Reduced KLK2 expression is a strong and independent predictor of poor prognosis in ERG-negative prostate cancer.
PSA
immunohistochemistry
prognosis
prostate cancer
tissue micro array
Journal
The Prostate
ISSN: 1097-0045
Titre abrégé: Prostate
Pays: United States
ID NLM: 8101368
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
26
04
2020
revised:
11
06
2020
accepted:
15
06
2020
pubmed:
7
7
2020
medline:
8
10
2020
entrez:
7
7
2020
Statut:
ppublish
Résumé
Kallikrein-related peptidase 2 (KLK2)-like KLK3 (prostate-specific antigen [PSA])-belongs to the highly conserved serine proteases of the glandular kallikrein protein family (KLK family). Studies suggested that measurement of KLK2 serum levels advanced the predictive accuracy of PSA testing in prostate cancer. To clarify the potential utility of KLK2 as a prognostic tissue biomarker, KLK2 expression was analyzed by immunohistochemistry in more than 12 000 prostate cancers. Normal epithelium cells usually showed weak to moderate KLK2 immunostaining, whereas KLK2 was negative in 23%, weak in 38%, moderate in 35%, and strong in 4% of 9576 analyzable cancers. Lost or reduced KLK2 immunostaining was associated with advanced tumor stage, high Gleason score, lymph node metastasis, increased cell proliferation, positive resection margin, and early PSA recurrence (P < .0001). Comparison with previously analyzed molecular alterations revealed a strong association of KLK2 loss and presence of TMPRSS2:ERG fusion (P < .0001), most of all analyzed common deletions (9 of 11; P ≤ .03), and decreased PSA immunostaining (P < .0001 each). Cancers with combined negative or weak immunostaining of KLK2 and PSA showed worse prognosis than cancers with at least moderate staining of one or both proteins (P < .0001). Multivariate analyses including established preoperative and postoperative prognostic parameters showed a strong independent prognostic impact of KLK2 loss alone or in combination of PSA, especially in erythroblast transformation-specific-negative cancers (P ≤ .006). Loss of KLK2 expression is a potentially useful prognostic marker in prostate cancer. Analysis of KLK2 alone or in combination with PSA may be useful for estimating cancer aggressiveness at the time of biopsy.
Sections du résumé
BACKGROUND
Kallikrein-related peptidase 2 (KLK2)-like KLK3 (prostate-specific antigen [PSA])-belongs to the highly conserved serine proteases of the glandular kallikrein protein family (KLK family). Studies suggested that measurement of KLK2 serum levels advanced the predictive accuracy of PSA testing in prostate cancer.
METHODS
To clarify the potential utility of KLK2 as a prognostic tissue biomarker, KLK2 expression was analyzed by immunohistochemistry in more than 12 000 prostate cancers.
RESULTS
Normal epithelium cells usually showed weak to moderate KLK2 immunostaining, whereas KLK2 was negative in 23%, weak in 38%, moderate in 35%, and strong in 4% of 9576 analyzable cancers. Lost or reduced KLK2 immunostaining was associated with advanced tumor stage, high Gleason score, lymph node metastasis, increased cell proliferation, positive resection margin, and early PSA recurrence (P < .0001). Comparison with previously analyzed molecular alterations revealed a strong association of KLK2 loss and presence of TMPRSS2:ERG fusion (P < .0001), most of all analyzed common deletions (9 of 11; P ≤ .03), and decreased PSA immunostaining (P < .0001 each). Cancers with combined negative or weak immunostaining of KLK2 and PSA showed worse prognosis than cancers with at least moderate staining of one or both proteins (P < .0001). Multivariate analyses including established preoperative and postoperative prognostic parameters showed a strong independent prognostic impact of KLK2 loss alone or in combination of PSA, especially in erythroblast transformation-specific-negative cancers (P ≤ .006).
CONCLUSIONS
Loss of KLK2 expression is a potentially useful prognostic marker in prostate cancer. Analysis of KLK2 alone or in combination with PSA may be useful for estimating cancer aggressiveness at the time of biopsy.
Substances chimiques
AR protein, human
0
ERG protein, human
0
Oncogene Proteins, Fusion
0
Receptors, Androgen
0
TMPRSS2-ERG fusion protein, human
0
Transcriptional Regulator ERG
0
KLK2 protein, human
EC 3.4.21.-
KLK3 protein, human
EC 3.4.21.-
Kallikreins
EC 3.4.21.-
Prostate-Specific Antigen
EC 3.4.21.77
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1097-1107Informations de copyright
© 2020 The Authors. The Prostate published by Wiley Periodicals LLC.
Références
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424.
Wilt TJ, Jones KM, Barry MJ, et al. Follow-up of prostatectomy versus observation for early prostate cancer. New England J Med. 2017;377(2):132-142.
Klotz L, Vesprini D, Sethukavalan P, et al. Long-term follow-up of a large active surveillance cohort of patients with prostate cancer. J Cin Oncol. 2015;33(3):272-277.
Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. New England J Med. 2011;364(18):1708-1717.
Hong SK. Kallikreins as biomarkers for prostate cancer. Biomed Res Int. 2014;2014:526341.
Lawrence MG, Lai J, Clements JA. Kallikreins on steroids: structure, function, and hormonal regulation of prostate-specific antigen and the extended kallikrein locus. Endocr Rev. 2010;31(4):407-446.
Avgeris M, Mavridis K, Scorilas A. Kallikrein-related peptidase genes as promising biomarkers for prognosis and monitoring of human malignancies. Biol Chem. 2010;391(5):505-511.
Fuhrman-Luck RA, Loessner D, Clements JA. Kallikrein-related peptidases in prostate cancer: from molecular function to clinical application. EJIFCC. 2014;25(3):269-281.
Klein RJ, Hallden C, Cronin AM, et al. Blood biomarker levels to aid discovery of cancer-related single-nucleotide polymorphisms: kallikreins and prostate cancer. Cancer Prev Res. 2010;3(5):611-619.
Tremblay RR, Deperthes D, Tetu B, Dube JY. Immunohistochemical study suggesting a complementary role of kallikreins hK2 and hK3 (prostate-specific antigen) in the functional analysis of human prostate tumors. Am J Pathol. 1997;150(2):455-459.
Yan W, Jamal M, Tan SH, et al. Molecular profiling of radical prostatectomy tissue from patients with no sign of progression identifies ERG as the strongest independent predictor of recurrence. Oncotarget. 2019;10(60):6466-6483.
He Z, Duan X, Zeng G. Identification of potential biomarkers and pivotal biological pathways for prostate cancer using bioinformatics analysis methods. Peer J. 2019;7:e7872.
Schlomm T, Iwers L, Kirstein P, et al. Clinical significance of p53 alterations in surgically treated prostate cancers. Mod Pathol. 2008;21(11):1371-1378.
Sauter G, Steurer S, Clauditz TS, et al. Clinical utility of quantitative Gleason grading in prostate biopsies and prostatectomy specimens. EurUrol. 2016;69(4):592-598.
Kononen J, Bubendorf L, Kallioniemi A, et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nature Med. 1998;4(7):844-847.
Weischenfeldt J, Simon R, Feuerbach L, et al. Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer. Cancer Cell. 2013;23(2):159-170.
Minner S, Enodien M, Sirma H, et al. ERG status is unrelated to PSA recurrence in radically operated prostate cancer in the absence of antihormonal therapy. Clin Cancer Res. 2011;17(18):5878-5888.
Krohn A, Seidel A, Burkhardt L, et al. Recurrent deletion of 3p13 targets multiple tumour suppressor genes and defines a distinct subgroup of aggressive ERG fusion-positive prostate cancers. J Pathol. 2013;231(1):130-141.
Burkhardt L, Fuchs S, Krohn A, et al. CHD1 is a 5q21 tumor suppressor required for ERG rearrangement in prostate cancer. Cancer Res. 2013;73(9):2795-2805.
Kluth M, Hesse J, Heinl A, et al. Genomic deletion of MAP3K7 at 6q12-22 is associated with early PSA recurrence in prostate cancer and absence of TMPRSS2:ERG fusions. Mod Pathol. 2013;26(7):975-983.
Kluth M, Amschler NN, Galal R, et al. Deletion of 8p is an independent prognostic parameter in prostate cancer. Oncotarget. 2017;8(1):379-392.
Krohn A, Diedler T, Burkhardt L, et al. Genomic deletion of PTEN is associated with tumor progression and early PSA recurrence in ERG fusion-positive and fusion-negative prostate cancer. Am J Pathol. 2012;181(2):401-412.
Kluth M, Ahrary R, Hube-Magg C, et al. Genomic deletion of chromosome 12p is an independent prognostic marker in prostate cancer. Oncotarget. 2015;6(29):27966-27979.
Kluth M, Scherzai S, Buschek F, et al. 13q deletion is linked to an adverse phenotype and poor prognosis in prostate cancer. Genes Chromosomes Cancer. 2018;57(10):504-512.
Kluth M, Jung S, Habib O, et al. Deletion lengthening at chromosomes 6q and 16q targets multiple tumor suppressor genes and is associated with an increasingly poor prognosis in prostate cancer. Oncotarget. 2017;8(65):108923-108935.
Kluth M, Harasimowicz S, Burkhardt L, et al. Clinical significance of different types of p53 gene alteration in surgically treated prostate cancer. Int J Cancer. 2014;135(6):1369-1380.
Kluth M, Graunke M, Moller-Koop C, et al. Deletion of 18q is a strong and independent prognostic feature in prostate cancer. Oncotarget. 2016;7(52):86339-86349.
Bonk S, Kluth M, Hube-Magg C, et al. Prognostic and diagnostic role of PSA immunohistochemistry: a tissue microarray study on 21 000 normal and cancerous tissues. Oncotarget. 2019;10(52):5439-5453.
Minner S, Jessen B, Stiedenroth L, et al. Low level HER2 overexpression is associated with rapid tumor cell proliferation and poor prognosis in prostate cancer. Clin Cancer Res. 2010;16(5):1553-1560.
Spratt DE, Alshalalfa M, Fishbane N, et al. Transcriptomic heterogeneity of androgen receptor activity defines a de novo low AR-active subclass in treatment naive primary prostate cancer. Clin Cancer Res. 2019;25(22):6721-6730.
Mize GJ, Wang W, Takayama TK. Prostate-specific kallikreins-2 and -4 enhance the proliferation of DU-145 prostate cancer cells through protease-activated receptors-1 and -2. Mol Cancer Res. 2008;6(6):1043-1051.
Shang Z, Niu Y, Cai Q, et al. Human kallikrein 2 (KLK2) promotes prostate cancer cell growth via function as a modulator to promote the ARA70-enhanced androgen receptor transactivation. Tumour Biol. 2014;35(3):1881-1890.
Tomlins SA, Rhodes DR, Perner S, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. 2005;310(5748):644-648.
Brase JC, Johannes M, Mannsperger H, et al. TMPRSS2-ERG-specific transcriptional modulation is associated with prostate cancer biomarkers and TGF-beta signaling. BMC Cancer. 2011;11:507.
Barbieri CE, Baca SC, Lawrence MS, et al. Exome sequencing identifies recurrent SPOP, FOXA1, and MED12 mutations in prostate cancer. Nat Genet. 2012;44(6):685-689.
Shin S, Kim TD, Jin F, et al. Induction of prostatic intraepithelial neoplasia and modulation of androgen receptor by ETS variant 1/ETS-related protein 81. Cancer Res. 2009;69(20):8102-8110.
Sun C, Dobi A, Mohamed A, et al. TMPRSS2-ERG fusion, a common genomic alteration in prostate cancer activates C-MYC and abrogates prostate epithelial differentiation. Oncogene. 2008;27(40):5348-5353.
Taylor BS, Schultz N, Hieronymus H, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18(1):11-22.
Lapointe J, Li C, Giacomini CP, et al. Genomic profiling reveals alternative genetic pathways of prostate tumorigenesis. Cancer Res. 2007;67(18):8504-8510.
Sauter G, Clauditz T, Steurer S, et al. Integrating tertiary Gleason 5 patterns into quantitative Gleason grading in prostate biopsies and prostatectomy specimens. Eur Urol. 2018;73(5):674-683.
Heumann A, Heinemann N, Hube-Magg C, et al. High BCAR1 expression is associated with early PSA recurrence in ERG negative prostate cancer. BMC Cancer. 2018;18(1):37.
Schroeder C, Navid-Hill E, Meiners J, et al. Nuclear ELAC2 overexpression is associated with increased hazard for relapse after radical prostatectomy. Oncotarget. 2019;10(48):4973-4986.
Hoflmayer D, Steinhoff A, Hube-Magg C, et al. Expression of CCCTC-binding factor (CTCF) is linked to poor prognosis in prostate cancer. Mol Oncol. 2020;14(1):129-138.
Lim JCT, Yeong JPS, Lim CJ, et al. An automated staining protocol for seven-colour immunofluorescence of human tissue sections for diagnostic and prognostic use. Pathology. 2018;50(3):333-341.