Integrated analysis of the genomic instability of PTEN in clinically insignificant and significant prostate cancer

Stephen J. Murphy, Robert Jeffrey Karnes, Farhad Kosari, B. Edgardo R Parilla Castellar, Benjamin R. Kipp, Sarah H. Johnson, Simone Terra, Faye R. Harris, Geoffrey C. Halling, Janet L Schaefer Klein, Aqsa Nasir, Eric Bergstrahl, Laureano J. Rangel, William R. Sukov, George Vasmatzis, John C. Cheville

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Patients with clinically insignificant prostate cancer remain a major over-treated population. PTEN loss is one of the most recurrent alterations in prostate cancer associated with an aggressive phenotype, however, the occurrence of PTEN loss 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 PTEN loss 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 PTEN structural alterations. Fluorescence in situ hybridization probes were constructed from the sequencing data to detect the spectrum of these PTEN alterations. PTEN loss by mate pair sequencing and fluorescence in situ hybridization 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 PTEN loss, PTEN alterations were detected in both Gleason pattern 3 and 4 in 57% of cases by mate pair sequencing, 75% by in situ hybridization and 86% by immunohistochemistry. PTEN loss by sequencing was strongly associated with TMPRSS2-ERG fusion, biochemical recurrence, PTEN loss by in situ hybridization and protein loss by immunohistochemistry. The complex nature of PTEN rearrangements was unveiled by sequencing, detailing the heterogeneous events leading to homozygous loss of PTEN. PTEN point mutation was present in 5% of clinically significant tumors and not in insignificant cancer or high-grade prostatic intraepithelial neoplasia. PTEN loss is infrequent in clinically insignificant prostate cancer, and is associated with higher grade tumors. Detection of PTEN loss in Gleason score 6 cancer in a needle biopsy specimen indicates a higher likelihood of clinically significant prostate cancer.

Original languageEnglish (US)
Pages (from-to)143-156
Number of pages14
JournalModern Pathology
Volume29
Issue number2
DOIs
StatePublished - Feb 1 2016

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Murphy, S. J., Karnes, R. J., Kosari, F., Castellar, B. E. R. P., Kipp, B. R., Johnson, S. H., Terra, S., Harris, F. R., Halling, G. C., Klein, J. L. S., Nasir, A., Bergstrahl, E., Rangel, L. J., Sukov, W. R., Vasmatzis, G., & Cheville, J. C. (2016). Integrated analysis of the genomic instability of PTEN in clinically insignificant and significant prostate cancer. Modern Pathology, 29(2), 143-156. https://doi.org/10.1038/modpathol.2015.136