ABSTRACT Background Autosomal dominant polycystic kidney disease (ADPKD) is the most commonly inherited progressive kidney disease. Time-restricted eating (TRE) is a fasting regimen that restricts eating to a particular window (typically 8 hours/day), which could slow cyst growth based on preclinical models. Methods A 12-month, randomized, controlled, behavioral dietary intervention compared TRE with a control group given healthy eating advice without TRE (HE), without caloric restriction. Participants underwent baseline and 12-month measurements, including adherence (percentage of participants adhering to the 8-hour window; primary outcome), and MRI to determine height-adjusted total kidney volume (htTKV) and adiposity. Results Twenty-nine participants (23 females, mean standard ± deviation 48 ± 9 years) with a body mass index of 31.1±5 kg/m2 were randomized to TRE (n = 14) or HE (n = 15). Of the total participants, 71% (n = 10) of TRE and 87% (n = 13) of HE participants completed the intervention. The eating window was 9.6 ± 3.6 hours for TRE (60% achieving the 8-hour window) and 12.0 ± 2.0 for HE groups (P = .07). At month 12, both groups lost modest weight (−2.4 ± 6.4% and −3.6 ± 5.4% in the TRE and HE groups, respectively). Annual change in htTKV was 3.0 ± 8.5% and 4.6 ± 8.8% in the TRE and HE groups, respectively. Both change in weight (r = 0.67, P < .01) and change in visceral adiposity (r = 0.54, P < .01) were positively correlated with change in htTKV. Conclusion Both the TRE and HE group lost modest weight at 12 months. The targeted TRE adherence of ≥75% of participants was not achieved. Weight and adiposity loss may be more important drivers of kidney growth than the timing of eating.
Overweight and Obesity Are Predictors of Pain in the HALT-PKD Studies
Abstract Intraductal carcinoma of the prostate (IDC-P) is a lethal prostate cancer subtype that generally coexists with invasive high-grade prostate acinar adenocarcinoma (PAC) but exhibits distinct biological features compared with concomitant adenocarcinoma. In this study, we performed whole-exome, RNA, and DNA-methylation sequencing of IDC-P, concurrent invasive high-grade PAC lesions, and adjacent normal prostate tissues isolated from 22 radical prostatectomy specimens. Three evolutionary patterns of concurrent IDC-P and PAC were identified: early divergent, late divergent, and clonally distant. In contrast to those with a late divergent evolutionary pattern, tumors with clonally distant and early divergent evolutionary patterns showed higher genomic, epigenomic, transcriptional, and pathologic heterogeneity between IDC-P and PAC. Compared with coexisting PAC, IDC-P displayed increased expression of adverse prognosis–associated genes. Survival analysis based on an independent cohort of 505 patients with metastatic prostate cancer revealed that IDC-P carriers with lower risk International Society of Urological Pathology (ISUP) grade 1–4 adenocarcinoma displayed a castration-resistant free survival as poor as those with the highest risk ISUP grade 5 tumors that lacked concurrent IDC-P. Furthermore, IDC-P exhibited robust cell-cycle progression and androgen receptor activities, characterized by an enrichment of cellular proliferation–associated master regulators and genes involved in intratumoral androgen biosynthesis. Overall, this study provides a molecular groundwork for the aggressive behavior of IDC-P and could help identify potential strategies to improve treatment of IDC-P. Significance: The genomic, transcriptomic, and epigenomic characterization of concurrent intraductal carcinoma and adenocarcinoma of the prostate deepens the biological understanding of this lethal disease and provides a genetic basis for developing targeted therapies.
MAP3K7-IKK Inflammatory Signaling Modulates AR Protein Degradation and Prostate Cancer Progression
Abstract Androgen receptor (AR) is a major survival factor for prostate cancer. Inflammation is implicated in many cancer types, including prostate cancer. Activation of MAP3K7 (also termed TAK1) and downstream IκB kinase β (IKKβ) by proinflammatory cytokines such as TNFα stimulates NF-κB survival pathways. Paradoxically, MAP3K7 is often deleted in human prostate cancer. Here, we demonstrate that AR protein expression is lower in inflammatory tumor areas compared with non-inflammatory tissues in patients with prostate cancer. Map3k7 knockout increased AR protein levels and activity in the mouse prostate, and MAP3K7 and AR protein levels were inversely correlated in prostate cancer patient specimens. TNFα treatment increased AR protein ubiquitination and proteasomal degradation. Mechanistically, activation of IKKβ by TNFα induced phosphorylation and TRCP1/2 E3 ligase–mediated polyubiquitination and degradation of AR protein. TNFα suppressed prostate cancer proliferation, which could be rescued by blockade of AR degradation. These findings reveal a previously unrecognized tumor suppressive function of the inflammation-activated MAP3K7–IKKβ axis in degrading AR protein. Moreover, they suggest that aberrant elevation of AR protein could be a prognostic biomarker and therapeutic target for MAP3K7-deficient prostate cancer. Significance: This study identifies that MAP3K7–IKKβ signaling plays a tumor-suppressive role in prostate cancer by degrading AR, revealing potential prognostic and therapeutic strategies for MAP3K7-deficient tumors.
Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)
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Abstract TFE3-translocation renal cell carcinoma (TFE3-tRCC) is a rare and heterogeneous subtype of kidney cancer that has no standard treatment for advanced disease. We described comprehensive molecular characteristics of 63 untreated primary TFE3-tRCCs based on whole-exome and RNA sequencing. TFE3-tRCC is highly heterogeneous, both clinicopathologically and genotypically. ASPSCR1-TFE3 fusion, certain fusion isoforms and high somatic copy number alteration burdens were associated with aggressive features and poor outcomes. Apart from tumors with MED15-TFE3 fusion, most TFE3-tRCCs exhibited low PD-L1 expression and low T-cell infiltration. Unsupervised transcriptomic analysis revealed five molecular clusters with distinct angiogenesis, stroma, proliferation and KRAS down signatures, which showed association with fusion patterns and prognosis. Specifically, the high angiogenesis/stroma/proliferation cluster exclusively consisted of tumors with ASPSCR1-TFE3 fusion, which was likely to benefit from combination of immune checkpoint and anti-angiogenesis inhibitors. Our findings reveal the genomic and transcriptomic features of TFE3-tRCC and provide insights into precision medicine for this disease.
ZMYND8 preferentially binds phosphorylated EZH2 to promote a PRC2-dependent to -independent function switch in hypoxia-inducible factor–activated cancer
Significance The multiple-domain protein ZMYND8 is well known as a chromatin reader that recognizes methylated, acetylated, and/or mutated histones. Here we report that ZMYND8 is overexpressed in human ccRCC, and that it preferentially binds T487-phosphorylated EZH2. We show that in hypoxia-stimulated or von Hippel–Lindau–deficient cells, ZMYND8 binding of EZH2 is important for maintenance of EZH2 phosphorylation level, inhibition of PRC2 complex formation, and enhanced interaction between EZH2 and FOXM1. Our results reveal a reader function of ZMYND8 in recognizing a phosphorylation “code” on a nonhistone protein. Our findings also identify ZMYND8 binding as a facet of regulation and function of EZH2 phosphorylation in the Polycomb-dependent to -independent switch of EZH2/PRC2 activities.
Integrated Molecular Characterization of Fumarate Hydratase–deficient Renal Cell Carcinoma
AbstractPurpose:Fumarate hydratase–deficient renal cell carcinoma (FH-deficient RCC) is a rare but lethal subtype of RCC. Little is known about the genomic profile of FH-deficient RCC, and the therapeutic options for advanced disease are limited. To this end, we performed a comprehensive genomics study to characterize the genomic and epigenomic features of FH-deficient RCC.Experimental Design:Integrated genomic, epigenomic, and molecular analyses were performed on 25 untreated primary FH-deficient RCCs. Complete clinicopathologic and follow-up data of these patients were recorded.Results:We identified that FH-deficient RCC manifested low somatic mutation burden (median 0.58 mutations per megabase), but with frequent somatic copy-number alterations. The majority of FH-deficient RCCs were characterized by a CpG sites island methylator phenotype, displaying concerted hypermethylation at numerous CpG sites in genes of transcription factors, tumor suppressors, and tumor hallmark pathways. However, a few cases (20%) with low metastatic potential showed relatively low DNA methylation levels, indicating the heterogeneity of methylation pattern in FH-deficient RCC. Moreover, FH-deficient RCC is potentially highly immunogenic, characterized by increased tumor T-cell infiltration but high expression of immune checkpoint molecules in tumors. Clinical data further demonstrated that patients receiving immune checkpoint blockade–based treatment achieved improved progression-free survival over those treated with antiangiogenic monotherapy (median, 13.3 vs. 5.1 months; P = 0.03).Conclusions:These results reveal the genomic features and provide new insight into potential therapeutic strategies for FH-deficient RCC.
Abstract 4618: Integrative molecular classification of extrahepatic cholangiocarcinoma
Abstract Background and Aims: Cholangiocarcinoma (CCA) is the second most common primary hepatic malignancy. Based on its anatomical location, CCA can be divided into intrahepatic (iCCA) or extrahepatic (eCCA), with differences in etiology, pathogenesis and clinical management. Few studies have focused on the molecular profiling of eCCA as a single entity, even though it accounts for the most prevalent subtype. Thus, integrative genomic analysis of eCCA would provide critical understanding for the biological traits of this tumor. Methods: 189 FFPE primary eCCA treated by resection were collected at seven international centers from 1995 to 2015. Median survival of the cohort was of 48.5mo. Whole gene-expression profiles were submitted to unsupervised clustering by NMF consensus. Clusters were characterized by Gene Set Enrichment Analysis and Ingenuity Pathway Analysis. Activation of signaling pathways (mTOR/pRPS6 and HER2) was assessed by immunohistochemistry (IHC). Molecular features were correlated with clinico-pathological data. Screening of most prevalent somatic mutations and copy number aberrations is ongoing. Results: We have identified four distinct molecular subtypes of eCCA (cophenetic coefficient=0.995). Tumors classified within the metabolic class (18.7%) were enriched by gene signatures defining bile and fatty acid metabolism (p<0.001) and presented overexpression of classic hepatocyte markers, with HNF4A as the major activated upstream transcription factor (p<0.001). The proliferation class (22.5%) was associated with papillary histology (p=0.004) and presented enrichment of MYC (p<0.001), mTOR (p=0.018) and HER2 (p=0.024) signaling. Subclass mapping identified similarity with the iCCA proliferation subclass (p<0.001). The mesenchymal class (47.3%) was associated with signatures defining epithelial-mesenchymal transition (p<0.001) as well as stromal activation (p<0.001), which was in accordance with TGFB1 as the major activated upstream regulator (p<0.001) and the presence of higher desmoplasia at pathological analysis (p=0.046). Moreover, mesenchymal tumors were significantly associated with poor prognosis in terms of OS (33.2 vs 55.5mo, HR=2.02, p=0.022). Finally, tumors classified as immune class (11.5%) presented increased tumor-infiltrating lymphocytes (p=0.001) and were characterized by enrichment of IFNγ signaling (p<0.001). Conclusions: Transcriptome-based subtyping of eCCA identifies four distinct molecular classes (metabolic, proliferation, mesenchymal and immune) that correlate with clinical-pathological characteristics. These findings enhance the opportunities for therapeutic development in this tumor with dismal prognosis and without approved molecular treatments. Citation Format: Robert Montal, Wei Qiang Leow, Carla Montironi, Laia Bassaganyas, Agrin Moeini, Daniela Sia, Roser Pinyol, Laia Cabellos, Judit Peix, Miho Maeda, Carlos Villacorta, Parissa Tabrizian, Christine Sempoux, Beatriz Minguez, Tim Pawlik, Ismail Labgaa, Lewis Roberts, Manel Sole, Maria Isabel Fiel, Swan Thung, Sasan Roayaie, Augusto Villanueva, Myron Schwartz, Josep Maria Llovet. Integrative molecular classification of extrahepatic cholangiocarcinoma [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 4618.