Genes, Chromosomes and Cancer

doi: 10.1002/gcc.22491pmid: N/A

Mendel, Lionel; Ambrosetti, Damien; Bodokh, Yohan; Ngo‐Mai, Mélanie; Durand, Matthieu; Simbsler‐Michel, Cécile; Delhorbe, Mickael; Amiel, Jean; Pedeutour, Florence

doi: 10.1002/gcc.22513pmid: 29127730

The first case of TFEB‐amplified renal cell carcinoma was published in 2014. Since then, 29 additional cases have been described. The prognostic and therapeutic implications of this rare entity remain to be determined. We describe here the clinical, histological, and genetic features of three novel cases, and the first complete literature review. Four tumors were examined from three patients selected from the large collection of genetically characterized renal tumors in our institution. The pathological and immunohistochemical features were centrally reviewed by a uropathologist. Quantitative and structural genomic abnormalities were analyzed using comparative genomic hybridization, fluorescence in situ hybridization, and next generation sequencing. The three cases showed high‐level amplification but no translocation of TFEB. Histologically, two tumors showed a papillary or pseudopapillary architecture. They did not show similarities with renal cell carcinoma harboring translocation of TFEB. The tumors were locally advanced high‐grade lesions. They exhibited a metastatic course, which was rapidly leading to death in one patient. A second patient developed metastatic disease that did not respond to four lines of targeted treatments. The third patient had a protracted history of pulmonary and cardiac metastases. Complete clinical and biological data were examined and compared to those of the reported cases. Within the classification of renal tumors, TFEB‐amplified renal cell carcinoma may constitute a novel entity characterized histologically by high‐grade, papillary or pseudopapillary architecture, and necrotic remodeling and clinically by a poor outcome. Its pathogenesis has to be further characterized to develop appropriate targeted therapy.

Raza, Muhammad‐Zawwad; Allegrini, Simone; Dumontet, Charles; Jordheim, Lars Petter

doi: 10.1002/gcc.22514pmid: 29181864

Development of an organ and subsequently the whole system from an embryo is a highly integrated process. Although there is evidence that different systems are interconnected during developmental stages, the molecular understanding of this relationship is either not known or only to a limited extent. Nervous system development, amongst all, is maybe the most crucial and complex process. It relies on the correct distribution of specific neuronal growth factors and hormones to the specific receptors. Among the plethora of proteins that are involved in downstream signalling of neuronal growth factors, we find the kinase‐D interacting substrate of 220 kDa (KIDINS220), also known as ankyrin‐rich repeat membrane spanning (ARMS) protein. KIDINS220 has been shown to play a substantial role in the nervous system and vascular system development as well as in neuronal survival and differentiation. It serves as a downstream regulator for many important neuronal and vascular growth factors such as vascular endothelial growth factor (VEGF), the neurotrophin family, glutamate receptors and ephrin receptors. Moreover, activation and differentiation of B‐ and T‐cells, as well as tumour cell proliferation has also shown to be related to KIDINS220. This review comprehensively summarises the existing research data on this protein, with a particular interest in its role in cancer and in other pathologies.

Volckmar, Anna‐Lena; Sültmann, Holger; Riediger, Anja; Fioretos, Thoas; Schirmacher, Peter; Endris, Volker; Stenzinger, Albrecht; Dietz, Steffen

doi: 10.1002/gcc.22517pmid: 29205637

Recently, many genome‐wide profiling studies provided insights into the molecular make‐up of major cancer types. The deeper understanding of these genetic alterations and their functional consequences led to the discovery of novel therapeutic opportunities improving clinical management of cancer patients. While tissue‐based molecular patient stratification is the gold standard for precision medicine, it has certain limitations: Tissue biopsies are invasive sampling procedures carrying the risk of complications and may not represent the entire tumor due to underlying genetic heterogeneity. In this context, complementary characterization of genetic information in the blood of cancer patients can serve as minimal‐invasive ‘liquid biopsy’. Fragments of circulating cell‐free DNA (cfDNA) are released from tissues of healthy individuals as well as cancer patients. The fraction of cfDNA that is released from primary tumors or metastases (i.e. circulating tumor DNA, ctDNA) represents genetic aberrations in cancer cells, which are a potential source for diagnostic, prognostic, and predictive biomarkers. Recent studies have demonstrated technical feasibility and clinical applications including detection of drug targets and resistance mutations as well as longitudinal monitoring of tumors under therapy. To this end, a variety of pre‐analytical procedures for blood processing, isolation and quantification of cfDNA are being employed and several analytical methods and technologies ranging from PCR‐based single locus assays to genome‐wide approaches are available, which considerably differ in sensitivity, specificity, and throughput. However, broad implementation of ctDNA analysis in daily clinical practice requires a thorough understanding of theoretical, technical, and biological concepts and necessitates standardization and validation of pre‐analytical and analytical procedures across different technologies. Here, we review the pertinent literature and discuss the advantages and limitations of available methodologies and their potential applications in molecular diagnostics.

Hu, Yue; Gaedcke, Jochen; Emons, Georg; Beissbarth, Tim; Grade, Marian; Jo, Peter; Yeager, Meredith; Chanock, Stephen J.; Wolff, Hendrik; Camps, Jordi; Ghadimi, B. Michael; Ried, Thomas

doi: 10.1002/gcc.22512

Tsikrika, Foteini D.; Avgeris, Margaritis; Levis, Panagiotis K.; Tokas, Theodoros; Stravodimos, Konstantinos; Scorilas, Andreas

doi: 10.1002/gcc.22516pmid: 29181884

Clinical heterogeneity of bladder cancer prognosis requires the identification of bladder tumors' molecular profile to improve the prediction value of the established and clinically used markers. In this study, we have analyzed miR‐221/222 cluster expression in bladder tumors and its clinical significance for patients' prognosis and disease outcome. The study included 387 tissue specimens. Following extraction, total RNA was polyadenylated at 3′‐end and reversed transcribed. SYBR‐Green based qPCR assays were performed for the quantification of miR‐221/222 expression. Extensive statistical analysis was completed for the evaluation of miR‐221/222 cluster's clinical significance. The expression of miR‐221/222 is significantly downregulated in tumors compared to normal urothelium, while ROC curve and logistic regression analysis highlighted cluster's discriminatory ability. However, miR‐222 levels were increased in muscle‐invasive (T2‐T4) compared to superficial tumors (TaT1), and in high compared to low‐grade tumors. Kaplan‐Meier survival curves and Cox regression analysis revealed the stronger risk of TaT1 patients overexpressing miR‐222 for disease short‐term relapse and progression following treatment. Moreover, multivariate Cox models highlighted the independent prognostic value of miR‐222 overexpression for TaT1 patients' poor prognosis. Finally, the analysis of miR‐222 expression improved significantly the positive prediction strength of the clinically used prognostic markers of tumor stage, grade, EORTC risk‐stratification and recurrence at the first follow‐up cystoscopy for TaT1 patients' outcome, and resulted to higher clinical net benefit following decision curve analysis. In conclusion, the expression of miR‐221/222 cluster is deregulated in bladder tumors and miR‐222 overexpression results to a superior positive prediction of TaT1 patients' short‐term relapse and progression.