PTEN genomic deletion is an early event associated with ERG gene rearrangements in prostate cancer

Abstract

diagnostic category from benign prostate tissue to HGPIN and PCA ( P ≤ 0.001). Furthermore, in 29 patients where all three tissues were available, PTEN genomic aberrations in PCA were significantly different from those in benign tissue ( P = 0.005) and HGPIN ( P = 0.02), reflecting the accumulation of genomic aberrations in the early stages of disease progression. Within this cohort, 71.4% of homozygous and 44.2% of hemizygous PTEN deletions occurred simultaneously with ERG rearrangements ( P ≈ 0). Stratified according to Gleason score (GS), hemizygous PTEN deletions across various GS groups were observed at a higher frequency than homozygous deletions. However, PTEN homozygous deletions showed positive trends with higher GS, increasing in poorly differentiated PCA (GS 8-10) in comparison to moderately and well differentiated tumours (GS 6 and 7). CONCLUSIONWe show significant association between ERG gene rearrangements and PTEN genomic aberrations in subset of PCA. Our analysis also provides further support for the observation that homozygous PTEN deletions can occur within the subset of HGPIN lesions, and shows accumulating genetic aberrations with disease progression, evidenced by higher detection in PCA than in HGPIN and more PTEN homozygous deletions in GS 8-10 than in 6-7. KEYWORDSERG rearrangements, PTEN , fluorescence insitu hybridization, high-grade prostatic intra-epithelial neoplasia, prostate cancer, Gleason score, disease progression What's known on the subject? and What does the study add? So far we know that ERG rearrangements and PTEN deletions interact to induce prostate cancer in transgenic mice. The study confirms that an association also exists between the two genetic aberrations in human prostate cancer, as there is increased incidence of PTEN deletions in cases with ERG rearrangements. OBJECTIVETo investigate the interaction between, and significance of, ERG gene rearrangements and PTEN genomic deletions in relation to the development and progression of prostate cancer (PCA). PATIENTS AND METHODSWe interrogated an initial cohort of 220 men with localized PCA using fluorescence in situ hybridization for ERG rearrangements and PTEN genomic deletions. RESULTSThe incidences of ERG rearrangements and PTEN deletions in PCA were significantly higher than in high-grade prostatic intraepithelial neoplasia (HGPIN) and benign prostate tissue ( P < 0.001). ERG rearrangements and PTEN deletions were detected in 41.9 and 42.6% of patients' tumours, respectively. ERG rearrangements were never detected in benign prostate tissue, while PTEN aberrations were present at a basal level of 4.6%. PTEN hemizygous deletions showed higher frequency than homozygous deletions within each

Oncogene-specific activation of tyrosine kinase networks during prostate cancer progression

“…We recapitulated different stages of prostate cancer ranging from prostate intraepithelial neoplasia (PIN) to adenocarcinoma using the prostate in vivo regeneration model system (25,26). We chose four of the most commonly perturbed oncogenes in prostate cancer, both in androgen-dependent and -independent states: activated AKT (myristoylated AKT, resembling PTEN deletion, ∼40-70% of prostate cancers), AR amplification (∼20-60% of prostate cancers), ERG rearrangements (∼40-70% of prostate cancers), and activated K-RAS (K-RASG12V, resembling RAS/RAF pathway activation, observed in ∼40-50% of prostate cancers) (7,8,11,(27)(28)(29)(30).…”

Detection ofERGgene rearrangements andPTENdeletions in unsuspected prostate cancer of the transition zone

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14] More recently, several studies demonstrated significant association between ERG rearrangements and PTEN genomic deletions in localized PCA with prognostic implications. [15][16][17][18][19][20] Moreover, studies in transgenic mouse models confirmed that both aberrant expression of ERG and deletion of PTEN are required to develop frank invasive carcinoma, indicating that both genetic aberrations play an important role in driving prostate cancer development and progression. More comprehensive studies are, however required to determine the prognostic significance of these biomarkers for the future clinical management of PCA.…”

Heterogeneity and chronology of PTEN deletion and ERG fusion in prostate cancer

“…6,7 Studies comparing PTEN and ERG fusion status have demonstrated that these alterations frequently coexist. 3,4,[8][9][10][11][12] PTEN deletions are about three times more frequent in fusion-positive prostate cancers than in fusion-negative cancers. 10 The mechanisms explaining the frequent coexistence of PTEN deletions and TMPRSS2:ERG fusions in prostate cancer are unknown.…”