Adenomas from individuals with pathogenic biallelic variants in the MUTYH and NTHL1 genes demonstrate base excision repair tumour mutational signature profiles similar to colorectal cancers, expanding potential diagnostic and variant classification applications

Romy Walker; Jihoon Eric Joo; Khalid Mahmood; Mark Clendenning; Julia Como; Susan Preston; Sharelle L. Joseland; Bernard J. Pope; Ana Beatriz Deleame Medeiros; Brenely V. Murillo; Nicholas Pachter; Kevin M. Sweet; Allan D. Spigelman; Alexandra Groves; Margaret Gleeson; Krzysztof Bernatowicz; Nicola Kazia Poplawski; Lesley Andrews; Emma Healey; Steve Gallinger; Robert C. Grant; Aung Ko Win; John Llewelyn Hopper; Mark A. Jenkins; Giovana Tardin Torrezan; Christophe Rosty; Finlay Macrae; Ingrid Winship; Daniel D. Buchanan; Peter Georgeson

doi:10.1101/2024.08.08.24311713

Genetic & Genomic MedicinemedRxivAug 8, 2024

Preprint

Adenomas from individuals with pathogenic biallelic variants in the MUTYH and NTHL1 genes demonstrate base excision repair tumour mutational signature profiles similar to colorectal cancers, expanding potential diagnostic and variant classification applications

Romy Walker iD, Jihoon Eric Joo iD, Khalid Mahmood iD, Mark Clendenning iD, Julia Como iD, Susan Preston iD, Sharelle L. Joseland iD, Bernard J. Pope iD, Ana Beatriz Deleame Medeiros iD, Brenely V. Murillo, Nicholas Pachter iD, Kevin M. Sweet iD, Allan D. Spigelman iD, Alexandra Groves iD, Margaret Gleeson iD, Krzysztof Bernatowicz iD, Nicola Kazia Poplawski iD, Lesley Andrews iD, Emma Healey, Steve Gallinger iD, Robert C. Grant iD, Aung Ko Win iD, John Llewelyn Hopper iD, Mark A. Jenkins iD, Giovana Tardin Torrezan iD, , Peter Georgeson iD

Abstract

BackgroundColorectal cancers (CRCs) from people with biallelic germline likely pathogenic/pathogenic variants in MUTYH or NTHL1 exhibit specific single base substitution (SBS) mutational signatures, namely combined SBS18 and SBS36 (SBS18+SBS36), and SBS30, respectively. The aim was to determine if adenomas from biallelic cases demonstrated these mutational signatures at diagnostic levels. MethodsWhole-exome sequencing of FFPE tissue and matched blood-derived DNA was performed on 9 adenomas and 15 CRCs from 13 biallelic MUTYH cases, on 7 adenomas and 2 CRCs from 5 biallelic NTHL1 cases and on 27 adenomas and 26 CRCs from 46 non-hereditary (sporadic) participants. All samples were assessed for COSMIC v3.2 SBS mutational signatures. ResultsIn biallelic MUTYH cases, SBS18+SBS36 signature proportions in adenomas (mean{+/-}standard deviation, 65.6%{+/-}29.6%) were not significantly different to those observed in CRCs (76.2%{+/-}20.5%, p-value=0.37), but were significantly higher compared with non-hereditary adenomas (7.6%{+/-}7.0%, p-value=3.4x10-4). Similarly, in biallelic NTHL1 cases, SBS30 signature proportions in adenomas (74.5%{+/-}9.4%) were similar to those in CRCs (78.8%{+/-}2.4%) but significantly higher compared with non-hereditary adenomas (2.8%{+/-}3.6%, p-value=5.1x10-7). Additionally, a compound heterozygote with the c.1187G>A p.(Gly396Asp) pathogenic variant and the c.533G>C p.(Gly178Ala) variant of unknown significance (VUS) in MUTYH demonstrated high levels of SBS18+SBS36 in four adenomas and one CRC, providing evidence for reclassification of the VUS to pathogenic. ConclusionsSBS18+SBS36 and SBS30 were enriched in adenomas at comparable proportions observed in CRCs from biallelic MUTYH and biallelic NTHL1 cases, respectively. Therefore, testing adenomas may improve the identification of biallelic cases and facilitate variant classification, ultimately enabling opportunities for CRC prevention.

PDF DOI