectively (P= 0.016). OS in the 3 groups were immature but not significantly different. Second line therapy occurred in 87.5%, 92.9% and 81.8% in the V, I/I and I/V groups respectively (in those who progressed after initial therapy). Second line response rate post first line V, I/I and I/V were 11%, 0% and 0% respectively as per RECIST 1.1. 63% of patients receiving VEGF front line therapy subsequently received immune therapy. 95% of patients receiving first line immune/immune or immune/VEGF combination therapy received VEGF therapy in the second line. Only 70% of patients who progressed on second line therapy got 3 rd line therapy across all arms. Conclusions: Response rates after front line immune combination therapy are modest. The sequencing of PD-1 therapy after VEGF monotherapy appears particularly relevant in outcomes. A high proportion of patients are sequencing therapy and reaching third line which may help improve outcomes.
CRS with Nasal Polyposis; Distinguishing Characteristics Through Immune-Phenotyping
Authors: Ameeta Kumar, Oral Alpan, Mark Rubinstein, Kaelan Black, Mark Soltany, Patty Lee, Deborah Doyle, Bryan McKenzie, Ryan Murray, William Kim, Robert Bahadori, Katherine Bartholomay, Angela Roark, Heather Cade, Melanie Kaufman, Denise Loizou, Maria Zlotnick
Journal: Journal of Allergy and Clinical Immunology (2020)
Abstract 15297: High-Density Lipoprotein Function Associates With GlycA, a Novel Inflammation Marker, but Does Not Explain the Association Between GlycA and Incident Cardiovascular Events
Authors: Kayla A Riggs, Parag H Joshi, Amit Khera, Kavisha Singh, Oludamilola Akinmolayemi, Colby R Ayers, Anand Rohatgi
Journal: Circulation (2018)

Background: High-density lipoproteins (HDL) exert anti-atherosclerotic effects via reverse cholesterol transport, yet this process is impaired in the setting of inflammation. GlycA, a novel integra...
酶 C1r 和 C1s 可能显示一种皮肤癌(角质形成细胞源性皮肤鳞状细胞癌)的进展
Authors: P. Riihilä, K. Viiklepp, L. Nissinen, M. Farshchian, M. Kallajoki, A. Kivisaari, S. Meri, J. Peltonen, S. Peltonen, V.‐M. Kähäri
Journal: British Journal of Dermatology (2020)

皮肤癌的发病率在全世界范围内正在增加。表皮是皮肤的表层,主要细胞类型是角质形成细胞。角质形成细胞源性皮肤鳞状细胞癌 (cSCC) 是最常见的转移性(意味着它可以扩散)皮肤癌,其占皮肤癌相关死亡的 20%。cSCC 的主要风险因素包括长期暴露于太阳紫外线辐射。 cSCC 的进展如下所示:它以称为光化性角化病 (AK) 的癌前形式(尚未癌变)开始,然后变成局限性 cSCC,然后是原位 cSCC (cSCCIS),最终成为浸润性和转移性 cSCC。 这项来自芬兰的研究旨在寻找能够预测 cSCC 进展和侵袭性的生物标志物(体内的化学物质,作为疾病的体征)。 作者发现,与正常表皮角质形成细胞和正常皮肤相比,cSCC 细胞和肿瘤中称为 C1r 和 C1s(在我们的免疫系统中起作用)的酶的 mRNA(信使分子)水平显著升高。 在浸润性 cSCC 和侵袭型 cSCC(隐性营养不良性大疱性表皮松解相关 cSCC)中检测到了肿瘤细胞中 C1r 和 C1s 的丰富表达,而 cSCCIS、光化性角化病和正常皮肤组织样本中的 C1r 和 C1 表达较低。 通过敲除(减少)C1r 和 C1s 表达以及通过复合方法研究了 cSCC 细胞中 C1r 和 C1s 的作用,并且经证明可能抑制 cSCC 肿瘤的生长。 这些结果提供证据表明肿瘤细胞来源的 C1r 和 C1s 在 cSCC 的进展中发挥作用,并将它们识别为 cSCC 中的生物标志物和可能的治疗靶点。 本摘要涉及研究: 肿瘤细胞来源的补体组分 C1r 和 C1s 促进皮肤鳞状细胞癌的生长
ABLE: single-arm trial of nab-paclitaxel with ANTI-PD1 in advanced urothelial cancer.
Authors: Jason Brown, Stephanie Daignault, Zachery R. Reichert, Phillip Lee Palmbos, Ajjai Shivaram Alva
Journal: Journal of Clinical Oncology (2020)

520 Background: Anti-PD1 immune checkpoint inhibitor monotherapy is standard in cisplatin ineligible advanced urothelial cancer (aUC) patients (pts) that is PDL1 positive as well as in platinum refractory aUC. Nab-paclitaxel (Abraxane) monotherapy showed an overall response rate (ORR) of 27.7% in platinum refractory aUC. We conducted a single-arm trial of nab-paclitaxel and pembrolizumab in platinum refractory or cisplatin ineligible aUC (NCT03240016). Methods: Eligible pts had RECIST 1.1 measurable disease, grade 1 or lower neuropathy and adequate organ function. Study therapy consisted of nab-paclitaxel at starting dose of 125 mg/m 2 IV on days 1 and day 8 and pembrolizumab 200 mg IV on day 1 in 21-day cycles until progression, intolerable toxicity, death or consent withdrawal. Primary endpoint was ORR by RECIST 1.1criteria. Secondary endpoints included safety/toxicity, progression free survival, overall survival, complete response proportion, duration of response (DOR) and duration of therapy (DOT). Results: Seventeen pts were enrolled between 02/2018 to 04/2019; 16 were response evaluable. Seven were of upper tract origin, 14/17 men, mean age 70.9 yrs (52 – 83), 71% pure urothelial, 8/17 platinum refractory; 9/17 cisplatin ineligible by Galsky criteria, and ECOG PS was 0, 1 or 2 in 6, 8 and 3 pts respectively. Unconfirmed ORR was 9/16 (56.25%: 95% CI [30-80%]), confirmed in 7; 14 pts experienced some tumor shrinkage; 2 pts had CR and 7 pts PR. Median DOR was 18 wks (95% CI: 6-NR) and median PFS 5.4 m (95% CI: 3.9-5.7). Pts received a median 6 cycles (range 1-11) with median DOT 4.4 m (0.7-7.6). Median follow up was 5.1 m. Grade ≥3 adverse events (AE) occurred in 15/17 pts including fatigue (n=5), peripheral neuropathy (n=3), anemia (n=3) and oral mucositis (n=3). Five pts had immune mediated AEs including 1 encephalitis; 5 pts discontinued treatment due to AEs, all attributed to nab-paclitaxel. Conclusions: The combination of nab-paclitaxel and pembrolizumab in advanced urothelial cancer exhibited promising activity but with moderate toxicity. A follow-up expansion study with nab-paclitaxel starting dose at 100 mg/m 2 in 19 additional pts is being initiated. Correlative studies including PD-L1 expression and TILs are underway. Clinical trial information: NCT03240016.
Targeting the receptor for advanced glycation end products (RAGE) in type 1 diabetes
Authors: Selena Le Bagge, Amelia K. Fotheringham, Sherman S. Leung, Josephine M. Forbes
Journal: Medicinal Research Reviews (2020)

Type 1 diabetes (T1D) is one of the most common chronic diseases manifesting in early life, with the prevalence increasing worldwide at a rate of approximately 3% per annum. The prolonged hyperglycaemia characteristic of T1D upregulates the receptor for advanced glycation end products (RAGE) and accelerates the formation of RAGE ligands, including advanced glycation end products, high-mobility group protein B1, S100 calcium-binding proteins, and amyloid-beta. Interestingly, changes in the expression of RAGE and these ligands are evident in patients before the onset of T1D. RAGE signals via various proinflammatory cascades, resulting in the production of reactive oxygen species and cytokines. A large number of proinflammatory ligands that can signal via RAGE have been implicated in several chronic diseases, including T1D. Therefore, it is unsurprising that RAGE has become a potential therapeutic target for the treatment and prevention of disease. In this review, we will explore how RAGE might be targeted to prevent the development of T1D.
Defining the genetic evolution of epigenetic alterations in bladder cancer.
Authors: Timothy Nguyen Clinton, Hannah Wise, Nima Almassi, Shweta S. Chavan, Wenhuo Hu, Sizhi Paul Gao, Aphrothiti Hanrahan, Shawn Dason, Eugene J. Pietzak, Maria Isabel Carlo, Samuel Aaron Funt, Min Yuen Teo, Gopa Iyer, Bernard H. Bochner, Jonathan E. Rosenberg, Dean F. Bajorin, Maria E. Arcila, Hikmat Al-Ahmadie, Barry S. Taylor, David B. Solit
Journal: Journal of Clinical Oncology (2020)

529 Background: Large-scale efforts have sought to define the genomic landscape of urothelial carcinomas of the bladder with the goal of identifying novel therapeutic targets. Many bladder cancers harbor mutations in genes that regulate chromatin state, such as KDM6A, ARID1A and KMT2D. There remains uncertainty as to the timing at which alterations in chromatin modifying genes (CMG) arise during the evolution of urothelial cancer. Methods: We leveraged a prospective genomic profiling initiative to characterize driver alterations in urothelial cancer. To define the timing at which mutations arose during disease pathogenesis, we performed whole exome (WES) or targeted sequencing analysis of matched pairs of primary and metastatic tumors. Results: CMG mutations were identified in 76% of UC samples in the prospective MSK-IMPACT tumor sequencing cohort (N=1057); most frequent in KDM6A (31%), KMT2D (28%) and ARID1A (27%). Comparison of primary low-grade (N=65), high-grade (N=742) and metastatic (N=250) samples revealed KDM6A, FGFR3 and KMT2C were more frequently mutated in low-grade tumors. WES and targeted sequencing of 63 matched pairs demonstrate a high degree of concordance among likely oncogenic mutations. Notably, 100% (18/18) of pairs were concordant for mutations in KDM6A suggesting that, when present KDM6A mutations arise early during tumor development. Mutations in ARID1A were present only in the metastatic samples of a subset of tumors (29%) suggesting that ARID1A mutations arise later in disease pathogenesis. Several additional oncogenic drivers were found in only the metastatic sample ( FGFR3, TSC1, PIK3CA) of select tumor pairs. Conclusions: Primary and metastatic pairs were largely concordant for known and likely oncogenic mutations. Evolutionary analysis of sequencing data suggested that KDM6A mutations arise early in tumor development whereas ARID1A mutations were enriched and present only in the metastatic samples of a subset of patients. Despite the high frequency of FGFR3 mutations in low grade tumors, discordance of FGFR3 mutational status was observed in small fraction of patients suggesting that profiling of metastatic tumors or cell free DNA would be preferable to identify patients for FGFR inhibitor therapy.