Single-Cell Genetic Analysis Reveals Insights into Clonal Development of Prostate Cancers and Indicates Loss of PTEN as a Marker of Poor Prognosis

• Published in: The American journal of pathology Vol. 184; no. 10; pp. 2671 - 2686
• Main Authors: Heselmeyer-Haddad, Kerstin M, Berroa Garcia, Lissa Y, Bradley, Amanda, Hernandez, Leanora, Hu, Yue, Habermann, Jens K, Dumke, Christoph, Thorns, Christoph, Perner, Sven, Pestova, Ekaterina, Burke, Catherine, Chowdhury, Salim A, Schwartz, Russell, Schäffer, Alejandro A, Paris, Pamela L, Ried, Thomas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2014; American Society for Investigative Pathology
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - pathology; Aged; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Chromosomal Instability; Comparative Genomic Hybridization; Disease Progression; Humans; In Situ Hybridization, Fluorescence; Male; Middle Aged; Oncogene Proteins, Fusion - genetics; Pathology; Ploidies; Prognosis; Prostate - pathology; Prostatectomy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; Regular; Single-Cell Analysis
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2014.06.030

Gauging the risk of developing progressive disease is a major challenge in prostate cancer patient management. We used genetic markers to understand genomic alteration dynamics during disease progression. By using a novel, advanced, multicolor fluorescence in situ hybridization approach, we enumerated copy numbers of six genes previously identified by array comparative genomic hybridization to be involved in aggressive prostate cancer [ TBL1XR1 , CTTNBP2 , MYC (alias c- myc ), PTEN , MEN1 , and PDGFB ] in six nonrecurrent and seven recurrent radical prostatectomy cases. An ERG break-apart probe to detect TMPRSS2-ERG fusions was included. Subsequent hybridization of probe panels and cell relocation resulted in signal counts for all probes in each individual cell analyzed. Differences in the degree of chromosomal and genomic instability (ie, tumor heterogeneity) or the percentage of cells with TMPRSS2-ERG fusion between samples with or without progression were not observed. Tumors from patients that progressed had more chromosomal gains and losses, and showed a higher degree of selection for a predominant clonal pattern. PTEN loss was the most frequent aberration in progressers (57%), followed by TBL1XR1 gain (29%). MYC gain was observed in one progresser, which was the only lesion with an ERG gain, but no TMPRSS2-ERG fusion. According to our results, a probe set consisting of PTEN , MYC , and TBL1XR1 would detect progressers with 86% sensitivity and 100% specificity. This will be evaluated further in larger studies.