Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer

Parolia, Abhijit; Cieślik, Marcin; Chu, Shih-Chun; Xiao, Lanbo; Ouchi, Takahiro; Zhang, Yuping; Wang, Xiaoju; Vats, Pankaj; Cao, Xuhong; Pitchiaya, Sethuramasundaram; Su, Fengyun; Wang, Rui; Feng, Felix Y.; Wu, Yi-Mi; Lonigro, Robert J.; Robinson, Dan R.; Chinnaiyan, Arul M.

doi:10.1038/s41586-019-1347-4

Cited by 206 publications

(232 citation statements)

References 59 publications

Supporting

Mentioning

211

Contrasting

Order By: Relevance

“…Modern technologies and understanding of the epigenome allow the possibility of probing CRE(s) involved in regulating genes implicated in disease. Despite FOXA1 being recurrently mutated [5][6][7][8]11 and playing potent oncogenic roles in prostate cancer etiology 9,10,13 , the CREs involved in its transcriptional regulation are poorly understood. Understanding how FOXA1 is expressed can provide a complementary strategy to antagonize FOXA1 in prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Sequencing efforts identified coding somatic single-nucleotide variants (SNVs) mapping to FOXA1 in up to 9% [5][6][7][8][9][10] and 13% [9][10][11] of primary and mCRPC patients, respectively. These coding somatic SNVs target the Forkhead and transactivation domains of FOXA1 12 , altering its pioneering functions to promote prostate cancer development 10,13 .…”

mentioning

confidence: 99%

“…Outside of coding SNVs, whole-genome sequencing also identified somatic SNVs and indels in the 3'UTR and C-terminus of FOXA1 in~12% of mCPRC patients 14 . In addition to SNVs, the FOXA1 locus is a target of structural rearrangements in both primary and metastatic prostate cancer tumors, inclusive of duplications, amplifications, and translocations 9,10 . Taken together, FOXA1 is recurrently mutated taking into account both its coding and flanking noncoding sequences across various stages of prostate cancer development.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer

et al. 2020

View full text Add to dashboard Cite

Prostate cancer is the second most commonly diagnosed malignancy among men worldwide. Recurrently mutated in primary and metastatic prostate tumors, FOXA1 encodes a pioneer transcription factor involved in disease onset and progression through both androgen receptor-dependent and androgen receptor-independent mechanisms. Despite its oncogenic properties however, the regulation of FOXA1 expression remains unknown. Here, we identify a set of six cis-regulatory elements in the FOXA1 regulatory plexus harboring somatic singlenucleotide variants in primary prostate tumors. We find that deletion and repression of these cis-regulatory elements significantly decreases FOXA1 expression and prostate cancer cell growth. Six of the ten single-nucleotide variants mapping to FOXA1 regulatory plexus significantly alter the transactivation potential of cis-regulatory elements by modulating the binding of transcription factors. Collectively, our results identify cis-regulatory elements within the FOXA1 plexus mutated in primary prostate tumors as potential targets for therapeutic intervention.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer

et al. 2020

View full text Add to dashboard Cite

show abstract

“…To predict TFs regulating a query gene set, BART first apply Model-based Analysis of Regulation of Gene Expression (MARGE) (8) to derive a genomic cis-regulatory (enhancer) profile from the input gene set using a semi-supervised learning approach leveraging compendium ChIP-seq data for active enhancer histone mark H3K27ac, then generate a ranked list of TFs that have a highly correlated binding profile with the cis-regulatory profile. While proven to work for identifying functional TFs from many case studies (7,(9)(10)(11)(12), BART requires users to download large ChIP-seq data libraries that can be storage and memory-consuming, and sometimes runs slow primarily due to step-wise regression computation in MARGE.…”

Section: Introductionmentioning

confidence: 99%

BARTweb: a web server for transcription factor association analysis

Wang

Zhang

et al. 2020

Preprint

View full text Add to dashboard Cite

Identifying active transcription factors (TFs) that bind to cis-regulatory regions in the genome to regulate differential gene expression is a key task in gene regulation research. TF binding profiles from numerous existing ChIP-seq data can be utilized for association analysis with query data for TF identification, as alternative to DNA sequence motif analysis. Here, we present BARTweb, an interactive webserver for identifying TFs whose genomic binding patterns associate with input genomic features, by leveraging over 13,000 public ChIP-seq datasets for human and mouse. Using an updated Binding Analysis for Regulation of Transcription (BART) algorithm, BARTweb can identify functional TFs that regulate a gene set, or have a binding profile correlated with a ChIP-seq profile or enriched in a genomic region set, without a priori information of the cell type. Compared with the original BART package, BARTweb substantially reduces the execution time of a typical job by two orders of magnitude. We also show that BARTweb outperforms other existing tools in identifying true TFs from collected experimental data. BARTweb is a useful webserver for performing functional analysis of gene regulation. BARTweb is freely available at http://bartweb.org.

show abstract

“…point mutations taken together (22/31 FOXA1 mutants; AUC=0.957 vs. AUC=0.830; conf=0.988). divergences present within FOXA1 mutations in prostate cancer cohorts[48][49][50] . In the HPV-subtype of head and neck squamous carcinomas (TCGA-HNSC), NSD1 was found to have a divergent subgrouping consisting of frameshifts and nonsense mutations not overlapping with a protein domain (32/52 samples, AUC=0.976 vs. AUC=0.932, conf=0.970).…”

mentioning

confidence: 99%

Systematic interrogation of mutation groupings reveals divergent downstream expression programs within key cancer genes

Grzadkowski

Manning

Somers

et al. 2020

Preprint

View full text Add to dashboard Cite

6Genes implicated in tumorigenesis often exhibit diverse sets of genomic variants in the tumor 7 cohorts within which they are frequently mutated. We sought to identify the downstream expres-8 sion effects of these perturbations and to find whether or not this heterogeneity at the genomic 9 level is reflected in a corresponding heterogeneity at the transcriptomic level. Applying a novel 10 hierarchical framework for organizing the mutations present in a cohort along with machine learn-11 ing pipelines trained on sample expression profiles we systematically interrogated the signatures 12 associated with combinations of perturbations recurrent in cancer. This allowed us to catalogue 13 the mutations with discernible downstream expression effects across a number of tumor cohorts 14 as well as to uncover and characterize a multitude of cases where subsets of a genes mutations are 15 clearly divergent in their function from the remaining mutations of the gene. 16 Each tumor faces a common set of obstacles arising from internal dynamics and external de-18 fense mechanisms 1 . Tumor cohorts, however, are replete with diverse yet recurrent tactics for 19 overcoming these shared obstacles. Tumorigenesis can thus be perceived as a landscape within 20 which each tumor navigates a unique, multidimensional path, weaving between segments trodden 21 by other tumors. A number of the early breakthroughs in cancer treatment directly resulted from 22 coarse demarcations of these paths into distinct subtypes based on "landmarks"-usually defined 23 by mutations and/or markers derived from proteomic or transcriptomic data-that were then used 24 to engineer subtype-specific treatments [2][3][4] . 25 Although these biomarker-based treatment matching criteria have proven effective in some 26 precision medicine applications, there is a sizable subset of patients whose tumors harbor no dis-27 cernible drug targets, thus diminishing their likelihood of successful treatment and survival [5][6][7][8] . 28 Developing a more thorough understanding of the downstream effects of landmark events could 29 therefore improve tailored treatment design outcomes. In particular, we envision a tactic which de-30 tects whether two genomic alterations (or combinations thereof) have a shared downstream effect, 31 and can therefore be grouped together when weighing treatment options. This type of approach 32 should also be able to detect whether two such alterations or groupings result in divergent tran-33 scriptional programs and can therefore be considered distinct. Despite recent efforts to profile the 34 downstream effects of mutations recurrent in cancer, for most mutations we still know little about 35 the programs they trigger. As a result, most clinical guidelines depend on only a limited sub-36 set of specific perturbations within a gene or on other coarse biomarker-based demarcations 9,10 . 37A clearer discernment of the convergences and divergences between the downstream programs 38 present within cancer genes is thus a crucial prerequisi...

show abstract

Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer

Cited by 206 publications

References 59 publications

Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer

Noncoding mutations target cis-regulatory elements of the FOXA1 plexus in prostate cancer

BARTweb: a web server for transcription factor association analysis

Systematic interrogation of mutation groupings reveals divergent downstream expression programs within key cancer genes

Contact Info

Product

Resources

About