Up-regulation of mismatch repair genes MSH6, PMS2 and MLH1 parallels development of genetic instability and is linked to tumor aggressiveness and early PSA recurrence in prostate cancer.
DNA mismatch repair (MMR) is integral to the maintenance of genetic stability. We aimed to evaluate the clinical impact of MMR gene expression in prostate cancer. The MMR genes MSH6, MLH1 and PMS2 were analyzed by immunohistochemistry on a tissue microarray containing 11152 prostate cancer specimens. Results were compared with ETS-related gene status and deletions of PTEN, 3p13, 5q21 and 6q15. MSH6, MLH1 and PMS2 expression was detectable in 89.5%, 85.4% and 85.0% of cancers and was particularly strong in cancers with advanced pathological tumor stage (P < 0.0001 each), high Gleason grade (P < 0.0001 each), nodal metastasis (P ≤ 0.0083) and early biochemical recurrence (P < 0.0001). High levels of MMR gene expression paralleled features of genetic instability, such as the number of genomic deletions per cancer; strong expression of all three MMR genes was found in 24%, 29%, 30%, 33% and 42% of cancers with no, one, two, three or four to five deletions (P < 0.0001). The prognostic value of the analyzed MMR genes was largely driven by the subset of cancers lacking ERG fusion (P < 0.0001), while the prognostic impact of MMR gene overexpression was only marginal in ERG-positive cancers. Multivariate analyses suggested an independent prognostic relevance of MMR genes in ERG-negative prostate cancers when compared with prognostic parameters available at the time of initial biopsy. In conclusion, MMR overexpression is common in prostate cancer and is linked to poor outcome as well as features indicating genetic instability. ERG fusion should be analyzed along with MMR gene expression in potential clinical tests.
Institute of Pathology.
Waldemar
W
Wilczak
Institute of Pathology.
Semin
S
Rashed
Institute of Pathology.
Claudia
C
Hube-Magg
Institute of Pathology.
Martina
M
Kluth
Institute of Pathology, r.simon@uke.de.
Ronald
R
Simon
Institute of Pathology.
Franziska
F
Büscheck
Institute of Pathology.
Till Sebastian
TS
Clauditz
General, Visceral and Thoracic Surgery Department and Clinic.
Katharina
K
Grupp
Institute of Pathology.
Sarah
S
Minner
Institute of Pathology.
Maria Christina
MC
Tsourlakis
Institute of Pathology.
Christina
C
Möller-Koop
Martini-Clinic, Prostate Cancer Center and.
Markus
M
Graefen
Martini-Clinic, Prostate Cancer Center and.
Meike
M
Adam
Martini-Clinic, Prostate Cancer Center and.
Alexander
A
Haese
Institute of Pathology.
Corinna
C
Wittmer
Institute of Pathology.
Guido
G
Sauter
General, Visceral and Thoracic Surgery Department and Clinic.
Jakob Robert
JR
Izbicki
Martini-Clinic, Prostate Cancer Center and.
Hartwig
H
Huland
Martini-Clinic, Prostate Cancer Center and.|Department of Urology, Section for Translational Prostate Cancer Research, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Thorsten
T
Schlomm
Institute of Pathology.
Stefan
S
Steurer
Institute of Pathology.
Till
T
Krech
Institute of Pathology.
Patrick
P
Lebok
D014408:Biomarkers, Tumor / Q000032:analysis; D016022:Case-Control Studies; D053843:DNA Mismatch Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005500:Follow-Up Studies; D042822:Genomic Instability; D006801:Humans; D007124:Immunoenzyme Techniques; D008207:Lymphatic Metastasis; D008297:Male; D000070976:Mismatch Repair Endonuclease PMS2 / Q000235:genetics*; D000070957:MutL Protein Homolog 1 / Q000235:genetics*; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000235:genetics / Q000473:pathology*; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood*; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics / Q000473:pathology*; D015854:Up-Regulation
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D015514:Oncogene Proteins, Fusion; D017430:Prostate-Specific Antigen; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1