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Genome-wide linkage analysis of TMPRSS2-ERG fusion in familial prostate cancer.

TitleGenome-wide linkage analysis of TMPRSS2-ERG fusion in familial prostate cancer.
Publication TypeJournal Article
Year of Publication2009
AuthorsHofer MD, Kuefer R, Maier C, Herkommer K, Perner S, Demichelis F, Paiss T, Vogel W, Rubin MA, Hoegel J
JournalCancer Res
Volume69
Issue2
Pagination640-6
Date Published2009 Jan 15
ISSN1538-7445
KeywordsAged, Chromosomes, Human, Pair 21, Cohort Studies, Genetic Linkage, Genetic Predisposition to Disease, Genome, Human, Humans, In Situ Hybridization, Fluorescence, Male, Middle Aged, Neoplasm Staging, Oncogene Proteins, Fusion, Prostatic Neoplasms
Abstract

Fusion of the 5'-untranslated region of androgen-regulated TMPRSS2 promoter with ETS transcription factor family members is found frequently in prostate cancers, and recent work suggests that the most common TMPRSS2-ERG fusion is associated with an aggressive clinical phenotype compared with fusion-negative prostate cancer. Thus far, analysis of the fusion has been limited to sporadic cases of prostate cancer. In the current study, we explore for an enrichment of TMPRSS2-ERG fusion in familial prostate cancer. TMPRSS2-ERG fusion was identified using a break-apart fluorescence in situ hybridization assay on tissue microarrays. Presence of TMPRSS2-ERG fusion was associated with higher Gleason scores (P = 0.027). Of 75 patients with established history of prostate cancer, we detected the TMPRSS2-ERG fusion in 44 (59%) patients. Almost three quarters (73%) of fusion-positive patients accumulated within 16 specific families whereas only 27% were single fusion-positive cases within one family. Based on reported prevalence rates, we calculated a sibling recurrence risk ratio of up to 18.9. A subset (63%) of families with uniformly TMPRSS2-ERG-positive prostate cancer underwent a genome-wide linkage scan at 500 markers. This revealed several loci located on chromosomes #9, #18, and X that were suggestive of linkage to the TMPRSS2-ERG fusion-positive prostate cancer phenotype with linkage-of-disease scores up to 2.16 and nonparametric linkage scores up to 2.77. This suggests the presence of an inherited susceptibility to developing the TMPRSS2-ERG fusion. Given the association of TMPRSS2-ERG fusion and aggressive prostate cancer, close surveillance of relatives of patients with established fusion-positive prostate cancer or a family history of prostate cancer in general would be warranted.

DOI10.1158/0008-5472.CAN-08-2008
Alternate JournalCancer Res.
PubMed ID19147579