title: Genome-wide linkage analysis of TMPRSS2-ERG fusion in familial prostate cancer.
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.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, 2Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Matthias D
authors.initials: MD
authors.lastname: Hofer
authors.forename: Rainer
authors.initials: R
authors.lastname: Kuefer
authors.forename: Christiane
authors.initials: C
authors.lastname: Maier
authors.forename: Kathleen
authors.initials: K
authors.lastname: Herkommer
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
authors.forename: Francesca
authors.initials: F
authors.lastname: Demichelis
authors.forename: Thomas
authors.initials: T
authors.lastname: Paiss
authors.forename: Walter
authors.initials: W
authors.lastname: Vogel
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.forename: Josef
authors.initials: J
authors.lastname: Hoegel
mesh_terms: D000368:Aged; D002891:Chromosomes, Human, Pair 21; D015331:Cohort Studies; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D015514:Oncogene Proteins, Fusion; C515553:TMPRSS2-ERG fusion protein, human