TMPRSS2-ERG gene fusion causing ERG overexpression precedes chromosome copy number changes in prostate carcinomas and paired HGPIN lesions.
TMPRSS2-ETS gene fusions have been found recurrently in prostate carcinomas, but not in the presumed precursor lesion, high-grade prostatic intraepithelial neoplasia (HGPIN). However, HGPIN lesions may share chromosomal changes with prostate cancer. To determine the relative order of genetic events in prostate carcinogenesis, we have analyzed 34 prostate carcinomas, 19 paired HGPIN lesions, 14 benign prostate hyperplasias, and 11 morphologically normal prostatic tissues for TMPRSS2-ERG and TMPRSS2-ETV1 rearrangements and genomic imbalances. TMPRSS2 exon 1 was fused in-frame with ERG exon 4 in 17 of 34 (50%) prostate carcinomas and in 4 of 19 (21%) HGPIN lesions, but in none of controls. The findings were further validated by sequencing analysis and by the real-time polymerase chain reaction quantification of TMPRSS2-ERG fusion transcript and the ERG exons 5/6:exons 1/2 expression ratio. Chromosome copy number changes were detected by comparative genomic hybridization in 42% of clinically confined carcinomas and in none of the 16 HGPIN lesions analyzed. We demonstrate for the first time that the TMPRSS2-ERG fusion gene can be detected in a proportion of HGPIN lesions and that this molecular rearrangement is an early event that may precede chromosome-level alterations in prostate carcinogenesis.
Cerveira
Nuno
N
Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
Ribeiro
Franclim R
FR
Peixoto
Ana
A
Costa
Vera
V
Henrique
Rui
R
Jerónimo
Carmen
C
Teixeira
Manuel R
MR
D002277:Carcinoma / Q000235:genetics*; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D018628:Gene Dosage; D050939:Gene Fusion; D006801:Humans; D008297:Male; D009693:Nucleic Acid Hybridization; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics*; D000071230:Transcriptional Regulator ERG
D004268:DNA-Binding Proteins; C072312:ERG protein, human; C095239:ETV1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human