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Integrated Genomic Characterization of the Kallikrein Gene Locus in Cancer

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Integrated Genomic Characterization of the Kallikrein Gene Locus in Cancer ANTICANCER RESEARCH 32: 957-964 (2012) Integrated Genomic Characterization of the Kallikrein Gene Locus in Cancer ANDREW H. GIRGIS1, ANNA BUI1, NICOLE M. WHITE1,2 and GEORGE M. YOUSEF1,2 1Department of Laboratory Medicine and the Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ΟΝ, Canada; 2Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ΟΝ, Canada Abstract. Background: The kallikrein-related peptidases of molecules, permitting for a more comprehensive view of (KLKs) have been implicated in many types of cancer, the interactions between these molecules (7). This in turn has including prostate and ovarian. Materials and Methods: We resulted in a paradigm shift to view cancer from a systems- performed a comprehensive in silico study to characterize the based approach, focusing on pathways and networks of KLK locus using transcriptomic (gene expression) and genomic genes rather than on individual genes. Assessing systems- (mutations and DNA copy number) data in prostate cancer based variations associated with cancer promises the (n=194), serous ovarian cancer (n=506), glioblastoma personalization of the disease state and, in turn, the multiforme (n=206), and sarcoma (n=207) from The Cancer personalization of treatment options, thereby marking the era Genome Atlas and independent publicly available datasets to of personalized medicine (8). Earlier reports have shown the assess KLKs as cancer biomarkers. Results: Overall, there was potential value of in silico analysis for KLKs (9-11). More mRNA overexpression in prostate and serous ovarian cancer recently, high quality publically accessible genomic datasets and decreased expression in glioblastoma multiforme. There have been made available for many types of cancer (12-15). was higher frequency of genomic loss in serous ovarian cancer, Recent large-scale initiatives to characterize glioblastoma and rare KLK gene mutations observed in serous ovarian multiforme (GBM) and serous ovarian cancer have led to the cancer and GBM. Dysregulation of KLKs correlates with discovery of molecularly distinct subtypes according to gene survival: for prostate cancer, a combination of dysregulation of expression and methylation changes, and linked to specific KLK1, 5 and 13 was associated with worse disease-free genetic alterations (13, 16). In this study, we performed a survival. Conclusion: We conclude that specific dysregulation comprehensive analysis of the kallikrein gene family at the of KLKs at the genetic and transcriptomic levels have useful transcriptomic and genomic levels in four common prognostic value. malignancies, including prostate cancer, serous ovarian cancer, GBM and seven major subtypes of soft-tissue The kallikrein-related peptidases (KLKs) have been shown to sarcoma. Our objectives were to integrate the changes in the be associated with a number of cancer types (1), including KLK locus at the transcriptomic (gene expression) and prostate (2), ovarian (3) and kidney cancer (4, 5). The KLKs genetic (mutations and DNA copy-number aberrations) are a 15-member gene family, KLK1 to KLK15, of serine levels. We also examined the correlation between KLK proteases located on chromosome 19q13.4 (6) and their role expression and genetic alterations with cancer prognosis for as cancer diagnostic and prognostic markers is evolving (2). these four malignancies, including their respective molecular Recently, molecular profiling techniques have allowed for the subtypes that have been recently described (13, 16). simultaneous high-throughput comparison of several classes Materials and Methods Dataset acquisition. Analyses were conducted on datasets for Correspondence to: George M. Yousef, MD, Ph.D., FRCPC (Path), prostate cancer (n=157), metastatic prostate cancer (n=37), serous Department of Laboratory Medicine, St. Michael’s Hospital, 30 ovarian cancer (n=506), GBM (n=206) and seven major subtypes Bond Street, Toronto, ON, M5B 1W8, Canada. Tel: +1 4168646060 of soft-tissue sarcoma (n=207) as described by the Cancer Ext: 677605, Fax: +1 4168645648, e-mail: [email protected] Genome Atlas Research Network (12, 13), Barretina et al. (14), and Taylor et al. (15). Copy-number, mutation and survival data Key Words: Tumor markers, kallikrein-related peptidase, KLK, copy were quarried through the MSKCC cBio Cancer Genomics Portal number aberrations, gene expression, prostate cancer, ovarian (http://www.cbioportal.org) and gene expression data for GBM cancer, glioblastoma multiforme, sarcoma. and serous ovarian cancer through The Cancer Genome Atlas 0250-7005/2012 $2.00+.40 957 ANTICANCER RESEARCH 32: 957-964 (2012) Table I. Expression of kallikrein genes in serous ovarian cancer and glioblastoma multiforme compared to respective normal counterparts. Gene Serous ovarian Glioblastoma cancer multiforme n=506 n=424 Down (%) Up (%) Down (%) Up (%) KLK1 62 18 39 7 KLK2 3180 KLK3 11342 KLK4 6471 KLK5 4 91 100 0 KLK6 13 75 81 7 KLK7 6 85 100 0 KLK8 577970 KLK9 117312 KLK10 16 38 99 0 KLK11 36 38 43 19 KLK12 14 45 20 41 KLK13 763258 KLK14 <1 4 4 1 KLK15 13 5 41 2 Up: up-regulated; Down: down-regulated. Table II. Expression of kallikrein in primary and metastatic prostate cancer compared to normal. Gene Primary Metastatic p-value* prostate cancer prostate cancer n=131 n=19 Figure 1. Penetrance plots of copy-number aberrations of the 19q13.4/KLK locus located between the two vertical lines in A) Prostate Down (%) Up (%) Down (%) Up (%) cancer, B) glioblastoma multiforme, C) Serous ovarian cancer and D) Sarcoma. Copy-number gains are represented in red and losses as blue. KLK1 02 5 5 KLK2 2 0 16 5 0.01 KLK3 4 2 21 5 0.0171 KLK4 5 16 32 0 0.0006 Gene expression analysis. Gene expression (mRNA) changes of the KLK5 0160 16 15 KLKs were analyzed compared to normal counterparts for all KLK6 02 016 types of cancer (Tables I and II) with cut-off parameters of ±0.5 KLK7 00 0 0 used to determine over and underexpression. The two-tailed KLK8 08 0 5 Pearson’s Chi-square test was used to determine significant KLK9 0110 16 expression differences between each individual KLK in primary KLK10 03 011 versus metastatic prostate cancer (Table II). A similar analysis was KLK11 31 14 32 53 0.0024 conducted comparing expression of KLKs between the proposed KLK12 0 24 0 63 0.0164 molecular subtypes of GBM and ovarian cancer described KLK13 0110 32 KLK14 08 032 0.0083 previously (13,16). KLK15 0300 47 Copy-number and mutation analysis. Frequency of copy-number Up: up-regulated; Down: down-regulated. *Pearson’s Chi-square test gains and losses were generated for each type of cancer and their (two-tailed p-value <0.05). Significant associations are shown in bold. respective proposed molecular subtypes using high-resolution segmented data (Table III; Figure 1). Previous results based on the GISTIC2.0 (18) and RAE (19) algorithms were used to compile genetic alterations of the KLK locus. Values of +1 and +2 define Data Portal (http://tcga-data.nci.nih.gov/tcga/tcgaHome2.jsp). putative gains and amplifications, respectively. Similarly, values of Robust multiarray average (RMA) normalized (17) gene –1 and –2 as putative hemizygous and homozygous deletions, expression data for the sarcoma and prostate cancer datasets were respectively. The two-tailed Pearson’s Chi-square test was used to downloaded from the Gene Expression Omnibus (GSE21032, determine significant copy-number differences between each type GSE21124). of cancer and molecular subtype (Table III). Frequency of 958 Girgis et al: Characterization of Kallikrein Locus in Cancer Figure 2. KLK1, 5, and 13 expression signature is associated with worse disease-free survival in prostate cancer (Z-score ≥2.0 to normal; p=0.000065). (A) Kaplan-Meier survival curve of cases with the altered gene expression set of KLK1, 5 or 13 relative to other tumors (Z-score ±2.0 to normal). (B) In prostate cancer although there was no overall significant dysregulation of KLK13 between normal and cancer, a subset of tumors showed significantly higher expression for KLK13 and this was associated with poor survival (p<0.001; Mann-Whitney U-Test). previously catalogued mutation data was compiled for the KLKs in heterogeneity of these types of cancer does not significantly GBM and in serous ovarian cancer. Mutual exclusivity analysis impact the expression patterns of KLKs. This stable pattern of using the Fisher’s Exact Test was conducted through the MSKCC dysregulation independently of the molecular heterogeneity cBio Cancer Genomics Portal (http://www.cbioportal.org). may be of clinical utility since the same KLK can be a valid Patient survival analysis. Survival analysis according to KLK genetic alterations and gene signatures was conducted for prostate biomarker for different subtypes. cancer, GBM and serous ovarian cancer through the MSKCC cBio In regards to copy-number aberrations (Table III; Figure Cancer Genomics Portal (http://www.cbioportal.org) (Figures 2-4). 1), frequent copy-number aberrations of the 19q13.4/KLK locus were observed in >10% of cases in metastatic prostate Results and Discussion cancer, all the molecularly distinct subtypes of serous ovarian cancer and GBM, as well as in 6 out of the 7 soft-tissue With respect to KLK mRNA gene expression changes, when sarcoma subtypes. Only primary prostate cancer and synovial compared to normal, we observed an overall overexpression in sarcoma demonstrated insignificant frequency of KLK copy- prostate cancer (7 KLKs exhibited overexpression in at least number aberrations. Metastatic prostate cancer demonstrated 10% of cases; 1 underexpression) (Table II), and serous ovarian significantly higher frequency of copy-number aberrations of cancer (Table I) (11 KLKs exhibited overexpression; 6 the 19q13.4/KLK locus compared to primary prostate cancer. underexpression), whereas overall decreased expression in Likewise, significantly higher copy-number gains of the GBM (Table I) (11 underexpression; 2 overexpression). We did 19q13.4/KLK locus were observed in the proposed classical not observe significant mRNA dysregulation of the KLKs in molecular subtype of GBM relative to the other subtypes the soft-tissue sarcoma subtypes.
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