Cancer Biomark. 2013;13(2):67-73.

Serum concentrations of brain-derived neurotrophic factor (BDNF) are decreased in colorectal cancer patients.

Brierley GV1, Priebe IK1, Purins L1, Fung KYC1, Tabor B1, Lockett T1, Nice E2, Gibbs P3, Tie J3,  McMurrick P4, Moore J5, Ruszkiewicz A6, Burgess A3, and Cosgrove LJ1

1 CSIRO Preventative Health National Research Flagship, Australia

2 Ludwig Institute for Cancer Research, Melbourne, Australia

3 Royal Melbourne Hospital, Melbourne, Australia

4 Cabrini Hospital, Melbourne, Australia

5 Royal Adelaide Hospital, Adelaide, Australia

6  SA Pathology, Adelaide, Australia

 

Corresponding Author:

Leah J Cosgrove, PhD

CSIRO Division of Animal, Food and Health Sciences

PO Box 10041, Adelaide BC, South Australia, 5000, Australia

(E) leah.cosgrove@csiro.au;  (T) +61 8 83038833; (F) + 61 8 83038899

 

Abstract

OBJECTIVE: To determine the usefulness of brain-derived neurotrophic factor (BDNF) as a diagnostic biomarker for colorectal cancer (CRC).

MATERIALS AND METHODS: ELISA immunoassay was used to examine BDNF concentrations in the sera of two different retrospective cohorts consisting of CRC patients and age/gender matched controls. Cohort 1 consisted of 99 controls and 97 CRC patients, whereas cohort 2 consisted of 47 controls and 91 CRC patients.

RESULTS: In cohort 1, the median concentration of BDNF was significantly (p< 0.0001) lower in CRC patient samples (18.8 ng/mL, range 4.0-56.5 ng/mL) than control samples (23.4 ng/mL, range 3.0-43.1 ng/mL). This finding was validated in an independent patient cohort (CRC patients: 23.0 ng/mL, range 6.0-45.9 ng/mL; control patients: 32.3 ng/mL, range 14.2-62.4 ng/mL). BDNF concentrations did not differ significantly between Dukes’ staging in the patient cohort, however patients with Stages A, B, C and D (p< 0.01 for each stage) tumours had significantly reduced BDNF levels compared to healthy controls. Receiver operating characteristic analysis was performed to determine the ability of BDNF to discriminate between healthy controls and those with CRC. At 95% specificity, BDNF concentrations distinguished CRC patients with 25% and 18% sensitivity, respectively, in cohorts 1 and 2 (cohort 1: AUC=0.79, 95% CI 0.70-0.87; cohort 2: AUC =0.69, 95% CI 0.61-0.76).

CONCLUSION: The serum levels of BDNF were significantly lower in colorectal cancer patients when compared to a control population, and this did not differ between different Dukes’ stages.

PMID: 23838134

 

Supplement

Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide and is considered a disease of affluence due to its high incidence in westernised countries such as the US, UK, Europe, Australia and New Zealand [1]. Up to 70% of cases are sporadic where lifestyle and environmental factors, such as diet, obesity, physical inactivity, and smoking, have been identified as major risk factors. CRC is believed to develop as a result of an accumulation of genetic and epigenetic changes in colonic epithelium that occurs over 10-15 years, and represents an ideal opportunity for development of diagnostic tests that can be implemented in population wide screening programs. Currently the most widely used test in a screening population is the faecal occult blood test. While non-invasive, this test suffers from low specificity and is not able to detect early stage disease. Furthermore, the value of this test is hampered by poor patient compliance, with faecal aversion identified as one of the primary reasons contributing to suboptimal participation in population screening[2].

Many biomarker discovery studies have been reported in attempt to identify appropriate molecular markers that can be used in a non-invasive diagnostic test for CRC. The primary goal of these studies is to identify biomarkers that are able to detect the disease early (Stage I or II disease, or ideally adenomas or premalignant polyps) when the chance for cure is greatest. Furthermore, the majority of these studies focus on biomarkers that are tumour specific or that are indicative of the disease process. While valuable, a panel of biomarkers that also includes potential marker(s) that are representative of known risk factors for the disease would be advantageous.

In this study, we focussed on brain-derived neurotrophic factor (BDNF) and evaluated its potential as a blood-based protein biomarker for CRC diagnosis. The role of BDNF in colorectal tumorigenesis is not well understood, however elevated expression has been detected in CRC tumour tissue in comparison to normal tissue and CRC cell lines have been shown to produce endogenous BDNF[3, 4].

BDNF is a potentially unique biomarker as lower levels in the circulation are also associated with obesity , and weight gain, known risk factors for CRC development. Accordingly, BDNF may be a biomarker that can be used to potentially predict or detect the disease in a subset of the population. For example, men who are overweight or obese have a 30-70% increased risk of developing CRC and in Europe, approximately 11% of CRC diagnoses have been associated with being overweight or obese[5].

In our study, we measured serum BDNF levels in two independent age and gender matched case-control cohorts (for cohort 1, n=99 for controls and n=97 for CRC patients and for cohort 2, n=47 for controls and n=91 for CRC patients). In both cohorts, circulating BDNF levels were decreased in CRC patients when compared to healthy controls (p<0.0001). Further analysis using receiver operator characteristics also determined that BDNF performed equally well as a diagnostic marker at all disease stages (determined at 95% specificity) in the cohorts tested.

These results encourage further studies into the value of BDNF as a diagnostic marker for CRC, in particular for identifying those who are at higher risk for developing the disease. For example, it would be valuable to determine the performance of this biomarker in combination with BMI or other markers associated with overweight or obesity such as adipokines.

 

Acknowledgements

We thank the Victorian Cancer Biobank (Melbourne, Victoria) for their assistance with sample collection. This work was funded by the CSIRO Preventative Health National Research Flagship aand a NHMRC Development Grant.

 

References

1.            Ferlay, J., et al., Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer, 2011. 127(12): p. 2893-917.

2.            Vart, G., R. Banzi, and S. Minozzi, Comparing participation rates between immunochemical and guaiac faecal occult blood tests: a systematic review and meta-analysis. Prev Med, 2012. 55(2): p. 87-92.

3.            Akil, H., et al., Fine-tuning roles of endogenous brain-derived neurotrophic factor, TrkB and sortilin in colorectal cancer cell survival. PLoS One, 2011. 6(9): p. e25097.

4.            Brunetto de Farias, C., et al., BDNF/TrkB content and interaction with gastrin-releasing peptide receptor blockade in colorectal cancer. Oncology, 2010. 79(5-6): p. 430-9.

5.            Bardou, M., A.N. Barkun, and M. Martel, Obesity and colorectal cancer. Gut, 2013. 62(6): p. 933-47.

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