Tumour biomarkers are measurable changes in cancer cells that could be used to improve available therapies. The identification of early biomarkers could increase early diagnosis rates and provide insight into tumour biology including aggressiveness. In addition tumour subtype-specific biomarkers could help identify the treatments most likely to be effective and also be used to measure response. The search for biomarkers in renal cell carcinoma (RCC) is an active field, with various types of potential biomarker reported (reviewed in Mickley et al., 2015).
The majority of renal tumours are clear cell RCC associated with the loss of VHL protein due to mutation or promoter hypermethylation. Consequently, most current treatments target disrupted downstream pathways such as VEGF signalling. Choueiri et al., (2008) found that VHL status could be a prognostic as well as a predicative biomarker as patients lacking VHL responded better to anti-VEGF therapies. The presence of driver MET mutations in papillary RCC is also highly predictive of response to MET/VEGFR2 inhibitor foretanib (Choueiri et al., 2013). Serum VEGF levels can then act as a pharmacodynamic biomarker. Other potential diagnostic biomarkers of RCC – mTOR, Akt, S6K and PTEN – are not specific to RCC pathology but could be used in combination with other biomarkers to identify key tumourigenic pathways.
Natural genetic variations have also been identified as prognostic biomarkers for existing treatments. In patients treated with sunitinib certain SNPs in either CYP3A5, NR1I3 or ABCB1 improved progression free survival (PFS) (van der Veldt et al., 2011) but two SNPs in VEGFR3 were associated with decreased PFS (Garcia-Donas et al., 2011). In patients receiving pazopanib SNPs in either IL8 or HIF1A were associated with reduced PFS (Xu et al., 2011). Identification of such variations could help streamline treatment choices.
Epigenetic changes due to CpG island methylation could also be prognostic biomarkers. Wei et al. (2015) identified five regions of variable methylation close to the PITX1, FOXE3, TWF2, EHBP1L1 and RIN1 genes that could help predict overall survival with patients categorised as either low-risk or high-risk. Changes in methylation are common in cancer cells and PITX1, TWF2 and RIN1 are periphery genes associated with a diverse network of other genes and signalling pathways associated with tumourigenesis.
Another class of molecules proposed as diagnostic and prognostic biomarkers are miRNAs which, through modifying post-transcription translation, have roles in several key tumourigenic pathways. Varied expression of several different individual, combinations and panels of circulating miRNAs have been proposed for early screening and prognosis assessments (Gu et al., 2015, Wang et al., 2015). Confirmation of these biomarkers could enable less invasive detection of primary and relapse tumours quickly.
Most biomarker studies have been single studies on relatively small patient populations, and significantly larger studies would be better suited to verify widely-applicable biomarkers. Kidney Cancer Scotland recently announced funding for Dr Grant Stewart at the University of Edinburgh and Professor David Harris at St Andrews’ University to search for therapeutic biomarkers in over 900 patient samples in the SCOTRRCC database.
It is hoped that the identification of suitable biomarkers will vastly increase treatment response rates and reduce RCC mortality through earlier diagnosis and more effective treatment. Biomarkers might also identify novel therapeutic pathways for research, particularly in less common cancers. However such biomarkers would need to be validated in independent cohorts and be easily applicable to the clinical setting, preferable from easily accessible samples. More research is required before every RCC patient can receive personalised treatment, but ongoing research and new technologies continue to advance the field.
- Choueiri TK, Vaziri SA, Jaeger E, Elson P, Wood L, Bhalla IP, Small EJ, Weinberg V, Sein N, Simko J, Golshayan AR, Sercia L, Zhou M, Waldman FM, Rini BI, Bukowski RM, Ganapathi R (2008). von Hippel-Lindau gene status and response to vascular endothelial growth factor targeted therapy for metastatic clear cell renal cell carcinoma. J Urol. 180(3):860-6. PMID: 18635227.
- Choueiri TK, Vaishampayan U, Rosenberg JE, Logan TF, Harzstark AL, Bukowski RM, Rini BI, Srinivas S, Stein MN, Adams LM, Ottesen LH, Laubscher KH, Sherman L, McDermott DF, Haas NB, Flaherty KT, Ross R, Eisenberg P, Meltzer PS, Merino MJ, Bottaro DP, Linehan WM, Srinivasan R (2013). Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J Clin Oncol. 31(2):181-6. PMID: 23213094.
- Garcia-Donas J, Esteban E, Leandro-García LJ, Castellano DE, del Alba AG, Climent MA, Arranz JA, Gallardo E, Puente J, Bellmunt J, Mellado B, Martínez E, Moreno F, Font A, Robledo M, Rodríguez-Antona C (2011). Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study. Lancet Oncol. 12(12):1143-50. PMID: 22015057.
- Gu L, Li H, Chen L, Ma X, Gao Y, Li X, Zhang Y, Fan Y, Zhang X (2015). MicroRNAs as prognostic molecular signatures in renal cell carcinoma: a systematic review and meta-analysis. Oncotarget. 6(32):32545-60. PMID: 26416448.
- Mickley A, Kovaleva O, Kzhyshkowska J, & Gratchev A (2015). Molecular and immunologic markers of kidney cancer-potential applications in predictive, preventive and personalized medicine. The EPMA journal, 6 PMID: 26500709.
- van der Veldt AA, Eechoute K, Gelderblom H, Gietema J, Guchelaar HJ, van Erp NP, van den Eertwegh AJ, Haanen JB, Mathijssen RH, Wessels JA (2011). Genetic polymorphisms associated with a prolonged progression-free survival in patients with metastatic renal cell cancer treated with sunitinib. Clin Cancer Res. 17(3):620-9. PMID: 21097692.
- Wang C, Hu J, Lu M, Gu H, Zhou X, Chen X, Zen K, Zhang CY, Zhang T, Ge J, Wang J, Zhang C (2015). A panel of five serum miRNAs as a potential diagnostic tool for early-stage renal cell carcinoma. Sci Rep. 5:7610. PMID: 25556603.
- Wei JH, Haddad A, Wu KJ, Zhao HW, Kapur P, Zhang ZL, Zhao LY, Chen ZH, Zhou YY, Zhou JC, Wang B, Yu YH, Cai MY, Xie D, Liao B, Li CX, Li PX, Wang ZR, Zhou FJ, Shi L, Liu QZ, Gao ZL, He DL, Chen W, Hsieh JT, Li QZ, Margulis V, Luo JH (2015). A CpG-methylation-based assay to predict survival in clear cell renal cell carcinoma. Nat Commun. 6:8699. PMID: 26515236.
- Xu CF, Bing NX, Ball HA, Rajagopalan D, Sternberg CN, Hutson TE, de Souza P, Xue ZG, McCann L, King KS, Ragone LJ, Whittaker JC, Spraggs CF, Cardon LR, Mooser VE, Pandite LN (2011). Pazopanib efficacy in renal cell carcinoma: evidence for predictive genetic markers in angiogenesis-related and exposure-related genes. J Clin Oncol. 29(18):2557-64. PMID: 21576632.