Accessible Requires Authentication Published by De Gruyter July 27, 2018

Mining human cancer datasets for kallikrein expression in cancer: the ‘KLK-CANMAP’ Shiny web tool

Chenwei Wang, Leire Moya, Judith A. Clements, Colleen C. Nelson and Jyotsna Batra
From the journal Biological Chemistry


The dysregulation of the serine-protease family kallikreins (KLKs), comprising 15 genes, has been reportedly associated with cancer. Their expression in several tissues and physiological fluids makes them potential candidates as biomarkers and therapeutic targets. There are several databases available to mine gene expression in cancer, which often include clinical and pathological data. However, these platforms present some limitations when comparing a specific set of genes and can generate considerable unwanted data. Here, several datasets that showed significant differential expression (p<0.01) in cancer vs. normal (n=118), metastasis vs. primary (n=15) and association with cancer survival (n=21) have been compiled in a user-friendly format from two open and/or publicly available databases Oncomine and OncoLnc for the 15 KLKs. The data have been included in a free web application tool: the KLK-CANMAP This tool integrates, analyses and visualises data and it was developed with the R Shiny framework. Using KLK-CANMAP box-plots, heatmaps and Kaplan-Meier graphs can be generated for the KLKs of interest. We believe this new cancer KLK focused web tool will benefit the KLK community by narrowing the data visualisation to only the genes of interest.


We thank Ms. Sarah Schubert for helping extracting the data from the open Oncomine and free OncoLnc databases. We also thank the support of our funding organisations the Cancer Council Queensland, the National Health and Medical Research Council Career Development Fellowship (Dr. Jyotsna Batra) and the Prostate Cancer Foundation of Australia through the Movember Foundation.


Adhyam, M. and Gupta, A.K. (2012). A review on the clinical utility of psa in cancer prostate. Indian J. Surg. Oncol. 3, 120–129. Search in Google Scholar

Anaya, J. (2016). Oncolnc: Linking tcga survival data to mrnas, mirnas, and lncrnas. Peer. J. Comput. Sci. 2, e67. Search in Google Scholar

Avgeris, M. and Scorilas, A. (2016). Kallikrein-related peptidases (klks) as emerging therapeutic targets: Focus on prostate cancer and skin pathologies. Expert Opin. Ther. Targets 20, 801–818. Search in Google Scholar

Batra, J., O’Mara, T., Patnala, R., Lose, F., and Clements, J.A. (2012). Genetic polymorphisms in the human tissue kallikrein (KLK) locus and their implication in various malignant and non-malignant diseases. Biol. Chem. 393, 1365–1390. Search in Google Scholar

Brittner, M. (2005). International genomics consortium expression project for oncology (expo). Available at: Search in Google Scholar

Bokhorst, L.P., Bangma, C.H., van Leenders, G.J., Lous, J.J., Moss, S.M., Schroder, F.H., and Roobol, M.J. (2014). Prostate-specific antigen-based prostate cancer screening: reduction of prostate cancer mortality after correction for nonattendance and contamination in the rotterdam section of the european randomized study of screening for prostate cancer. Eur. Urol. 65, 329–336. Search in Google Scholar

Borgoño, C.A. and Diamandis, E.P. (2004). The emerging roles of human tissue kallikreins in cancer. Nat. Rev. Cancer 4, 876. Search in Google Scholar

Borgoño, C.A., Michael, I.P., Shaw, J.L.V., Luo, L.-Y., Ghosh, M.C., Soosaipillai, A., Grass, L., Katsaros, D., and Diamandis, E.P. (2007). Expression and functional characterization of the cancer-related serine protease, human tissue kallikrein 14. J. Biol. Chem. 282, 2405–2422. Search in Google Scholar

Chang, W., Cheng, J., Allaire, J., Xie, Y., and McPherson, J. (2017). shiny: Web application framework for R, version 1.0.5. Available at: Search in Google Scholar

Diamandis, E.P. and Yousef, G.M. (2002). Human tissue kallikreins: a family of new cancer biomarkers. Clin. Chem. 48, 1198–1205. Search in Google Scholar

Emami, N. and Diamandis, E.P. (2008). Utility of kallikrein-related peptidases (klks) as cancer biomarkers. Clin. Chem. 54, 1600–1607. Search in Google Scholar

Friedl, P. and Alexander, S. (2011). Cancer invasion and the microenvironment: plasticity and reciprocity. Cell 147, 992–1009. Search in Google Scholar

Harrington, D.P. and Fleming, T.R. (1982). A class of rank test procedures for censored survival data. Biometrika 69, 553–566. Search in Google Scholar

Harvey, T.J., Hooper, J.D., Myers, S.A., Stephenson, S.A., Ashworth, L.K., and Clements, J.A. (2000). Tissue-specific expression patterns and fine mapping of the human kallikrein (klk) locus on proximal 19q13.4. J. Biol. Chem. 275, 37397–37406. Search in Google Scholar

Jemal, A., Ward, E., Wu, X., Martin, H.J., McLaughlin, C.C., and Thun, M.J. (2005). Geographic patterns of prostate cancer mortality and variations in access to medical care in the united states. Cancer Epidemiol. Biomark. Prevent. 14, 590–595. Search in Google Scholar

Kaplan, E.L. and Meier, P. (1958). Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53, 457–481. Search in Google Scholar

Koumandou, V.L. and Scorilas, A. (2013). Evolution of the plasma and tissue kallikreins, and their alternative splicing isoforms. PLoS One 8, e68074. Search in Google Scholar

Kraut, H. and Frey, E. (1930). Der Nachweis eines Kreislaufhormons in der Pankreasdrüse (IV. Mitteilung über dieses Kreislaufhormon). Hoppe-Seyler‘s Z. Physiol. Chem. 189, 97–106. Search in Google Scholar

Kryza, T., Silva, M.L., Loessner, D., Heuze-Vourc’h, N., and Clements, J.A. (2016). The kallikrein-related peptidase family: dysregulation and functions during cancer progression. Biochimie 122, 283–299. Search in Google Scholar

Lai, J., An, J., Srinivasan, S., Clements, J.A., and Batra, J. (2016). A computational analysis of the genetic and transcript diversity at the kallikrein locus. Biol. Chem. 397, 1307–1313. Search in Google Scholar

MacDonald, R.J. and Margolius, H.S. (1988). Molecular biology of tissue kallikrein. Biochem. J. 253, 313–321. Search in Google Scholar

Metastatic Breast Cancer Network. (2017). Incidence and incidence rates. Search in Google Scholar

Nelson, P.S., Gan, L., Ferguson, C., Moss, P., Gelinas, R., Hood, L., and Wang, K. (1999). Molecular cloning and characterization of prostase, an androgen-regulated serine protease with prostate-restricted expression. Proc. Natl. Acad. Sci. USA 96, 3114–3119. Search in Google Scholar

Pathak, M., Wong, S.S., Dreveny, I., and Emsley, J. (2013). Structure of plasma and tissue kallikreins. J. Thromb. Haemost. 110, 423–433. Search in Google Scholar

Petraki, C.D., Karavana, V.N., Luo, L.Y., and Diamandis, E.P. (2002). Human kallikrein 10 expression in normal tissues by immunohistochemistry. J. Histochem. Cytochem. 50, 1247–1261. Search in Google Scholar

Poddar, N.K., Maurya, S.K., and Saxena, V. (2017). Role of serine proteases and inhibitors in cancer. In: Proteases in Physiology and Pathology, Vol. 1, S. Chakraborti and N. Dhalla, eds. (Singapore: Springer), pp. 257–287. Search in Google Scholar

Prassas, I., Eissa, A., Poda, G., and Diamandis, E.P. (2015). Unleashing the therapeutic potential of human kallikrein-related serine proteases. Nat. Rev. Drug Discov. 14, 183. Search in Google Scholar

Rhodes, D.R., Yu, J., Shanker, K., Deshpande, N., Varambally, R., Ghosh, D., Barrette T., Pandey A., and Chinnaiyan, A.M. (2004). ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia. 6, 1–6. Search in Google Scholar

Schmitt, M., Magdolen, V., Yang, F., Kiechle, M., Bayani, J., Yousef, G.M., Scorilas, A., Diamandis, E.P., and Dorn, J. (2013). Emerging clinical importance of the cancer biomarkers kallikrein-related peptidases (klk) in female and male reproductive organ malignancies. Radiol. Oncol. 47, 319–329. Search in Google Scholar

Shankavaram, U.T., Reinhold, W.C., Nishizuka, S., Major, S., Morita, D., Chary, K.K., Reimers, M.A., Scherf, U., Kahn, A., Dolginow, D., et al. (2007). Transcript and protein expression profiles of the nci-60 cancer cell panel: an integromic microarray study. Mol. Cancer. Ther. 6, 820–832. Search in Google Scholar

Shaw, J.L.V. and Diamandis, E.P. (2007). Distribution of 15 human kallikreins in tissues and biological fluids. Clin. Chem. 53, 1423–1432. Search in Google Scholar

Shin, G., Kang, T.W., Yang, S., Baek, S.J., Jeong, Y.S., and Kim, S.Y. (2011). Gent: gene expression database of normal and tumor tissues. Cancer Inform. 10, 149–157. Search in Google Scholar

Sievert, C., Parmer, C., Hocking, T., Chamberlain, S., Ram, K., Corvellec, M., and Despouy, P. (2017). Plotly: create interactive web graphics via ‘plotly.Js’, version 4.7.1. Available at: Search in Google Scholar

Stamey, T.A., Yang, N., Hay, A.R., McNeal, J.E., Freiha, F.S., and Redwine, E. (1987). Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N. Engl. J. Med. 317, 909–916. Search in Google Scholar

TCGA. (2015). The cancer genome atlas research. National Cancer Institute and National Human Genome Research Institute. Search in Google Scholar

Wan, Q., Dingerdissen, H., Fan, Y., Gulzar, N., Pan, Y., Wu, T.J., Yan, C., Zhang, H., and Mazumder, R. (2015). Bioxpress: an integrated rna-seq-derived gene expression database for pan-cancer analysis. Database, 2015: bav019-bav019. DOI 10.1093/database/bav019. Search in Google Scholar

Warnes, G.R., Bolker, B., Bonebakker, L., Gentleman, R., Huber, W., Liaw, A., Lumley, T., Maechler, M., Magnusson, A., Moeller, S., et al. (2016) gplots: Various R Programming Tools for Plotting Data, version 3.0.1. Search in Google Scholar

Weiner, A.B., Matulewicz, R.S., Eggener, S.E., and Schaeffer, E.M. (2016). Increasing incidence of metastatic prostate cancer in the united states (2004–2013). Prostate Cancer Prostatic Dis. 19, 395. Search in Google Scholar

Young, C.Y., Andrews, P.E., Montgomery, B.T., and Tindall, D.J. (1992). Tissue-specific and hormonal regulation of human prostate-specific glandular kallikrein. Biochemistry 31, 818–824. Search in Google Scholar

Yousef, G.M. and Diamandis, E.P. (2001). The new human tissue kallikrein gene family: structure, function, and association to disease. Endocr. Rev. 22, 184–204. Search in Google Scholar

Yousef, G.M., Chang, A., and Diamandis, E.P. (2000). Identification and characterization of klk-l4, a new kallikrein-like gene that appears to be down-regulated in breast cancer tissues. J. Biol. Chem. 275, 11891–11898. Search in Google Scholar

Yousef, G.M., White, N.M., Michael, I.P., Cho, J.C., Robb, J.D., Kurlender, L., Khan, S., and Diamandis, E.P. (2005). Identification of new splice variants and differential expression of the human kallikrein 10 gene, a candidate cancer biomarker. Tumour Biol. 26, 227–235. Search in Google Scholar

Zbytek, B., Carlson, J.A., Granese, J., Ross, J., Mihm, M.N., and Slominski, A. (2008). Current concepts of metastasis in melanoma. Expert. Rev. Dermatol. 3, 569–585. Search in Google Scholar

Supplementary Material

The online version of this article offers supplementary material (

Received: 2017-12-21
Accepted: 2018-04-10
Published Online: 2018-07-27
Published in Print: 2018-09-25

©2018 Walter de Gruyter GmbH, Berlin/Boston