Genome-wide linkage analysis of TMPRSS2-ERG fusion in familial prostate cancer.
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.
Hofer
Matthias D
MD
Department of Pathology, Brigham and Women's Hospital, 2Harvard Medical School, Boston, Massachusetts, USA.
Kuefer
Rainer
R
Maier
Christiane
C
Herkommer
Kathleen
K
Perner
Sven
S
Demichelis
Francesca
F
Paiss
Thomas
T
Vogel
Walter
W
Rubin
Mark A
MA
Hoegel
Josef
J
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
D015514:Oncogene Proteins, Fusion; C515553:TMPRSS2-ERG fusion protein, human