The Genomics of Prostate Cancer: emerging understanding with technologic advances

Rubin, Mark A.; Demichelis, Francesca

doi:10.1038/modpathol.2017.166

Cited by 48 publications

(40 citation statements)

References 139 publications

(180 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although the MIPOL1 loci (the adjacent coding gene) is often described as the insertion point for these ETV1 translocations, the 38 kb region between MIPOL1 and FOXA1 harbors the non-coding gene AL121790.1 (also known as ENSG00000258414 and EST14 ) that has been reported to exhibit androgen-regulated and prostate-specific expression 22 . Fusion of AL121790.1 with ETV1 is consistent with other ETS rearrangements in prostate cancer, which typically involve an AR driven promoter 1 . Analysis of RNA sequencing data from 33 cancer types revealed that AL121790.1 expression is strongly correlated with FOXA1 expression (Spearman correlation = 0.84) (Fig.…”

Section: Resultssupporting

confidence: 73%

“…Prostate cancer is the second leading cause of cancer-related death in men, and has a well-described somatic coding genome defined by distinct molecular subclasses and high heterogeneity 1 . The mutation rate of prostate cancer is relatively low (0.9 and 4.4 mutations per Mb in primary and metastatic disease, respectively) 2,3 and is characterized by an age-related CG>TG mutational signature 4 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Frequent mutation of the FOXA1 untranslated region in prostate cancer

et al. 2018

View full text Add to dashboard Cite

Prostate cancer has a low somatic mutation rate but non-coding regions remain underexplored. We sequenced the untranslated regions (UTRs) of 72 established driver genes in 428 patients with metastatic prostate cancer and identified FOXA1 3′-UTR mutations in 12% of patients. The mutations were predominantly insertions or deletions, covered the entire UTR without motif enrichment, and were not detected in other cancers. FOXA1 lies in head-on orientation with the androgen-regulated non-coding gene AL121790.1, resulting in strong prostate lineage-specific bidirectional transcription across the FOXA1 3′-UTR. This suggests transcriptional activity as a cause for the localized hypermutation. The indel-dominant pattern of somatic mutation extends into the FOXA1 coding region, where it is shaped by clonal selection to yield a cluster of non-frameshift indels inside the forkhead domain. Somatic FOXA1 3′-UTR mutations may prove useful for diagnostic and screening approaches, given their high frequency and lineage specificity.

show abstract

Section: Resultssupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Frequent mutation of the FOXA1 untranslated region in prostate cancer

et al. 2018

View full text Add to dashboard Cite

show abstract

“…While biopsy-based RNA expression signatures have shown clinical utility in several cancers, understanding the biology of all clinically important foci, within a given organ, can be challenging when the multiplicity as well as the histologic and genomic diversity of cancer foci is high. Prostate cancer is heterogeneous and is multifocal, with multiple, genomically independent tumors identified in up to 80% of men undergoing radical prostatectomy for clinically localized disease (12)(13)(14)(15). Hence, there has been enormous interest in identifying prostate cancer prognostic biomarkers that are unaffected by tissue sampling bias.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic heterogeneity in multifocal prostate cancer

et al. 2018

Self Cite

View full text Add to dashboard Cite

BACKGROUND. Commercial gene expression assays are guiding clinical decision making in patients with prostate cancer, particularly when considering active surveillance. Given heterogeneity and multifocality of primary prostate cancer, such assays should ideally be robust to the coexistence of unsampled higher grade disease elsewhere in the prostate in order to have clinical utility. Herein, we comprehensively evaluated transcriptomic profiles of primary multifocal prostate cancer to assess robustness to clinically relevant multifocality. METHODS. We designed a comprehensive, multiplexed targeted RNA-sequencing assay capable of assessing multiple transcriptional classes and deriving commercially available prognostic signatures, including the Myriad Prolaris Cell Cycle Progression score, the Oncotype DX Genomic Prostate Score, and the GenomeDX Decipher Genomic Classifier. We applied this assay to a retrospective, multi-institutional cohort of 156 prostate cancer samples. Derived commercial biomarker scores for 120 informative primary prostate cancer samples from 44 cases were determined and compared. RESULTS. Derived expression scores were positively correlated with tumor grade (r S = 0.53-0.73; all P < 0.001), both within the same case and across the entire cohort. In cases of extreme gradediscordant multifocality (co-occurrence of grade group 1 [GG1] and ≥GG4 foci], gene expression scores were significantly lower in low-(GG1) versus high-grade (≥GG4) foci (all P < 0.001). No significant differences in expression scores, however, were observed between GG1 foci from prostates with and without coexisting higher grade cancer (all P > 0.05). CONCLUSIONS. Multifocal, low-grade and high-grade prostate cancer foci exhibit distinct prognostic expression signatures. These findings demonstrate that prognostic RNA expression assays performed on low-grade prostate cancer biopsy tissue may not provide meaningful information on the presence of coexisting unsampled aggressive disease.

show abstract

“…Genome sequencing studies in PCa have revealed many recurrent DNA alterations leading to deregulated biological processes involved in prostate development, cell-cycle regulation, androgen signaling, and chromatin organization, among others [ 15 , 16 , 17 ]. From these data, it has also been established that PCa is a cancer entity with a relatively low mutational burden of approximately 1 mutation per megabase [ 18 ].…”

Section: The Genomic Landscape Of Primary Prostate Cancermentioning

confidence: 99%

Genome-Based Classification and Therapy of Prostate Cancer

et al. 2018

View full text Add to dashboard Cite

In the past decade, multi-national and multi-center efforts were launched to sequence prostate cancer genomes, transcriptomes, and epigenomes with the aim of discovering the molecular underpinnings of tumorigenesis, cancer progression, and therapy resistance. Multiple biological markers and pathways have been discovered to be tumor drivers, and a molecular classification of prostate cancer is emerging. Here, we highlight crucial findings of these genome-sequencing projects in localized and advanced disease. We recapitulate the utility and limitations of current clinical practices to diagnosis, prognosis, and therapy, and we provide examples of insights generated by the molecular profiling of tumors. Novel treatment concepts based on these molecular alterations are currently being addressed in clinical trials and will lead to an enhanced implementation of precision medicine strategies.

show abstract

The Genomics of Prostate Cancer: emerging understanding with technologic advances

Cited by 48 publications

References 139 publications

Frequent mutation of the FOXA1 untranslated region in prostate cancer

Frequent mutation of the FOXA1 untranslated region in prostate cancer

Transcriptomic heterogeneity in multifocal prostate cancer

Genome-Based Classification and Therapy of Prostate Cancer

Contact Info

Product

Resources

About