Minimum altered regions in early prostate cancer progression identified by high resolution whole genome tiling path BAC array comparative hybridization.
BACKGROUND
Carcinoma of the prostate (CaP) is a serious health problem. The altered molecular mechanisms that lead to this disease are poorly understood.


METHODS
Specimens from radical prostatectomies and blood were collected from 18 CaP surgery patients. For CGH studies, 20 CaP-related samples (16 Gleason grade 3, 3 higher grades, 1 BPH sample) and 18 samples of patient-matched normal epithelial cells were obtained by laser-assisted microdissection from frozen sections of the 18 prostatectomy specimens. High resolution SMRT aCGH was used to compare genomic profiles of prostatic samples to patient-matched blood and pooled female DNA. TMPRSS2-ERG fusion transcript analysis was performed by RT-PCR in relation to alterations detected at the TMPRSS2 locus.


RESULTS
Our comprehensive aCGH approach allowed us to define 35 regions of recurrent alterations while excluding germline copy number polymorphisms. Novel regions identified include 2q14.2, containing INHBB, and 17q21.31. The TMPRSS2 locus at 21q22.3 may be a hotspot for rearrangements with 75% of the alterations resulting in the expression of a TMPRSS2-ERG fusion transcript. Differences in fusion expression in different areas in an individual tumor focus and expression in adjacent normal epithelium supported intrafocal heterogeneity and field cancerization, respectively. Both features challenge our efforts to develop more objective markers for diagnosis and prediction of the severity of CaP.


CONCLUSIONS
The high-density array enabled precise mapping of genomic alterations and consequently definition of minimum altered regions smaller than previously reported thus facilitating identification of those genes that contribute to the cancer transformation process.
Watson
Spencer K
SK
Department of Cancer Genetics and Developmental Biology, Vancouver, British Columbia, Canada.
Woolcock
Bruce W
BW
Fee
John N
JN
Bainbridge
Terry C
TC
Webber
Douglas
D
Kinahan
Thomas J
TJ
Lam
Wan L
WL
Vielkind
Juergen R
JR
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D019457:Chromosome Breakage; D022202:Chromosomes, Artificial, Bacterial; D002877:Chromosomes, Human; D055028:Comparative Genomic Hybridization; D018450:Disease Progression; D004847:Epithelial Cells / Q000502:physiology; D018628:Gene Dosage; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics / Q000379:methods; D006801:Humans; D008297:Male; D042282:Microdissection; D011110:Polymorphism, Genetic; D011467:Prostate / Q000473:pathology / Q000502:physiology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology