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Diagnostic and prognostic biomarker potential of kallikrein family genes in different cancer types - PubMed

  • ️Mon Jan 01 2018

Diagnostic and prognostic biomarker potential of kallikrein family genes in different cancer types

Prashant D Tailor et al. Oncotarget. 2018.

Abstract

Purpose: The aim of this study was to compare and contrast the expression of all members of the Kallikrein (KLK) family of genes across 15 cancer types and to evaluate their utility as diagnostic and prognostic biomarkers.

Results: Severe alterations were found in the expression of different Kallikrein genes across various cancers. Interestingly, renal clear cell and papillary carcinomas have similar kallikrein expression profiles, whereas, chromophobe renal cell carcinoma has a unique expression profile. Several KLK genes have excellent biomarker potential (AUC > 0.90) for chromophobe renal cell carcinoma (KLK2, KLK3, KLK4, KLK7, KLK15), renal papillary carcinoma (KLK1, KLK6, KLK7), clear cell renal cell carcinoma (KLK1, KLK6), thyroid carcinoma (KLK2, KLK4, KLK13, KLK15) and colon adenocarcinoma (KLK6, KLK7, KLK8, KLK10). Several KLK genes were significantly associated with mortality in clear cell renal cell carcinoma (KLK2: HR = 1.69; KLK4: HR = 1.63; KLK8: HR = 1.71; KLK10: HR = 2.12; KLK11: HR = 1.76; KLK14: HR = 1.86), papillary renal cell carcinoma (KLK6: HR = 3.38, KLK7: HR = 2.50), urothelial bladder carcinoma (KLK5: HR = 1.89, KLK6: HR = 1.71, KLK8: HR = 1.60), and hepatocellular carcinoma (KLK13: HR = 1.75).

Methods: The RNA-seq gene expression data were downloaded from The Cancer Genome Atlas (TCGA). Statistical analyses, including differential expression analysis, receiver operating characteristic curves and survival analysis (Cox proportional-hazards regression models) were performed.

Conclusions: A comprehensive analysis revealed the changes in the expression of different KLK genes associated with specific cancers and highlighted their potential as a diagnostic and prognostic tool.

Keywords: TCGA; cancer; gene expression; kallikreins; prognosis.

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Conflict of interest statement

CONFLICTS OF INTEREST None.

Figures

Figure 1
Figure 1. Kallikrein expression fold change in specific cancers

Each member of the kallikrein (KLK) family is listed vertically and the 15 cancers are displayed horizontally. Values highlighted in blue or orange represent a fold change greater than 2 or less than 0.5 (–2 fold) respectively while having a p-value of less than 0.0033. The vertical and horizontal order was determined by unsupervised clustering of both kallikreins and cancers.

Figure 2
Figure 2. Venn diagram comparing the expression changes of kallikreins in three types of renal cancers

Renal clear cell carcinoma and renal papillary carcinoma show similarities in the kallikrein expression changes whereas Chromophobe renal cell carcinoma shows a distinct kallikrein expression profile. Yellow font reflects downregulation whereas red font indicates upregulation of kallikrein expression in carcinoma.

Figure 3
Figure 3. Receiver operating curves (ROC) of kallikreins upregulated in cancers

The diagnostic power of individual KLK genes to differentiate cancer patients and respective controls was assessed using the area under the curve (AUC) of the receiver operating characteristic (ROC) curves. The ROC curves and AUC values of top performing KLKs (AUC > 0.90) are shown. The boxplots represent the distribution of expression in tumor and control samples.

Figure 4
Figure 4. Receiver operating curves (ROC) of kallikreins downregulated in cancers

The diagnostic power of individual KLK genes to differentiate cancer patients and respective controls was assessed using the area under the curve (AUC) of the receiver operating characteristic (ROC) curves. The ROC curves and AUC values of top performing KLKs (AUC > 0.90) are shown. Expression of these KLKs is negligible in tumor samples as compared to controls. The boxplots represent the distribution of expression in tumor and control samples.

Figure 5
Figure 5. Kallikreins associated with cancer prognosis

Kallikreins were independently assessed across the 15 cancers to determine if the expression of kallikrein is associated with overall survival. Kaplan–Meier survival analysis and log-rank test were used to compare differences in overall survival between groups classified using median expression as cut-off. Survival curves, hazard ratio (HR) and p-values are shown.

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