Abstract
Large-scale genetic aberrations that underpin prostate cancer development and progression, such as copy-number alterations (CNAs), have been described but the consequences of specific changes in many identified loci is limited. Germline SNPs in the 3q26.31 locus are associated with aggressive prostate cancer, and is the location of NAALADL2, a gene overexpressed in aggressive disease. The closest gene to NAALADL2 is TBL1XR1, which is implicated in tumour development and progression. Using publicly-available cancer genomic data we report that NAALADL2 and TBL1XR1 gains/amplifications are more prevalent in aggressive sub-types of prostate cancer when compared to primary cohorts. In primary disease, gains/amplifications occurred in 15.99% (95% CI: 13.02–18.95) and 14.96% (95% CI: 12.08–17.84%) for NAALADL2 and TBL1XR1 respectively, increasing in frequency in higher Gleason grade and stage tumours. Gains/amplifications result in transcriptional changes and the development of a pro-proliferative and aggressive phenotype. These results support a pivotal role for copy-number gains in this genetic region.
Highlights
Large-scale genetic aberrations that underpin prostate cancer development and progression, such as copy-number alterations (CNAs), have been described but the consequences of specific changes in many identified loci is limited
In this study we present evidence that somatic copy-number gains in NAALADL2 and TBL1XR1 are more frequent in high grade and aggressive forms of prostate cancer
These results are bolstered by studies which have identified CNAs in this region in metastatic castrate resistant prostate cancer (mCRPC), to our knowledge this is the first time these gains have been reported in neuroendocrine disease[47]
Summary
Large-scale genetic aberrations that underpin prostate cancer development and progression, such as copy-number alterations (CNAs), have been described but the consequences of specific changes in many identified loci is limited. Gains/ amplifications occurred in 15.99% (95% CI: 13.02–18.95) and 14.96% (95% CI: 12.08–17.84%) for NAALADL2 and TBL1XR1 respectively, increasing in frequency in higher Gleason grade and stage tumours. Gains/amplifications result in transcriptional changes and the development of a pro-proliferative and aggressive phenotype These results support a pivotal role for copy-number gains in this genetic region. An important pathological predictor of prostate cancer aggressiveness is Gleason grade, used to assess risk of progression and stratify patients for treatment, the underlying genomic changes which accompany more aggressive tumours remains incompletely defined. The same study showed even higher binding preference to HOXB13 and FOXA1 to this site, suggesting co-occupancy by these important transcription factors, both of which have been shown to be involved in AR cistrome reprogramming[15,16]
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