Novel Methylated DNA Markers Accurately Discriminate Lynch Syndrome Associated Colorectal Neoplasia

Abstract

Aim: Acquired molecular changes in Lynch syndrome (LS) colorectal tumors have been largely unstudied. We identified methylated DNA markers (MDMs) for discrimination of colorectal neoplasia in LS and determined if these MDMs were comparably discriminant in sporadic patients. Patients&methods: For LS discovery, we evaluated DNA from 53 colorectal case and control tissues using next generation sequencing. For validation, blinded methylation-specific PCR assays to the selected MDMs were performed on 197 cases and controls. Results:OPLAH was the most discriminant MDM with areas under the receiver operating characteristic curve ≥0.97 for colorectal neoplasia in LS and sporadic tissues. ALKBH5, was uniquely hypermethylated in LS neoplasms. Conclusion: Highly discriminant MDMs for colorectal neoplasia in LS were identified with potential use in screening and surveillance.

Keywords::

• biomarkers
• colorectal neoplasms
• colorectal neoplasms
• colorectal prevention and control
• hereditary nonpolyposis
• DNA methylation
• colorectal physiology

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.tandfonline.com/doi/suppl/10.2217/epi-2020-0132

Financial&competing interests disclosure

Funding was provided by Eugene and Eva Lane, the Mayo Foundation, the Hispanic Clinical and Translational Research Education and Career Development (HCTRECD) Award R25MD007607 and Exact Sciences. Additional support was provided by CA214679 (to JBK). The Clinical Core of the Mayo Clinic for Cell Signaling in Gastroenterology (P30DK084567) provided a subset of the biospecimens. During course of this study and data analyses, DA Ahlquist&JB Kisiel, Messrs. Taylor&Mahoney and TC Yab were employees of Mayo Clinic and are listed as inventors in an intellectual property agreement between Mayo Clinic and Exact Sciences, under which they could receive royalties, in accordance with Mayo Clinic policy. DA Ahlquist currently serves as senior scientific advisor to Exact Sciences. GP Lidgard is Chief Science Officer at Exact Sciences. Exact Sciences provided partial funding and valuable assay reagents but played no role in the design, conduct, or data analyses for this study. CR Boland has given lectures for Ambry Genetics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

Funding was provided by Eugene and Eva Lane, the Mayo Foundation, the Hispanic Clinical and Translational Research Education and Career Development (HCTRECD) Award R25MD007607 and Exact Sciences. Additional support was provided by CA214679 (to JBK). The Clinical Core of the Mayo Clinic for Cell Signaling in Gastroenterology (P30DK084567) provided a subset of the biospecimens. During course of this study and data analyses, DA Ahlquist&JB Kisiel, Messrs. Taylor&Mahoney and TC Yab were employees of Mayo Clinic and are listed as inventors in an intellectual property agreement between Mayo Clinic and Exact Sciences, under which they could receive royalties, in accordance with Mayo Clinic policy. DA Ahlquist currently serves as senior scientific advisor to Exact Sciences. GP Lidgard is Chief Science Officer at Exact Sciences. Exact Sciences provided partial funding and valuable assay reagents but played no role in the design, conduct, or data analyses for this study. CR Boland has given lectures for Ambry Genetics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.