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Lookup NU author(s): Rachel Phelps, Dr Richard Gallon, Christine Hayes, Dr Tom Lee, Professor Rakesh Heer, Dr Ciaron McAnulty, Dr Mauro Santibanez Koref, Professor Sir John BurnORCiD, Dr Michael Jackson
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2022 by the authors. Identification of mismatch repair (MMR)-deficient colorectal cancers (CRCs) is recommended for Lynch syndrome (LS) screening, and supports targeting of immune checkpoint inhibitors. Microsatellite instability (MSI) analysis is commonly used to test for MMR deficiency. Testing biopsies prior to tumour resection can inform surgical and therapeutic decisions, but can be limited by DNA quantity. MSI analysis of voided urine could also provide much needed surveillance for genitourinary tract cancers in LS. Here, we reconfigure an existing molecular inversion probe-based MSI and BRAF c.1799T > A assay to a multiplex PCR (mPCR) format, and demonstrate that it can sample >140 unique molecules per marker from <1 ng of DNA and classify CRCs with 96–100% sensitivity and specificity. We also show that it can detect increased MSI within individual and composite CRC biopsies from LS patients, and within preoperative urine cell free DNA (cfDNA) from two LS patients, one with an upper tract urothelial cancer, the other an undiagnosed endometrial cancer. Approximately 60–70% of the urine cfDNAs were tumour-derived. Our results suggest that mPCR sequence-based analysis of MSI and mutation hotspots in CRC biopsies could facilitate presurgery decision making, and could enable postal-based screening for urinary tract and endometrial tumours in LS patients.
Author(s): Phelps R, Gallon R, Hayes C, Glover E, Gibson P, Edidi I, Lee T, Mills S, Shaw A, Heer R, Ralte A, McAnulty C, Santibanez-Koref M, Burn J, Jackson MS
Publication type: Article
Publication status: Published
Journal: Cancers
Year: 2022
Volume: 14
Issue: 15
Online publication date: 08/08/2022
Acceptance date: 21/07/2022
Date deposited: 20/09/2022
ISSN (electronic): 2072-6694
Publisher: MDPI
URL: https://doi.org/10.3390/cancers14153838
DOI: 10.3390/cancers14153838
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