PTEN loss is a promising prognostic and predictive biomarker in prostate cancer. Because it occurs most commonly via PTEN gene deletion, we developed a clinical-grade, automated, and inexpensive immunohistochemical assay to detect PTEN loss. We studied the sensitivity and specificity of PTEN immunohistochemistry relative to four-color fluorescence in situ hybridization (FISH) for detection of PTEN gene deletion in a multi-institutional cohort of 731 primary prostate tumors. Intact PTEN immunostaining was 91% specific for the absence of PTEN gene deletion (549/602 tumors with two copies of the PTEN gene by FISH showed intact expression of PTEN by immunohistochemistry) and 97% sensitive for the presence of homozygous PTEN gene deletion (absent PTEN protein expression by immunohistochemistry in 65/67 tumors with homozygous deletion). PTEN immunohistochemistry was 65% sensitive for the presence of hemizygous PTEN gene deletion, with protein loss in 40/62 hemizygous tumors. We reviewed the 53 cases where immunohistochemistry showed PTEN protein loss and FISH showed two intact copies of the PTEN gene. On re-review, there was ambiguous immunohistochemistry loss in 6% (3/53) and failure to analyze the same tumor area by both methods in 34% (18/53). Of the remaining discordant cases, 41% (13/32) revealed hemizygous (n=8) or homozygous (n=5) PTEN gene deletion that was focal in most cases (11/13). The remaining 19 cases had two copies of the PTEN gene detected by FISH, representing truly discordant cases. Our automated PTEN immunohistochemistry assay is a sensitive method for detection of homozygous PTEN gene deletions. Immunohistochemistry screening is particularly useful to identify cases with heterogeneous PTEN gene deletion in a subset of tumor glands. Mutations, small insertions, or deletions and/or epigenetic or microRNA-mediated mechanisms may lead to PTEN protein loss in tumors with normal or hemizygous PTEN gene copy number.Modern Pathology advance online publication, 13 May 2016; doi:10.1038/modpathol.2016.88.
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2016 May 13 [Epub ahead of print]
Tamara L Lotan, Wei Wei, Olga Ludkovski, Carlos L Morais, Liana B Guedes, Tamara Jamaspishvili, Karen Lopez, Sarah T Hawley, Ziding Feng, Ladan Fazli, Antonio Hurtado-Coll, Jesse K McKenney, Jeffrey Simko, Peter R Carroll, Martin Gleave, Daniel W Lin, Peter S Nelson, Ian M Thompson, Lawrence D True, James D Brooks, Raymond Lance, Dean Troyer, Jeremy A Squire
Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA., MD Anderson Cancer Center, Houston, TX, USA., Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada., Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA., Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA., Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada., Pathology, UCSF, San Francisco, CA, USA., Canary Foundation, Palo Alto, CA, USA., MD Anderson Cancer Center, Houston, TX, USA., Vancouver Prostate Centre, Vancouver, BC, Canada., Vancouver Prostate Centre, Vancouver, BC, Canada., Pathology, Cleveland Clinic, Cleveland, OH, USA., Pathology, UCSF, San Francisco, CA, USA., Urology, UCSF, San Francisco, CA, USA., Canary Foundation, Palo Alto, CA, USA., Urology, University of Washington, Seattle, WA, USA., Urology, University of Washington, Seattle, WA, USA., Urology, UTHSCSA, San Antonio, TX, USA., Pathology, University of Washington, Seattle, WA, USA., Urology, Stanford University School of Medicine, Stanford, CA, USA., Urology, Eastern Virginia Medical School, Norfolk, VA, USA., Urology, Eastern Virginia Medical School, Norfolk, VA, USA., Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada.