Patients with clinically insignificant prostate cancer remain a major over-treated population. PTENloss is one of the most recurrent alterations in prostate cancer associated with an aggressive phenotype, however, the occurrence of PTENloss in insignificant prostate cancer has not been reported and its role in the separation of insignificant from significant prostate cancer is unclear. An integrated analysis of PTENloss was, therefore, performed for structural variations, point mutations and protein expression in clinically insignificant (48 cases) and significant (76 cases) prostate cancers treated by radical prostatectomy. Whole-genome mate pair sequencing was performed on tumor cells isolated by laser capture microdissection to characterize PTENstructural alterations. Fluorescence in situhybridization probes were constructed from the sequencing data to detect the spectrum of these PTENalterations. PTENloss by mate pair sequencing and fluorescence in situhybridization occurred in 2% of insignificant, 13% of large volume Gleason score 6, and 46% of Gleason score 7 and higher cancers. In Gleason score 7 cancers with PTENloss, PTENalterations were detected in both Gleason pattern 3 and 4 in 57% of cases by mate pair sequencing, 75% by in situhybridization and 86% by immunohistochemistry. PTENloss by sequencing was strongly associated with TMPRSS2-ERGfusion, biochemical recurrence, PTENloss by in situhybridization and protein loss by immunohistochemistry. The complex nature of PTENrearrangements was unveiled by sequencing, detailing the heterogeneous events leading to homozygous loss of PTEN. PTENpoint mutation was present in 5% of clinically significant tumors and not in insignificant cancer or high-grade prostatic intraepithelial neoplasia. PTENloss is infrequent in clinically insignificant prostate cancer, and is associated with higher grade tumors. Detection of PTENloss in Gleason score 6 cancer in a needle biopsy specimen indicates a higher likelihood of clinically significant prostate cancer.