Genomic deletion of MAP3K7 at 6q12-22 is associated with early PSA recurrence in prostate cancer and absence of TMPRSS2:ERG fusions

TY - JOUR

T1 - Genomic deletion of MAP3K7 at 6q12-22 is associated with early PSA recurrence in prostate cancer and absence of TMPRSS2:ERG fusions

AU - Kluth, Martina

AU - Hesse, Jana

AU - Heinl, Anna

AU - Krohn, Antje

AU - Steurer, Stefan

AU - Sirma, Hüseyin

AU - Simon, Ronald

AU - Mayer, Pascale-Sophia

AU - Schumacher, Udo

AU - Grupp, Katharina

AU - Izbicki, Jakob R

AU - Pantel, Klaus

AU - Dikomey, Ekkehard

AU - Korbel, Jan O

AU - Plass, Christoph

AU - Sauter, Guido

AU - Schlomm, Thorsten

AU - Minner, Sarah

PY - 2013/7/1

Y1 - 2013/7/1

N2 - 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.

AB - 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.

KW - Adult

KW - Aged

KW - Blotting, Western

KW - Chromosomes, Human, Pair 6

KW - Gene Deletion

KW - Humans

KW - In Situ Hybridization, Fluorescence

KW - MAP Kinase Kinase Kinases

KW - Male

KW - Middle Aged

KW - Neoplasm Recurrence, Local

KW - Oncogene Proteins, Fusion

KW - Polymerase Chain Reaction

KW - Prostate-Specific Antigen

KW - Prostatic Neoplasms

KW - Tissue Array Analysis

KW - Tumor Markers, Biological

U2 - 10.1038/modpathol.2012.236

DO - 10.1038/modpathol.2012.236

M3 - SCORING: Journal article

C2 - 23370768

VL - 26

SP - 975

EP - 983

JO - MODERN PATHOL

JF - MODERN PATHOL

SN - 0893-3952

IS - 7

ER -