Genomic deletion of MAP3K7 at 6q12-22 is associated with early PSA recurrence in prostate cancer and absence of TMPRSS2:ERG fusions.
6q12-22 is the second most commonly deleted genomic region in prostate cancer. Mapping studies have described a minimally deleted area at 6q15, containing MAP3K7/TAK1, which was recently shown to have tumor suppressive properties. To determine prevalence and clinical significance of MAP3K7 alterations in prostate cancer, a tissue microarray containing 4699 prostate cancer samples was analyzed by fluorescence in situ hybridization. Heterozygous MAP3K7 deletions were found in 18.48% of 2289 interpretable prostate cancers. MAP3K7 deletions were significantly associated with advanced tumor stage (P<0.0001), high Gleason grade (P<0.0001), lymph node metastasis (P<0.0108) and early biochemical recurrence (P<0.0001). MAP3K7 alterations were typically limited to the loss of one allele as homozygous deletions were virtually absent and sequencing analyses revealed no evidence for MAP3K7 mutations in 15 deleted and in 14 non-deleted cancers. There was a striking inverse association of MAP3K7 deletions and TMPRSS2:ERG fusion status with 26.7% 6q deletions in 1125 ERG-negative and 11.1% 6q deletions in 1198 ERG-positive cancers (P<0.0001). However, the strong prognostic role of 6q deletions was retained in both ERG-positive and ERG-negative cancers (P<0.0001 each). In summary, our study identifies MAP3K7 deletion as a prominent feature in ERG-negative prostate cancer with strong association to tumor aggressiveness. MAP3K7 alterations are typically limited to one allele of the gene. Together with the demonstrated tumor suppressive function in cell line experiments and lacking evidence for inactivation through hypermethylation, these results indicate MAP3K7 as a gene for which haploinsufficency is substantially tumorigenic.
Institute of Pathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Martina
M
Kluth
Jana
J
Hesse
Anna
A
Heinl
Antje
A
Krohn
Stefan
S
Steurer
Hüseyin
H
Sirma
Ronald
R
Simon
Pascale-Sophia
PS
Mayer
Udo
U
Schumacher
Katharina
K
Grupp
Jakob R
JR
Izbicki
Klaus
K
Pantel
Ekkehard
E
Dikomey
Jan O
JO
Korbel
Christoph
C
Plass
Guido
G
Sauter
Thorsten
T
Schlomm
Sarah
S
Minner
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D015153:Blotting, Western; D002896:Chromosomes, Human, Pair 6; D017353:Gene Deletion; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D020930:MAP Kinase Kinase Kinases / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D016133:Polymerase Chain Reaction; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D046888:Tissue Array Analysis; D000099151:MAP Kinase Kinase Kinase 7
D014408:Biomarkers, Tumor; D020930:MAP Kinase Kinase Kinases; D015514:Oncogene Proteins, Fusion; D017430:Prostate-Specific Antigen; D000099151:MAP Kinase Kinase Kinase 7; C515553:TMPRSS2-ERG fusion protein, human