Testing mutual exclusivity of ETS rearranged prostate cancer.
Prostate cancer is a clinically heterogeneous and multifocal disease. More than 80% of patients with prostate cancer harbor multiple geographically discrete cancer foci at the time of diagnosis. Emerging data suggest that these foci are molecularly distinct consistent with the hypothesis that they arise as independent clones. One of the strongest arguments is the heterogeneity observed in the status of E26 transformation specific (ETS) rearrangements between discrete tumor foci. The clonal evolution of individual prostate cancer foci based on recent studies demonstrates intertumoral heterogeneity with intratumoral homogeneity. The issue of multifocality and interfocal heterogeneity is important and has not been fully elucidated due to lack of the systematic evaluation of ETS rearrangements in multiple tumor sites. The current study investigates the frequency of multiple gene rearrangements within the same focus and between different cancer foci. Fluorescence in situ hybridization (FISH) assays were designed to detect the four most common recurrent ETS gene rearrangements. In a cohort of 88 men with localized prostate cancer, we found ERG, ETV1, and ETV5 rearrangements in 51% (44/86), 6% (5/85), and 1% (1/86), respectively. None of the cases demonstrated ETV4 rearrangements. Mutual exclusiveness of ETS rearrangements was observed in the majority of cases; however, in six cases, we discovered multiple ETS or 5' fusion partner rearrangements within the same tumor focus. In conclusion, we provide further evidence for prostate cancer tumor heterogeneity with the identification of multiple concurrent gene rearrangements.
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Maria A
MA
Svensson
Christopher J
CJ
LaFargue
Theresa Y
TY
MacDonald
Dorothee
D
Pflueger
Naoki
N
Kitabayashi
Ashley M
AM
Santa-Cruz
Karl E
KE
Garsha
Ubaradka G
UG
Sathyanarayana
Janice P
JP
Riley
Chol S
CS
Yun
Dea
D
Nagy
Jerry W
JW
Kosmeder
Gary A
GA
Pestano
Ashutosh K
AK
Tewari
Francesca
F
Demichelis
Mark A
MA
Rubin
D000368:Aged; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D050939:Gene Fusion; D015321:Gene Rearrangement; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D008297:Male; D008875:Middle Aged; D057054:Molecular Imaging / Q000379:methods; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D045663:Quantum Dots; D046888:Tissue Array Analysis; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D000071230:Transcriptional Regulator ERG
D004268:DNA-Binding Proteins; C072312:ERG protein, human; C095239:ETV1 protein, human; C086680:ETV5 protein, human; D015514:Oncogene Proteins, Fusion; C515553:TMPRSS2-ERG fusion protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG