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Novel stool-based protein biomarkers for improved colorectal cancer screening : a case-control study

(2017) ANNALS OF INTERNAL MEDICINE. 167(12). p.855-866
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Abstract
Background: The fecal immunochemical test (FIT) for detecting hemoglobin is used widely for noninvasive colorectal cancer (CRC) screening, but its sensitivity leaves room for improvement. Objective: To identify novel protein biomarkers in stool that outperform or complement hemoglobin in detecting CRC and advanced adenomas. Design: Case-control study. Setting: Colonoscopy-controlled referral population from several centers. Participants: 315 stool samples from one series of 12 patients with CRC and 10 persons without colorectal neoplasia (control samples) and a second series of 81 patients with CRC, 40 with advanced adenomas, and 43 with nonadvanced adenomas, as well as 129 persons without colorectal neoplasia (control samples); 72 FIT samples from a third independent series of 14 patients with CRC, 16 with advanced adenomas, and 18 with nonadvanced adenomas, as well as 24 persons without colorectal neoplasia (control samples). Measurements: Stool samples were analyzed by mass spectrometry. Classification and regression tree (CART) analysis and logistic regression analyses were performed to identify protein combinations that differentiated CRC or advanced adenoma from control samples. Antibody-based assays for 4 selected proteins were done on FIT samples. Results: In total, 834 human proteins were identified, 29 of which were statistically significantly enriched in CRC versus con-trol stool samples in both series. Combinations of 4 proteins reached sensitivities of 80% and 45% for detecting CRC and advanced adenomas, respectively, at 95% specificity, which was higher than that of hemoglobin alone (P < 0.001 and P = 0.003, respectively). Selected proteins could be measured in small sample volumes used in FIT-based screening programs and discriminated between CRC and control samples (P < 0.001). Limitation: Lack of availability of antibodies prohibited validation of the top protein combinations in FIT samples. Conclusion: Mass spectrometry of stool samples identified novel candidate protein biomarkers for CRC screening. Several protein combinations outperformed hemoglobin in discriminating CRC or advanced adenoma from control samples. Proof of concept that such proteins can be detected with antibody-based assays in small sample volumes indicates the potential of these biomarkers to be applied in population screening.
Keywords
FECAL-OCCULT-BLOOD, HUMAN FECES, LABEL-FREE, PROTEOMICS, COMPLEMENT, DISCOVERY, MORTALITY, DIAGNOSIS, MARKERS, GROWTH

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Chicago
Bosch, Linda JW, Meike de Wit, Thang V Pham, Veerle MH Coupe, Annemieke C Hiemstra, Sander R Piersma, Gideon Oudgenoeg, et al. 2017. “Novel Stool-based Protein Biomarkers for Improved Colorectal Cancer Screening : a Case-control Study.” Annals of Internal Medicine 167 (12): 855–866.
APA
Bosch, L. J., de Wit, M., Pham, T. V., Coupe, V. M., Hiemstra, A. C., Piersma, S. R., Oudgenoeg, G., et al. (2017). Novel stool-based protein biomarkers for improved colorectal cancer screening : a case-control study. ANNALS OF INTERNAL MEDICINE, 167(12), 855–866.
Vancouver
1.
Bosch LJ, de Wit M, Pham TV, Coupe VM, Hiemstra AC, Piersma SR, et al. Novel stool-based protein biomarkers for improved colorectal cancer screening : a case-control study. ANNALS OF INTERNAL MEDICINE. 2017;167(12):855–66.
MLA
Bosch, Linda JW, Meike de Wit, Thang V Pham, et al. “Novel Stool-based Protein Biomarkers for Improved Colorectal Cancer Screening : a Case-control Study.” ANNALS OF INTERNAL MEDICINE 167.12 (2017): 855–866. Print.
@article{8557777,
  abstract     = {Background: The fecal immunochemical test (FIT) for detecting hemoglobin is used widely for noninvasive colorectal cancer (CRC) screening, but its sensitivity leaves room for improvement. 
Objective: To identify novel protein biomarkers in stool that outperform or complement hemoglobin in detecting CRC and advanced adenomas. 
Design: Case-control study. 
Setting: Colonoscopy-controlled referral population from several centers. 
Participants: 315 stool samples from one series of 12 patients with CRC and 10 persons without colorectal neoplasia (control samples) and a second series of 81 patients with CRC, 40 with advanced adenomas, and 43 with nonadvanced adenomas, as well as 129 persons without colorectal neoplasia (control samples); 72 FIT samples from a third independent series of 14 patients with CRC, 16 with advanced adenomas, and 18 with nonadvanced adenomas, as well as 24 persons without colorectal neoplasia (control samples). 
Measurements: Stool samples were analyzed by mass spectrometry. Classification and regression tree (CART) analysis and logistic regression analyses were performed to identify protein combinations that differentiated CRC or advanced adenoma from control samples. Antibody-based assays for 4 selected proteins were done on FIT samples. 
Results: In total, 834 human proteins were identified, 29 of which were statistically significantly enriched in CRC versus con-trol stool samples in both series. Combinations of 4 proteins reached sensitivities of 80\% and 45\% for detecting CRC and advanced adenomas, respectively, at 95\% specificity, which was higher than that of hemoglobin alone (P {\textlangle} 0.001 and P = 0.003, respectively). Selected proteins could be measured in small sample volumes used in FIT-based screening programs and discriminated between CRC and control samples (P {\textlangle} 0.001). 
Limitation: Lack of availability of antibodies prohibited validation of the top protein combinations in FIT samples. 
Conclusion: Mass spectrometry of stool samples identified novel candidate protein biomarkers for CRC screening. Several protein combinations outperformed hemoglobin in discriminating CRC or advanced adenoma from control samples. Proof of concept that such proteins can be detected with antibody-based assays in small sample volumes indicates the potential of these biomarkers to be applied in population screening.},
  author       = {Bosch, Linda JW and de Wit, Meike and Pham, Thang V and Coupe, Veerle MH and Hiemstra, Annemieke C and Piersma, Sander R and Oudgenoeg, Gideon and Scheffer, George L and Mongera, Sandra and Droste, Jochim Terhaar Sive and Oort, Frank A and van Turenhout, Sietze T and Ben Larbi, Ilhame and Louwagie, Joost and Van Criekinge, Wim and van der Hulst, Rene WM and Mulder, Chris JJ and Carvalho, Beatriz and Fijneman, Remond JA and Jimenez, Connie R and Meijer, Gerrit A},
  issn         = {0003-4819},
  journal      = {ANNALS OF INTERNAL MEDICINE},
  language     = {eng},
  number       = {12},
  pages        = {855--866},
  title        = {Novel stool-based protein biomarkers for improved colorectal cancer screening : a case-control study},
  url          = {http://dx.doi.org/10.7326/M17-1068},
  volume       = {167},
  year         = {2017},
}

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