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01-12-2021 | Colonoscopy | Research article

A fecal-based test for the detection of advanced adenoma and colorectal cancer: a case-control and screening cohort study

Authors: Lian-Jing Cao, Xiao-Lin Peng, Wen-Qiong Xue, Rong Zhang, Jiang-Bo Zhang, Ting Zhou, Zi-Yi Wu, Gai-Rui Li, Tong-Min Wang, Yong-Qiao He, Da-Wei Yang, Ying Liao, Xia-Ting Tong, Fang Wang, Ke-Xin Chen, Shi-Hong Zhang, Li-Qing Zhu, Pei-Rong Ding, Wei-Hua Jia

Published in: BMC Medicine | Issue 1/2021

Abstract

Background

Colorectal cancer (CRC) is the leading cause of cancer death worldwide. Screening is a confirmed way to reduce the incidence and mortality rates of CRC. This study aimed to identify a fecal-based, noninvasive, and accurate method for detection of colorectal cancer (CRC) and advanced adenoma (AA).

Methods

Through detection in tissue (n = 96) and fecal samples (n = 88) and tested in an independent group of fecal samples (n = 294), the methylated DNA marker ITGA4 and bacterial markers Fusobacterium nucleatum (Fn) and Pepetostreptococcusanaerobius (Pa) were identified from the candidate biomarkers for CRC and AA detection. A prediction score (pd-score) was constructed using the selected markers and fecal immunochemical test (FIT) for distinguishing AA and CRC from healthy subjects by logistic regression method. The diagnostic performance of the pd-score was compared with FIT and validated in the external validation cohort (n = 117) and in a large CRC screening cohort.

Results

The pd-score accurately identified AA and CRC from healthy subjects with an area under the curve (AUC) of 0.958, at a specificity of 91.37%; the pd-score showed sensitivities of 95.38% for CRC and 70.83% for AA, respectively. In the external validation cohort, the sensitivities of the pd-score for CRC and AA detection were 94.03% and 80.00%, respectively. When applied in screening, the pd-score identified 100% (11/11) of CRC and 70.83% (17/24) of AA in participants with both colonoscopy results and qualified fecal samples, showing an improvement by 41.19% compared to FIT.

Conclusions

The current study developed a noninvasive and well-validated approach for AA and CRC detection, which could be applied widely as a diagnostic and screening test.

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Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30. https://doi.org/10.3322/caac.21590.CrossRefPubMed

Ferlizza E, Solmi R, Sgarzi M, Ricciardiello L, Lauriola M. The Roadmap of Colorectal Cancer Screening. Cancers. 2021;13(5):1101. https://doi.org/10.3390/cancers13051101.CrossRefPubMedPubMedCentral

Zhang S, Sun K, Zheng R, Zeng H, Wang S, Chen R, et al. Cancer incidence and mortality in China 2015. J Natl Cancer Center. 2020;1(1):–11. https://doi.org/10.1016/j.jncc.2020.12.001.

Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet. 2019;394(10207):1467–80.CrossRefPubMed

Meester RG, Doubeni CA, Lansdorp-Vogelaar I, Goede SL, Levin TR, Quinn VP, et al. Colorectal cancer deaths attributable to nonuse of screening in the United States. Ann Epidemiol. 2015;25(3):208–13 e1.CrossRefPubMed

Provenzale D, Ness RM, Llor X, Weiss JM, Abbadessa B, Cooper G, et al. NCCN Guidelines Insights: Colorectal Cancer Screening, Version 2.2020. J Natl Compr Cancer Netw. 2020;18(10):1312–20. https://doi.org/10.6004/jnccn.2020.0048.CrossRef

Zorzi M, Fedeli U, Schievano E, Bovo E, Guzzinati S, Baracco S, et al. Impact on colorectal cancer mortality of screening programmes based on the faecal immunochemical test. Gut. 2015;64(5):784–90. https://doi.org/10.1136/gutjnl-2014-307508.CrossRefPubMed

Lee JK, Liles EG, Bent S, Levin TR, Corley DA. Accuracy of fecal immunochemical tests for colorectal cancer: systematic review and meta-analysis. Ann Intern Med. 2014;160(3):171. https://doi.org/10.7326/M13-1484.CrossRefPubMedPubMedCentral

Robertson DJ, Lee JK, Boland CR, Dominitz JA, Giardiello FM, Johnson DA, et al. Recommendations on fecal immunochemical testing to screen for colorectal neoplasia: a consensus statement by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology. 2017;152(5):1217–37 e3. https://doi.org/10.1053/j.gastro.2016.08.053.CrossRefPubMed

10.

Chao S, Ying J, Liew G, Marshall W, Liew CC, Burakoff R. Blood RNA biomarker panel detects both left- and right-sided colorectal neoplasms: a case-control study. J Exp Clin Cancer Res. 2013;32(1):44. https://doi.org/10.1186/1756-9966-32-44.CrossRefPubMedPubMedCentral

11.

Ciarloni L, Ehrensberger SH, Imaizumi N, Monnier-Benoit S, Nichita C, Myung SJ, et al. Development and clinical validation of a blood test based on 29-gene expression for early detection of clorectal cancer. Clin Cancer Res. 2016;22(18):4604–11. https://doi.org/10.1158/1078-0432.CCR-15-2057.CrossRefPubMed

12.

Ferlizza E, Solmi R, Miglio R, Nardi E, Mattei G, Sgarzi M, et al. Colorectal cancer screening: Assessment of CEACAM6, LGALS4, TSPAN8 and COL1A2 as blood markers in faecal immunochemical test negative subjects. J Adv Res. 2020;24:99–107. https://doi.org/10.1016/j.jare.2020.03.001.CrossRefPubMedPubMedCentral

13.

Peterse EFP, Meester RGS, de Jonge L, Omidvari AH, Alarid-Escudero F, Knudsen AB, et al. Comparing the cost-effectiveness of innovative colorectal cancer screening tests. J Natl Cancer Inst. 2021;113(2):154–61. https://doi.org/10.1093/jnci/djaa103.CrossRefPubMed

14.

Imperiale TF, Ransohoff DF, Itzkowitz SH, Levin TR, Lavin P, Lidgard GP, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287–97. https://doi.org/10.1056/NEJMoa1311194.CrossRefPubMed

15.

Provenzale D, Gupta S, Ahnen DJ, Markowitz AJ, Chung DC, Mayer RJ, et al. NCCN guidelines insights: colorectal cancer screening, Version 1.2018. J Natl Compr Cancer Netw. 2018;16(8):939–49. https://doi.org/10.6004/jnccn.2018.0067.CrossRef

16.

National Cancer Center CEGotDoCGftSED Early Treatment of Colorectal C. China guideline for the screening, early detection and early treatment of colorectal cancer (2020, Beijing). Zhonghua Zhong Liu Za Zhi. 2021;43(1):16–38.

17.

Nguyen LH, Goel A, Chung DC. Pathways of colorectal carcinogenesis. Gastroenterology. 2020;158(2):291–302. https://doi.org/10.1053/j.gastro.2019.08.059.CrossRefPubMed

18.

Jung G, Hernández-Illán E, Moreira L, Balaguer F, Goel A. Epigenetics of colorectal cancer: biomarker and therapeutic potential. Nat Rev Gastroenterol Hepatol. 2020;17(2):111–30. https://doi.org/10.1038/s41575-019-0230-y.CrossRefPubMedPubMedCentral

19.

Yan W, Guo M. Epigenetics of colorectal cancer. Methods Mol Biol (Clifton, NJ). 2015;1238:405–24.CrossRef

20.

Kanai Y, Hirohashi S. Alterations of DNA methylation associated with abnormalities of DNA methyltransferases in human cancers during transition from a precancerous to a malignant state. Carcinogenesis. 2007;28(12):2434–42. https://doi.org/10.1093/carcin/bgm206.CrossRefPubMed

21.

Mu J, Huang Y, Cai S, Li Q, Song Y, Yuan Y, et al. Plausibility of an extensive use of stool DNA test for screening advanced colorectal neoplasia. Clin Chim Acta. 2020;501:42–7.CrossRefPubMed

22.

Rengucci C, De Maio G, Menghi M, Scarpi E, Guglielmo S, Fusaroli P, et al. Improved stool DNA integrity method for early colorectal cancer diagnosis. Cancer Epidemiol Biomarkers Prev. 2014;23(11):2553–60. https://doi.org/10.1158/1055-9965.EPI-14-0379.CrossRefPubMed

23.

Calistri D, Rengucci C, Casadei Gardini A, Frassineti GL, Scarpi E, Zoli W, et al. Fecal DNA for noninvasive diagnosis of colorectal cancer in immunochemical fecal occult blood test-positive individuals. Cancer Epidemiol Biomarkers Prev. 2010;19(10):2647–54. https://doi.org/10.1158/1055-9965.EPI-10-0291.CrossRefPubMed

24.

Castellarin M, Warren RL, Freeman JD, Dreolini L, Krzywinski M, Strauss J, et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res. 2012;22(2):299–306. https://doi.org/10.1101/gr.126516.111.CrossRefPubMedPubMedCentral

25.

Feng Q, Liang S, Jia H, Stadlmayr A, Tang L, Lan Z, et al. Gut microbiome development along the colorectal adenoma-carcinoma sequence. Nat Commun. 2015;6(1):6528. https://doi.org/10.1038/ncomms7528.CrossRefPubMed

26.

Yu J, Feng Q, Wong SH, Zhang D, Liang QY, Qin Y, et al. Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer. Gut. 2017;66(1):70–8. https://doi.org/10.1136/gutjnl-2015-309800.CrossRefPubMed

27.

Thomas AM, Manghi P, Asnicar F, Pasolli E, Armanini F, Zolfo M, et al. Metagenomic analysis of colorectal cancer datasets identifies cross-cohort microbial diagnostic signatures and a link with choline degradation. Nat Med. 2019;25(4):667–78. https://doi.org/10.1038/s41591-019-0405-7.CrossRefPubMed

28.

Guo S, Li L, Xu B, Li M, Zeng Q, Xiao H, et al. A simple and novel fecal biomarker for colorectal cancer: ratio of Fusobacterium nucleatum to probiotics populations, based on their antagonistic effect. Clin Chem. 2018;64(9):1327–37. https://doi.org/10.1373/clinchem.2018.289728.CrossRefPubMed

29.

Jalanka J, Salonen A, Salojärvi J, Ritari J, Immonen O, Marciani L, et al. Effects of bowel cleansing on the intestinal microbiota. Gut. 2015;64(10):1562–8. https://doi.org/10.1136/gutjnl-2014-307240.CrossRefPubMed

30.

Chen H, Li N, Ren J, Feng X, Lyu Z, Wei L, et al. Participation and yield of a population-based colorectal cancer screening programme in China. Gut. 2019;68(8):1450–7. https://doi.org/10.1136/gutjnl-2018-317124.CrossRefPubMed

31.

Chen WD, Han ZJ, Skoletsky J, Olson J, Sah J, Myeroff L, et al. Detection in fecal DNA of colon cancer-specific methylation of the nonexpressed vimentin gene. J Natl Cancer Inst. 2005;97(15):1124–32. https://doi.org/10.1093/jnci/dji204.CrossRefPubMed

32.

Itzkowitz S, Brand R, Jandorf L, Durkee K, Millholland J, Rabeneck L, et al. A simplified, noninvasive stool DNA test for colorectal cancer detection. Am J Gastroenterol. 2008;103(11):2862–70. https://doi.org/10.1111/j.1572-0241.2008.02088.x.CrossRefPubMed

33.

Niu F, Wen J, Fu X, Li C, Zhao R, Wu S, et al. Stool DNA test of mthylated syndecan-2 for the early detection of colorectal neoplasia. Cancer Epidemiol Biomark Prev. 2017;26(9):1411–9. https://doi.org/10.1158/1055-9965.EPI-17-0153.CrossRef

34.

Ausch C, Kim YH, Tsuchiya KD, Dzieciatkowski S, Washington MK, Paraskeva C, et al. Comparative analysis of PCR-based biomarker assay methods for colorectal polyp detection from fecal DNA. Clin Chem. 2009;55(8):1559–63. https://doi.org/10.1373/clinchem.2008.122937.CrossRefPubMed

35.

Lind GE, Danielsen SA, Ahlquist T, Merok MA, Andresen K, Skotheim RI, et al. Identification of an epigenetic biomarker panel with high sensitivity and specificity for colorectal cancer and adenomas. Mol Cancer. 2011;10(1):85. https://doi.org/10.1186/1476-4598-10-85.CrossRefPubMedPubMedCentral

36.

Liang JQ, Li T, Nakatsu G, Chen YX, Yau TO, Chu E, et al. A novel faecal Lachnoclostridium marker for the non-invasive diagnosis of colorectal adenoma and cancer. Gut. 2020;69(7):1248–57. https://doi.org/10.1136/gutjnl-2019-318532.CrossRefPubMed

37.

Wong SH, Kwong TNY, Chow TC, Luk AKC, Dai RZW, Nakatsu G, et al. Quantitation of faecal Fusobacterium improves faecal immunochemical test in detecting advanced colorectal neoplasia. Gut. 2017;66(8):1441–8. https://doi.org/10.1136/gutjnl-2016-312766.CrossRefPubMed

38.

Nani BD, Lima PO, Marcondes FK, Groppo FC, Rolim GS, Moraes AB, et al. Changes in salivary microbiota increase volatile sulfur compounds production in healthy male subjects with academic-related chronic stress. PLoS One. 2017;12(3):e0173686. https://doi.org/10.1371/journal.pone.0173686.CrossRefPubMedPubMedCentral

39.

Rath S, Heidrich B, Pieper DH, Vital M. Uncovering the trimethylamine-producing bacteria of the human gut microbiota. Microbiome. 2017;5(1):54. https://doi.org/10.1186/s40168-017-0271-9.CrossRefPubMedPubMedCentral

40.

DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics. 1988;44(3):837–45. https://doi.org/10.2307/2531595.CrossRefPubMed

41.

Young GP, Rabeneck L, Winawer SJ. The Global Paradigm Shift in Screening for Colorectal Cancer. Gastroenterology. 2019;156(4):843–51 e2. https://doi.org/10.1053/j.gastro.2019.02.006.CrossRefPubMed

42.

Quintero E, Castells A, Bujanda L, Cubiella J, Salas D, Lanas A, et al. Colonoscopy versus fecal immunochemical testing in colorectal-cancer screening. N Engl J Med. 2012;366(8):697–706. https://doi.org/10.1056/NEJMoa1108895.CrossRefPubMed

43.

de Klerk CM, Vendrig LM, Bossuyt PM, Dekker E. Participant-related risk factors for false-positive and false-negative fecal immunochemical tests in colorectal cancer screening: systematic review and meta-analysis. Am J Gastroenterol. 2018;113(12):1778–87. https://doi.org/10.1038/s41395-018-0212-7.CrossRefPubMedPubMedCentral

44.

Amitay EL, Cuk K, Niedermaier T, Weigl K, Brenner H. Factors associated with false-positive fecal immunochemical tests in a large German colorectal cancer screening study. Int J Cancer. 2019;144(10):2419–27. https://doi.org/10.1002/ijc.31972.CrossRefPubMed

45.

Ahlquist DA. Multi-target stool DNA test: a new high bar for noninvasive screening. Dig Dis Sci. 2015;60(3):623–33. https://doi.org/10.1007/s10620-014-3451-5.CrossRefPubMed

46.

Bressler B, Paszat LF, Vinden C, Li C, He J, Rabeneck L. Colonoscopic miss rates for right-sided colon cancer: a population-based analysis. Gastroenterology. 2004;127(2):452–6. https://doi.org/10.1053/j.gastro.2004.05.032.CrossRefPubMed

47.

Patel SG, Ahnen DJ. Prevention of interval colorectal cancers: what every clinician needs to know. Clin Gastroenterol Hepatol. 2014;12(1):7–15. https://doi.org/10.1016/j.cgh.2013.04.027.CrossRefPubMed

48.

Cooper GS, Xu F, Barnholtz Sloan JS, Schluchter MD, Koroukian SM. Prevalence and predictors of interval colorectal cancers in medicare beneficiaries. Cancer. 2012;118(12):3044–52. https://doi.org/10.1002/cncr.26602.CrossRefPubMed

49.

Singh H, Nugent Z, Mahmud SM, Demers AA, Bernstein CN. Predictors of colorectal cancer after negative colonoscopy: a population-based study. Am J Gastroenterol. 2010;105(3):663–73; quiz 74. https://doi.org/10.1038/ajg.2009.650.CrossRefPubMed

50.

Samadder NJ, Curtin K, Tuohy TM, Pappas L, Boucher K, Provenzale D, et al. Characteristics of missed or interval colorectal cancer and patient survival: a population-based study. Gastroenterology. 2014;146(4):950–60. https://doi.org/10.1053/j.gastro.2014.01.013.CrossRefPubMed

51.

Digby J, Fraser CG, Carey FA, McDonald PJ, Strachan JA, Diament RH, et al. Faecal haemoglobin concentration is related to severity of colorectal neoplasia. J Clin Pathol. 2013;66(5):415–9. https://doi.org/10.1136/jclinpath-2013-201445.CrossRefPubMed

52.

Bormann F, Rodríguez-Paredes M, Lasitschka F, Edelmann D, Musch T, Benner A, et al. Cell-of-origin DNA methylation signatures are maintained during colorectal carcinogenesis. Cell Rep. 2018;23(11):3407–18. https://doi.org/10.1016/j.celrep.2018.05.045.CrossRefPubMed

53.

Nakatsu G, Li X, Zhou H, Sheng J, Wong SH, Wu WK, et al. Gut mucosal microbiome across stages of colorectal carcinogenesis. Nat Commun. 2015;6(1):8727. https://doi.org/10.1038/ncomms9727.CrossRefPubMed

54.

Zorzi M, Hassan C, Capodaglio G, Narne E, Turrin A, Baracco M, et al. Divergent long-term detection rates of proximal and distal advanced neoplasia in fecal immunochemical test screening programs: a retrospective cohort study. Ann Intern Med. 2018;169(9):602–9. https://doi.org/10.7326/M18-0855.CrossRefPubMed

55.

Chiu HM, Jen GH, Wang YW, Fann JC, Hsu CY, Jeng YC, et al. Long-term effectiveness of faecal immunochemical test screening for proximal and distal colorectal cancers. Gut. 2021. gutjnl-2020-322545; https://doi.org/10.1136/gutjnl-2020-322545.

56.

Wong MC, Ching JY, Chan VC, Lam TY, Shum JP, Luk AK, et al. Diagnostic accuracy of a qualitative fecal immunochemical test varies with location of neoplasia but not number of specimens. Clin Gastroenterol Hepatol. 2015;13(8):1472–9. https://doi.org/10.1016/j.cgh.2015.02.021.CrossRefPubMed

57.

Wang L, Lo CH, He X, Hang D, Wang M, Wu K, et al. Risk factor profiles differ for cancers of different regions of the colorectum. Gastroenterology. 2020;159(1):241–56 e13. https://doi.org/10.1053/j.gastro.2020.03.054.CrossRefPubMed

58.

Flemer B, Lynch DB, Brown JM, Jeffery IB, Ryan FJ, Claesson MJ, et al. Tumour-associated and non-tumour-associated microbiota in colorectal cancer. Gut. 2017;66(4):633–43. https://doi.org/10.1136/gutjnl-2015-309595.CrossRefPubMed

59.

Missiaglia E, Jacobs B, D'Ario G, Di Narzo AF, Soneson C, Budinska E, et al. Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features. Ann Oncol. 2014;25(10):1995–2001. https://doi.org/10.1093/annonc/mdu275.CrossRefPubMed

60.

Yamauchi M, Morikawa T, Kuchiba A, Imamura Y, Qian ZR, Nishihara R, et al. Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Gut. 2012;61(6):847–54. https://doi.org/10.1136/gutjnl-2011-300865.CrossRefPubMed

61.

Arain MA, Sawhney M, Sheikh S, Anway R, Thyagarajan B, Bond JH, et al. CIMP status of interval colon cancers: another piece to the puzzle. Am J Gastroenterol. 2010;105(5):1189–95. https://doi.org/10.1038/ajg.2009.699.CrossRefPubMed

62.

Mima K, Cao Y, Chan AT, Qian ZR, Nowak JA, Masugi Y, et al. Fusobacterium nucleatum in colorectal carcinoma tissue according to tumor location. Clin Transl Gastroenterol. 2016;7(11):e200. https://doi.org/10.1038/ctg.2016.53.CrossRefPubMedPubMedCentral

63.

Rahbari NN, Carr PR, Jansen L, Chang-Claude J, Weitz J, Hoffmeister M, et al. Time of metastasis and outcome in colorectal cancer. Ann Surg. 2019;269(3):494–502. https://doi.org/10.1097/SLA.0000000000002564.CrossRefPubMed

64.

Le H, Ziogas A, Taylor TH, Lipkin SM, Zell JA. Survival of distinct Asian groups among colorectal cancer cases in California. Cancer. 2009;115(2):259–70. https://doi.org/10.1002/cncr.24034.CrossRefPubMed

Title: A fecal-based test for the detection of advanced adenoma and colorectal cancer: a case-control and screening cohort study
Authors: Lian-Jing Cao
Xiao-Lin Peng
Wen-Qiong Xue
Rong Zhang
Jiang-Bo Zhang
Ting Zhou
Zi-Yi Wu
Gai-Rui Li
Tong-Min Wang
Yong-Qiao He
Da-Wei Yang
Ying Liao
Xia-Ting Tong
Fang Wang
Ke-Xin Chen
Shi-Hong Zhang
Li-Qing Zhu
Pei-Rong Ding
Wei-Hua Jia
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Colonoscopy
Colorectal Cancer
Colorectal Cancer
Biomarkers
Published in: BMC Medicine / Issue 1/2021
Electronic ISSN: 1741-7015
DOI: https://doi.org/10.1186/s12916-021-02123-0

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

A fecal-based test for the detection of advanced adenoma and colorectal cancer: a case-control and screening cohort study

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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