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A novel panel of short mononucleotide repeats linked to informative polymorphisms enabling effective high volume low cost discrimination between mismatch repair deficient and proficient tumours

Lookup NU author(s): Lisa Redford, Dr Ghanim Alhilal, Dr Stephanie Needham, Ottilia O'Brien, Julie Coaker, Dr Osagie Izuogu, Dr Richard Gallon, Dr Harsh Sheth, Dr Mauro Santibanez Koref, Dr Michael Jackson, Professor Sir John BurnORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2018 Redford et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Somatic mutations in mononucleotide repeats are commonly used to assess the mismatch repair status of tumours. Current tests focus on repeats with a length above 15bp, which tend to be somatically more unstable than shorter ones. These longer repeats also have a substantially higher PCR error rate, and tests that use capillary electrophoresis for fragment size analysis often require expert interpretation. In this communication, we present a panel of 17 short repeats (length 7–12bp) for sequence-based microsatellite instability (MSI) testing. Using a simple scoring procedure that incorporates the allelic distribution of the mutant repeats, and analysis of two cohort of tumours totalling 209 samples, we show that this panel is able to discriminate between MMR proficient and deficient tumours, even when constitutional DNA is not available. In the training cohort, the method achieved 100% concordance with fragment analysis, while in the testing cohort, 4 discordant samples were observed (corresponding to 97% concordance). Of these, 2 showed discrepancies between fragment analysis and immunohistochemistry and one was reclassified after re-testing using fragment analysis. These results indicate that our approach offers the option of a reliable, scalable routine test for MSI.

Publication metadata

Author(s): Redford L, Alhilal G, Needham S, O'Brien O, Coaker J, Tyson J, Amorim LM, Middleton I, Izuogu O, Arends M, Oniscu A, Alonso AM, Laguna SM, Gallon R, Sheth H, Santibanez-Koref M, Jackson MS, Burn J

Publication type: Article

Publication status: Published

Journal: PLoS ONE

Year: 2018

Volume: 13

Issue: 8

Online publication date: 29/08/2018

Acceptance date: 14/08/2017

Date deposited: 02/10/2018

ISSN (electronic): 1932-6203

Publisher: Public Library of Science

URL: https://doi.org/10.1371/journal.pone.0203052

DOI: 10.1371/journal.pone.0203052

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