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1. A Somatically Acquired Enhancer of the Androgen Receptor Is a Noncoding Driver in Advanced Prostate Cancer.

Author

Takeda DY, Spisák S, Seo JH, Bell C, O'Connor E, Korthauer K, Ribli D, Csabai I, Solymosi N, Szállási Z, Stillman DR, Cejas P, Qiu X, Long HW, Tisza V, Nuzzo PV, Rohanizadegan M, Pomerantz MM, Hahn WC, and Freedman ML

Subjects
Acetylation, Adult, Aged, Antineoplastic Agents pharmacology, Benzamides, CRISPR-Cas Systems genetics, Cell Line, Tumor, Cell Survival drug effects, DNA Methylation, Gene Editing, Histones metabolism, Humans, Male, Middle Aged, Neoplasm Metastasis, Nitriles, Phenylthiohydantoin analogs & derivatives, Phenylthiohydantoin pharmacology, Prostatic Neoplasms, Castration-Resistant metabolism, Receptors, Androgen genetics, Enhancer Elements, Genetic genetics, Prostatic Neoplasms, Castration-Resistant pathology, Receptors, Androgen metabolism
Abstract

Increased androgen receptor (AR) activity drives therapeutic resistance in advanced prostate cancer. The most common resistance mechanism is amplification of this locus presumably targeting the AR gene. Here, we identify and characterize a somatically acquired AR enhancer located 650 kb centromeric to the AR. Systematic perturbation of this enhancer using genome editing decreased proliferation by suppressing AR levels. Insertion of an additional copy of this region sufficed to increase proliferation under low androgen conditions and to decrease sensitivity to enzalutamide. Epigenetic data generated in localized prostate tumors and benign specimens support the notion that this region is a developmental enhancer. Collectively, these observations underscore the importance of epigenomic profiling in primary specimens and the value of deploying genome editing to functionally characterize noncoding elements. More broadly, this work identifies a therapeutic vulnerability for targeting the AR and emphasizes the importance of regulatory elements as highly recurrent oncogenic drivers., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Published
2018
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2. Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal.

Author

Turajlic S, Xu H, Litchfield K, Rowan A, Horswell S, Chambers T, O'Brien T, Lopez JI, Watkins TBK, Nicol D, Stares M, Challacombe B, Hazell S, Chandra A, Mitchell TJ, Au L, Eichler-Jonsson C, Jabbar F, Soultati A, Chowdhury S, Rudman S, Lynch J, Fernando A, Stamp G, Nye E, Stewart A, Xing W, Smith JC, Escudero M, Huffman A, Matthews N, Elgar G, Phillimore B, Costa M, Begum S, Ward S, Salm M, Boeing S, Fisher R, Spain L, Navas C, Grönroos E, Hobor S, Sharma S, Aurangzeb I, Lall S, Polson A, Varia M, Horsfield C, Fotiadis N, Pickering L, Schwarz RF, Silva B, Herrero J, Luscombe NM, Jamal-Hanjani M, Rosenthal R, Birkbak NJ, Wilson GA, Pipek O, Ribli D, Krzystanek M, Csabai I, Szallasi Z, Gore M, McGranahan N, Van Loo P, Campbell P, Larkin J, and Swanton C

Subjects
Adult, Aged, Aged, 80 and over, Alleles, Biomarkers, Tumor, Chromosomes, Clonal Evolution, Disease Progression, Evolution, Molecular, Female, Genetic Heterogeneity, Genetic Variation, Humans, Longitudinal Studies, Male, Middle Aged, Models, Statistical, Mutation, Neoplasm Metastasis, Phenotype, Phylogeny, Prognosis, Prospective Studies, Sequence Analysis, DNA, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell pathology, Kidney Neoplasms genetics, Kidney Neoplasms pathology
Abstract

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance., (Copyright © 2018 Francis Crick Institute. Published by Elsevier Inc. All rights reserved.)

Published
2018
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