Blood Plasma Methylated DNA Markers in the Detection of Lymphoma: Discovery, Validation, and Clinical Pilot.

in American journal of hematology by Thomas E Witzig, William R Taylor, Douglas W Mahoney, William R Bamlet, Patrick H Foote, Kelli N Burger, Karen A Doering, Mary E Devens, Jacquelyn R Arndt, Maria C O'Connell, Calise K Berger, Anne J Novak, James R Cerhan, Jacquelyn Hennek, Slava Katerov, Hatim T Allawi, Dragan Jevremovic, Linda N Dao, Rondell P Graham, John B Kisiel

TLDR

  • The study aimed to find a way to detect lymphoma using DNA markers found in the blood. They used a technique called reduced representation bisulfite sequencing (RRBS) to find these markers in tissue samples. They then converted these markers into a test that could be done on blood samples. The study found that this test could detect lymphoma in 78% of cases with 90% specificity. They also found that excluding certain types of lymphoma improved the sensitivity of the test. The study suggests that this test could be used for early detection and monitoring of lymphoma.

Abstract

Lymphoma is one of the leading causes of cancer and cancer deaths and yet has not been amenable to population screening. The role of methylated DNA markers (MDMs) in the detection of lymphoma has not been extensively studied. We aimed to discover, validate, and test tissue-derived MDMs of lymphoma in archival plasma specimens. Reduced representation bisulfite sequencing (RRBS) was performed on a discovery set of frozen tissues. MDMs identified were converted to methylation-specific PCR assays and validated on independent formalin-fixed, paraffin-embedded (FFPE) tissues. Target enrichment long-probe quantitative-amplified signal (TELQAS) assays were developed and assayed in plasma-extracted, bisulfite-converted DNA from independent treatment-naïve lymphoma patients and healthy controls. Prediction of cancer status was modeled using random forest model with in silico cross-validation. After discovery and validation in tissue, 16 TELQAS assays (ZNF503, VWA5B1, HOXA9, GABRG3, ITGA5, MAX.chr17.7190, BNC1, CDK20, MAX.chr4.4069, TPBG, DNAH14, SYT6, CACNG8, FAM110B, ADRA1D, and NRN1) were selected for testing in plasma. These detected 78% (95% CI, 74%-82%) of lymphoma cases at 90% specificity. Excluding marginal zone and T-cell lymphomas, sensitivity increased to 84% (80%-88%). MDMs in plasma show promise to detect lymphoma and are candidates for inclusion in multi-cancer detection studies.

Overview

  • The study aimed to discover, validate, and test tissue-derived MDMs of lymphoma in archival plasma specimens using RRBS, TELQAS assays, and random forest model with in silico cross-validation. The study focused on detecting lymphoma in plasma and identified 16 TELQAS assays that detected 78% of lymphoma cases at 90% specificity. The study also excluded marginal zone and T-cell lymphomas, increasing sensitivity to 84% (80%-88%).
  • Comparative Analysis & Findings

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions or interventions detailed in the study. The study identified 16 TELQAS assays that detected 78% of lymphoma cases at 90% specificity. The study also excluded marginal zone and T-cell lymphomas, increasing sensitivity to 84% (80%-88%).
  • Key Findings

Implications and Future Directions

  • The study's findings suggest that MDMs in plasma show promise to detect lymphoma and are candidates for inclusion in multi-cancer detection studies. The study also highlights the importance of excluding marginal zone and T-cell lymphomas to improve sensitivity. Future research should focus on improving the specificity of the assays and expanding the panel of MDMs to include other types of lymphomas. The study also suggests that MDMs in plasma could be used for early detection and monitoring of lymphoma.
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