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Evaluation of a panel of tumor-specific differentially-methylated DNA regions in IRF4, IKZF1 and BCAT1 for blood-based detection of colorectal cancer.
Young, Graeme P; Symonds, Erin L; Nielsen, Hans Jørgen; Ferm, Linnea; Christensen, Ib J; Dekker, Evelien; van der Vlugt, Manon; Mallant-Hent, Rosalie C; Boulter, Nicky; Yu, Betty; Chan, Michelle; Tevz, Gregor; LaPointe, Lawrence C; Pedersen, Susanne K.
Afiliação
  • Young GP; Flinders Health and Medical Research Institute, Flinders University, Adelaide, Australia.
  • Symonds EL; Flinders Health and Medical Research Institute, Flinders University, Adelaide, Australia.
  • Nielsen HJ; Bowel Health Service, Flinders Medical Centre, Bedford Park, South Australia, Australia.
  • Ferm L; Department of Surgical Gastroenterology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark.
  • Christensen IJ; Department of Surgical Gastroenterology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark.
  • Dekker E; Department of Surgical Gastroenterology, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark.
  • van der Vlugt M; Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
  • Mallant-Hent RC; Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
  • Boulter N; Department of Gastroenterology, Flevo Hospital, Almere, The Netherlands.
  • Yu B; Clinical Genomics Pty Ltd, North Ryde, NSW, Australia.
  • Chan M; Clinical Genomics Pty Ltd, North Ryde, NSW, Australia.
  • Tevz G; Clinical Genomics Pty Ltd, North Ryde, NSW, Australia.
  • LaPointe LC; Clinical Genomics Pty Ltd, North Ryde, NSW, Australia.
  • Pedersen SK; Clinical Genomics Technologies Ltd, Edison, USA.
Clin Epigenetics ; 13(1): 14, 2021 01 21.
Article em En | MEDLINE | ID: mdl-33478584
BACKGROUND: Differentially-methylated regions (DMRs) are characteristic of colorectal cancer (CRC) and some occur more frequently than common mutations. This study aimed to evaluate the clinical utility of assaying circulating cell-free DNA for methylation in BCAT1, IKZF1 and IRF4 for detection of CRC. METHODS: A multiplexed real-time PCR assay targeting DMRs in each of the three genes was developed. Assay accuracy was explored in plasma specimens banked from observational cross-sectional trials or from volunteers scheduled for colonoscopy or prior to CRC surgery. RESULTS: 1620 specimens were suitable for study inclusion including 184 and 616 cases with CRC and adenomas, respectively, and 820 cases without neoplasia (overall median age, 63.0 years; 56% males). Combining the PCR signals for all targeted DMRs returned the best sensitivity for CRC (136/184, 73.9%, 95% CI 67.1-79.7), advanced adenomas (53/337, 15.7%, 95% CI 12.0-20.1) and high-grade dysplastic (HGD) adenomas (9/35, 25.7%, 95% CI 14.0-42.3) with a 90.1%, specificity for neoplasia (739/820, 95% CI 87.9-92.0, p < 0.01). Detection of methylation in all three genes were more likely in CRC cases than those without it (OR 28.5, 95% CI 7.3-121.2, p < 0.0001). Of the 81 positive cases without neoplasia, 62 (76.5%) were positive by a single PCR replicate only and predominantly due to detection of methylated BCAT1 (53.2%). Single replicate positivity was significantly higher than that in CRC (26/136, 19.1%, p < 0.0001), and single BCAT1 replicate positivity was more likely in cases without neoplasia than in CRC (OR 17.7, 95% CI 6.6-43.3, p < 0.0001). When a positive result was limited to those with ≥ 1 PCR replicate positive for either IKZF1 or IRF4, or at least two replicates positive for BCAT1, the multi-panel test maintained a high sensitivity for CRC (131/184, 71.2%, 95% CI 64.3-77.3) and HGD adenomas (8/35, 22.9%, 95% CI 11.8-39.3, p = 0.029) but improved specificity significantly (772/820, 94.1%, 95% CI 92.3-95.6, p < 0.0001 vs. any PCR replicate positive). CONCLUSION: The multi-panel methylation assay differentiates cases with CRC from those without it and does so with high specificity when criteria for BCAT1 detection are applied. The marker panel is flexible and studies in those at average risk for CRC are now warranted to determine which panel configuration best suits screening goals. TRIAL REGISTRATION: ACTRN12611000318987. Registered 25 March 2011, https://www.anzctr.org.au/ ACTRN12611000318987.
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Texto completo: 1 Coleções: 01-internacional Contexto em Saúde: 2_ODS3 Base de dados: MEDLINE Assunto principal: DNA de Neoplasias / Neoplasias Colorretais / Biomarcadores Tumorais / Programas de Rastreamento / Metilação de DNA Tipo de estudo: Diagnostic_studies / Observational_studies / Prevalence_studies / Prognostic_studies / Risk_factors_studies / Screening_studies Limite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Clin Epigenetics Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Contexto em Saúde: 2_ODS3 Base de dados: MEDLINE Assunto principal: DNA de Neoplasias / Neoplasias Colorretais / Biomarcadores Tumorais / Programas de Rastreamento / Metilação de DNA Tipo de estudo: Diagnostic_studies / Observational_studies / Prevalence_studies / Prognostic_studies / Risk_factors_studies / Screening_studies Limite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Clin Epigenetics Ano de publicação: 2021 Tipo de documento: Article