Comprehensive integrative profiling of upper tract urothelial carcinomas

Abstract Background Crosstalk between genetic, epigenetic, and immune alterations in upper tract urothelial carcinomas and their role in shaping muscle invasiveness and patient outcome are poorly understood. Results We perform an integrative genome- and methylome-wide profiling of diverse non-muscle-invasive and muscle-invasive upper tract urothelial carcinomas. In addition to mutations of FGFR3 and KDM6A, we identify ZFP36L1 as a novel, significantly mutated tumor suppressor gene. Overall, mutations of ZFP36 family genes (ZFP36, ZFP36L1, and ZFP36L2) are identified in 26.7% of cases, which display a high mutational load. Unsupervised DNA methylation subtype classification identifies two epi-clusters associated with distinct muscle-invasive status and patient outcome, namely, EpiC-low and EpiC-high. While the former is hypomethylated, immune-depleted, and enriched for FGFR3-mutated, the latter is hypermethylated, immune-infiltrated, and tightly associated with somatic mutations of SWI/SNF genes. Conclusions Our study delineates for the first time the key role for convergence between genetic and epigenetic alterations in shaping clinicopathological and immune upper tract urothelial carcinoma features.

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Multi-omics profiling of upper-tract urothelial carcinomas.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.4560 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 4560-4560

Author(s):

Gabriel G. Malouf ◽

Hui Yao ◽

Roger Mouawad ◽

Morgan Roupret ◽

Jean-Emannuel Kurtz ◽

...

Keyword(s):

Dna Methylation ◽

Bladder Cancer ◽

Enrichment Analysis ◽

Genetic Alterations ◽

Gene Set Enrichment Analysis ◽

Genetic Profile ◽

Cancer Dataset ◽

Upper Tract ◽

Urothelial Carcinomas ◽

Muscle Invasive

4560 Background: Upper-tract urothelial carcinomas (UTUC) may harbor similar genetic profile as compared to bladder cancer, although frequencies of mutated genes have been shown to differ between them. However, to the best of our knowledge, the epigenetic landscapes of UTUC and their association with genetic alterations and clinico-pathological tumor features remain unknown. Methods: We collected 40 UTUC samples (20 non-muscle invasive (NMI) and 20 muscle-invasive (MI) and carried out whole-exome sequencing (n = 30), DNA methylation using Infinium EPIC arrays (n = 35) and RNA sequencing (n = 20). Validation was performed on TCGA bladder cancer dataset. Results: We identified 3232 putative somatic mutations with an average of 2.1+/-2.6 mutations per megabase. Significantly mutated genes were FGFR3 (50%), KDM6A (27%), MLL2 (27%) and ARID1A/B (23%). No difference in term of genetic alterations were identified between MI- and NMI- UTUC. Unsupervised hierarchical clustering using most variable DNA methylation probes uncovered two robust DNA methylation epi-clusters. Epi-cluster C1 (n = 23; 65.7%) displayed markedly higher DNA methylation relative to Epi-cluster C2 (n = 12; 34.3%). Notably, all muscle-invasive samples were enriched in C1 (16/17, 94.1%); conversely, C2 was enriched with non-muscle-invasive samples (p = 0.0009). Overall, 14.209 probes were significantly hypermethylated in C1 as compared to C2 epi-cluster; Gene Set Enrichment Analysis (GSEA) demonstrated that those were enriched for PRC2 targets (p = 6x10-65). Integrative analysis with tumor genetic landscape showed that C1 epi-cluster was enriched for mutations in SWI/SNF complex as compared to C2 (p = 0.02). We then applied our epi-signature to bladder TCGA cohort and obtained two similar epi-clusters associated with patients overall survival (p = 0.035). Conclusions: Our study demonstrate for the first time that difference between MI- and NM- invasive UTUC might be related to epigenetic rather than genetic alterations. This might pave the way for testing epigenetic therapies in non-muscle invasive tumors with the aim to prevent recurrence and distant metastasis.

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Tumor heterogeneity evaluated by computed tomography detects muscle-invasive upper tract urothelial carcinoma that is associated with inflammatory tumor microenvironment

Scientific Reports ◽

10.1038/s41598-021-93414-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Keisuke Goto ◽

Yukiko Honda ◽

Kenichiro Ikeda ◽

Kenshiro Takemoto ◽

Toru Higaki ◽

...

Keyword(s):

Computed Tomography ◽

Standard Deviation ◽

Tumor Microenvironment ◽

Urothelial Carcinoma ◽

Texture Analysis ◽

Upper Tract Urothelial Carcinoma ◽

Invasive Tumor ◽

Upper Tract ◽

Muscle Invasive ◽

Muscle Invasive Tumor

AbstractTo detect muscle-invasive upper tract urothelial carcinoma, we evaluated the internal texture of the tumor using texture analysis of computed tomography images in 86 cases of upper tract urothelial carcinoma. The internal texture of the tumor was evaluated as the value of computed tomography attenuation number of the unenhanced image, and the median, standard deviation, skewness and kurtosis were calculated. Each parameter was compared with clinicopathological factors, and their associations with postoperative prognosis were investigated. Immunohistochemistry was performed to investigate the histological and molecular mechanisms of the inflammatory tumor microenvironment. The histogram of computed tomography attenuation number in non-muscle invasive tumor was single-peaked, whereas muscle invasive tumor showed a multi-peaked shape. In the parameters obtained by texture analysis, standard deviation was significantly associated with pathological stage (p < 0.0001), tumor grade (p = 0.0053), lymphovascular invasion (p = 0.0078) and concomitant carcinoma in situ (p = 0.0177) along with recurrence-free (p = 0.0191) and overall survival (p = 0.0184). The standard deviation value correlated with the amount of stromal components (p < 0.0001) and number of tumor-infiltrating macrophages (p < 0.0001). In addition, higher expression of high mobility group box 1 was found in heterogeneous tumor. Tumor heterogeneity evaluated by texture analysis was associated with muscle-invasive upper tract urothelial carcinoma and represented an inflammatory tumor microenvironment and useful as the clinical assessment to differentiate muscle invasive tumor.

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Evaluation of upper tract urothelial carcinomas by contrast-enhanced ultrasound

Radiología (English Edition) ◽

10.1016/j.rxeng.2018.10.001 ◽

2018 ◽

Vol 60 (6) ◽

pp. 496-503

Author(s):

A.A. Painel Seguel ◽

M.J. Martínez Pérez ◽

T. Ripollés González ◽

D.P. Gómez ◽

J. Vizuete del Río ◽

...

Keyword(s):

Contrast Enhanced Ultrasound ◽

Upper Tract ◽

Urothelial Carcinomas ◽

Contrast Enhanced

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Efficacy of BRAF and MEK Inhibition in Patients with BRAF-Mutant Advanced Melanoma and Germline CDKN2A Pathogenic Variants

Cancers ◽

10.3390/cancers13102440 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2440

Author(s):

Francesco Spagnolo ◽

Bruna Dalmasso ◽

Enrica Tanda ◽

Miriam Potrony ◽

Susana Puig ◽

...

Keyword(s):

Real World ◽

Response Rate ◽

Suppressor Gene ◽

Phase Iii ◽

Clinical Activity ◽

P Value ◽

Pathogenic Variants ◽

Phase Iii Trials ◽

The Difference ◽

First Time

Inherited pathogenic variants (PVs) in the CDKN2A tumor suppressor gene are among the strongest risk factors for cutaneous melanoma. Dysregulation of the p16/RB1 pathway may intrinsically limit the activity of MAPK-directed therapy due to the interplay between the two pathways. In our study, we assessed, for the first time, whether patients with germline CDKN2A PVs achieve suboptimal results with BRAF inhibitors (BRAFi)+/−MEK inhibitors (MEKi). We compared the response rate of nineteen CDKN2A PVs carriers who received first-line treatment with BRAFi+/−MEKi with an expected rate derived from phase III trials and “real-world” studies. We observed partial response in 16/19 patients (84%), and no complete responses. The overall response rate was higher than that expected from phase III trials (66%), although not statistically significant (p-value = 0.143; 95% CI = 0.60–0.97); the difference was statistically significant (p-value = 0.019; 95% CI = 0.62–0.97) in the comparison with real-world studies (57%). The clinical activity of BRAFi+/−MEKi in patients with germline CDKN2A PV was not inferior to that of clinical trials and real-world studies, which is of primary importance for clinical management and genetic counseling of this subgroup of patients.

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A review of the contemporary management of upper urinary tract urothelial carcinoma

Journal of Clinical Urology ◽

10.1177/2051415817717906 ◽

2017 ◽

Vol 11 (1) ◽

pp. 51-57

Author(s):

Abhishek Reekhaye ◽

Seshadri Sriprasad ◽

Sanjeev Madaan

Keyword(s):

Urinary Tract ◽

Urothelial Carcinoma ◽

Treatment Options ◽

Treatment Strategies ◽

Upper Urinary Tract ◽

Rare Tumour ◽

Endoscopic Techniques ◽

Upper Tract ◽

Urothelial Carcinomas ◽

Urinary Tract Urothelial Carcinoma

Upper tract urothelial carcinoma (UTUC) is relatively rare and accounts for approximately 5% of all urothelial carcinomas. The estimated annual incidence of UTUC in Western countries is about two new cases per 100,000 inhabitants. The management of patients with upper tract urothelial carcinomas has changed significantly over the last decade with improved diagnostic techniques and treatment options. The gold-standard treatment used to be open radical nephroureterectomy with removal of the ipsilateral bladder cuff. The use of minimally invasive techniques for the diagnosis and management of upper urinary tract urothelial carcinoma is however expanding and has led to a paradigm shift in treatment strategies of upper tract urothelial carcinomas. In this article, we review the current diagnostic modalities and various endoscopic techniques being currently used in the management of this relatively rare tumour.

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Impact of the preoperative prognostic nutritional index on survival outcomes in upper tract urothelial carcinomas

Cancer Medicine ◽

10.1002/cam4.2161 ◽

2019 ◽

Vol 8 (6) ◽

pp. 2971-2978 ◽

Cited By ~ 4

Author(s):

Wenbin Xue ◽

Ping Tan ◽

Hang Xu ◽

Lu Yang ◽

Qiang Wei

Keyword(s):

Prognostic Nutritional Index ◽

Survival Outcomes ◽

Upper Tract ◽

Nutritional Index ◽

Urothelial Carcinomas

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Epstein-Barr virus DNA load in tumour tissues correlates with poor differentiation status in non-muscle invasive urothelial carcinomas

BJU International ◽

10.1111/j.1464-410x.2010.09474.x ◽

2010 ◽

Vol 107 (1) ◽

pp. 150-154 ◽

Cited By ~ 3

Author(s):

Kun-Lung Chuang ◽

See-Tong Pang ◽

Shuen-Kuei Liao ◽

Chun Te Wu ◽

Ying Hsu Chang ◽

...

Keyword(s):

Epstein Barr Virus ◽

Barr Virus ◽

Urothelial Carcinomas ◽

Poor Differentiation ◽

Epstein Barr ◽

Differentiation Status ◽

Muscle Invasive

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Expression and Somatic Mutations of SDHFA2 (SDH5), a Novel Endocrine Tumor Suppressor Gene, in Parathyroid Tumors of Primary Hyperparathyroidism.

10.1210/endo-meetings.2010.part3.p2.p3-84 ◽

2010 ◽

pp. P3-84-P3-84

Author(s):

LF Starker ◽

A Delgado-Verdugo ◽

R Udelsman ◽

P Bjorklund ◽

T Carling

Keyword(s):

Tumor Suppressor ◽

Primary Hyperparathyroidism ◽

Tumor Suppressor Gene ◽

Somatic Mutations ◽

Endocrine Tumor ◽

Suppressor Gene ◽

Parathyroid Tumors

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APC Promoter Methylation in Gastrointestinal Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.653222 ◽

2021 ◽

Vol 11 ◽

Author(s):

Lila Zhu ◽

Xinyu Li ◽

Ying Yuan ◽

Caixia Dong ◽

Mengyuan Yang

Keyword(s):

Cpg Island ◽

Suppressor Gene ◽

Sporadic Colorectal Cancer ◽

Adenomatous Polyposis ◽

Epigenetic Alterations ◽

Loss Of Function ◽

Gene Methylation ◽

Research Directions ◽

Causative Factors

The adenomatous polyposis coli (APC) gene, known as tumor suppressor gene, has the two promoters 1A and 1B. Researches on APC have usually focused on its loss-of-function variants causing familial adenomatous polyposis. Hypermethylation, however, which is one of the key epigenetic alterations of the APC CpG sequence, is also associated with carcinogenesis in various cancers. Accumulating studies have successively explored the role of APC hypermethylation in gastrointestinal (GI) tumors, such as in esophageal, colorectal, gastric, pancreatic, and hepatic cancer. In sporadic colorectal cancer, the hypermethylation of CpG island in APC is even considered as one of the primary causative factors. In this review, we systematically summarized the distribution of APC gene methylation in various GI tumors, and attempted to provide an improved general understanding of DNA methylation in GI tumors. In addition, we included a robust overview of demethylating agents available for both basic and clinical researches. Finally, we elaborated our findings and perspectives on the overall situation of APC gene methylation in GI tumors, aiming to explore the potential research directions and clinical values.

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