TY - JOUR
T1 - Characterization of ETS gene aberrations in select histologic variants of prostate carcinoma
AU - Han, Bo
AU - Mehra, Rohit
AU - Suleman, Khalid
AU - Tomlins, Scott A.
AU - Wang, Lei
AU - Singhal, Nishi
AU - Linetzky, Katherine A.
AU - Palanisamy, Nallasivam
AU - Zhou, Ming
AU - Chinnaiyan, Arul M.
AU - Shah, Rajal B.
N1 - Funding Information:
We thank Anjana Menon for technical assistance and Jill Granger for editorial review of this article. This study was supported in part by Department of Defense (PC040517, W81XWH-06-1-0224), the National Institutes of Health (Prostate SPORE P50CA69568, RO1 CA102872), and the Early Detection Research Network (UO1 CA111275-01). AMC was supported by a Clinical Translational Research Award from the Burroughs Welcome Foundation and an award by the Doris Duke Charitable Foundation. SAT is a fellow of the Medical Scientist Training Program and is supported by the GPC Biotech Young Investigator Award from the Prostate Cancer Foundation.
PY - 2009/9
Y1 - 2009/9
N2 - Histologic variants of prostate carcinoma account for 5-10% of the disease and are typically seen in association with conventional acinar carcinoma. These variants often differ from the latter in clinical, immunophenotypic, and biologic potential. Recently, recurrent gene fusions between the androgen-regulated gene TMPRSS2 and the ETS transcription factors ERG, ETV1, ETV4, or ETV5 have been identified in a majority of conventional prostate carcinomas. However, the frequency and significance of this critical molecular event is unknown in the histologic variants of prostate carcinoma. Here, we used break-apart fluorescence in situ hybridization to assess TMPRSS2 and ETS aberrations in a series of select histologic variants: foamy gland carcinoma (N=17), ductal adenocarcinoma (N=18), mucinous carcinoma (N=18), and small cell carcinoma (N=7). A histologic variation of acinar adenocarcinoma, demonstrating glomeruloid morphology (N=9), was also investigated. Overall, 55% of histologic variant or variation morphologies demonstrated ETS aberrations (ERG in 54% and ETV1 in 1%). TMPRSS2:ERG fusion was identified in 83% (15/18), 71% (5/7), 50% (9/18), 33% (3/9), and 29% (5/17) of mucinous, small cell, ductal, glomeruloid, and foamy gland prostate carcinomas, respectively. Previously, we reported that 100% of androgen-independent metastatic prostate carcinomas harboring TMPRSS2:ERG gene fusion were associated with interstitial deletion (Edel). Interestingly, ERG rearrangement in small cell carcinomas occurred exclusively through Edel, supporting the notion that TMPRSS2:ERG with Edel is an aggressive molecular subtype. SPINK1, a biomarker expressed exclusively in a subset of ETS negative prostate carcinomas, was expressed in 6% of ETS negative histologic variants, specifically in ductal adenocarcinoma. Notably, 88% (43/49) variant morphologies in this cohort showed concordance of TMPRSS2:ERG fusion with associated conventional acinar type, suggesting that variant morphology is clonally related to the latter. Overall, our data provide insight into the origin, molecular mechanism, and phenotypic association of ETS fusions in histologic variants of prostate carcinoma.
AB - Histologic variants of prostate carcinoma account for 5-10% of the disease and are typically seen in association with conventional acinar carcinoma. These variants often differ from the latter in clinical, immunophenotypic, and biologic potential. Recently, recurrent gene fusions between the androgen-regulated gene TMPRSS2 and the ETS transcription factors ERG, ETV1, ETV4, or ETV5 have been identified in a majority of conventional prostate carcinomas. However, the frequency and significance of this critical molecular event is unknown in the histologic variants of prostate carcinoma. Here, we used break-apart fluorescence in situ hybridization to assess TMPRSS2 and ETS aberrations in a series of select histologic variants: foamy gland carcinoma (N=17), ductal adenocarcinoma (N=18), mucinous carcinoma (N=18), and small cell carcinoma (N=7). A histologic variation of acinar adenocarcinoma, demonstrating glomeruloid morphology (N=9), was also investigated. Overall, 55% of histologic variant or variation morphologies demonstrated ETS aberrations (ERG in 54% and ETV1 in 1%). TMPRSS2:ERG fusion was identified in 83% (15/18), 71% (5/7), 50% (9/18), 33% (3/9), and 29% (5/17) of mucinous, small cell, ductal, glomeruloid, and foamy gland prostate carcinomas, respectively. Previously, we reported that 100% of androgen-independent metastatic prostate carcinomas harboring TMPRSS2:ERG gene fusion were associated with interstitial deletion (Edel). Interestingly, ERG rearrangement in small cell carcinomas occurred exclusively through Edel, supporting the notion that TMPRSS2:ERG with Edel is an aggressive molecular subtype. SPINK1, a biomarker expressed exclusively in a subset of ETS negative prostate carcinomas, was expressed in 6% of ETS negative histologic variants, specifically in ductal adenocarcinoma. Notably, 88% (43/49) variant morphologies in this cohort showed concordance of TMPRSS2:ERG fusion with associated conventional acinar type, suggesting that variant morphology is clonally related to the latter. Overall, our data provide insight into the origin, molecular mechanism, and phenotypic association of ETS fusions in histologic variants of prostate carcinoma.
KW - ETS
KW - Fluorescence in situ hybridization
KW - Histologic variant
KW - Prostate carcinoma
KW - Rearrangement
UR - http://www.scopus.com/inward/record.url?scp=69549135270&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=69549135270&partnerID=8YFLogxK
U2 - 10.1038/modpathol.2009.79
DO - 10.1038/modpathol.2009.79
M3 - Article
C2 - 19465903
AN - SCOPUS:69549135270
SN - 0893-3952
VL - 22
SP - 1176
EP - 1185
JO - Modern Pathology
JF - Modern Pathology
IS - 9
ER -