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 E Joo; Khalid Mahmood; Mark Clendenning; Julia Como; Susan G Preston; Sharelle Joseland; Bernard J Pope; Ana B D Medeiros; Brenely V Murillo; Nicholas Pachter; Kevin Sweet; Allan D Spigelman; Alexandra Groves; Margaret Gleeson; Krzysztof Bernatowicz; Nicola Poplawski; Lesley Andrews; Emma Healey; Steven Gallinger; Robert C Grant; Aung K Win; John L Hopper; Mark A Jenkins; Giovana T Torrezan; Christophe Rosty; Finlay A Macrae; Ingrid M Winship; Daniel D Buchanan; Peter Georgeson

doi:10.1101/2024.08.08.24311713

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

medRxiv [Preprint]. 2024 Aug 9:2024.08.08.24311713. doi: 10.1101/2024.08.08.24311713.

Authors

Romy Walker^{1

2}, Jihoon E Joo^{1

2}, Khalid Mahmood^{1

2

3}, Mark Clendenning^{1

2}, Julia Como^{1

2}, Susan G Preston^{1

2}, Sharelle Joseland^{1

2}, Bernard J Pope^{1

3}, Ana B D Medeiros⁴, Brenely V Murillo⁵, Nicholas Pachter^{5

6

7}, Kevin Sweet⁸, Allan D Spigelman^{9

10

11}, Alexandra Groves⁹, Margaret Gleeson⁹, Krzysztof Bernatowicz¹², Nicola Poplawski^{12

13}, Lesley Andrews^{14

15}, Emma Healey^{16

17}, Steven Gallinger¹⁸, Robert C Grant¹⁹, Aung K Win^{2

20}, John L Hopper²⁰, Mark A Jenkins^{2

20}, Giovana T Torrezan^{4

21}, Christophe Rosty^{1

2

22

23}, Finlay A Macrae^{24

25

26}, Ingrid M Winship^{24

25}, Daniel D Buchanan^{1

2

24}, Peter Georgeson^{1

2}

Affiliations

¹ Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.
² University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, 3010, Australia.
³ Melbourne Bioinformatics, The University of Melbourne, Melbourne, VIC, 3053, Australia.
⁴ Clinical and Functional Genomics Group, International Research Centre/CIPE, A.C. Camargo Cancer Centre, Sao Paulo, 01508-010, Brazil.
⁵ Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, WA, 6008, Australia.
⁶ Medical School, University of Western Australia, Perth, WA, 6009, Australia.
⁷ School of Medicine, Curtin University, Perth, WA, 6845, Australia.
⁸ Division of Human Genetics, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA.
⁹ Hunter Family Cancer Service, Newcastle, NSW, 2298, Australia.
¹⁰ St Vincent's Cancer Genetics Unit, Sydney, NSW, 2290, Australia.
¹¹ Surgical Professorial Unit, UNSW Clinical School of Clinical Medicine, Sydney, NSW, 2052, Australia.
¹² Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA 5000, Australia.
¹³ Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
¹⁴ Hereditary Cancer Centre, Prince of Wales Hospital, Randwick, New South Wales, Australia.
¹⁵ School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia.
¹⁶ Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Randwick, New South Wales 2031 Australia.
¹⁷ Illawarra Cancer Care Centre, Wollongong Hospital, Wollongong, New South Wales 2500 Australia.
¹⁸ Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
¹⁹ Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
²⁰ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, VIC, 3053, Australia.
²¹ National Institute of Science and Technology in Oncogenomics and Therapeutic Innovation, Sao Paulo 01508-010, Brazil.
²² Envoi Specialist Pathologists, Brisbane, QLD, 4059, Australia.
²³ University of Queensland, Brisbane, QLD, 4072, Australia.
²⁴ Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, 3000, Australia.
²⁵ Department of Medicine, The University of Melbourne, Parkville, VIC, 3000, Australia.
²⁶ Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Parkville, VIC, 3000, Australia.

Abstract

Background: Colorectal 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.

Methods: Whole-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.

Results: In 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=3.4×10^-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=5.1×10^-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.

Conclusions: SBS18+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.

Keywords: Colorectal cancer; MUTYH; NTHL1; SBS18; SBS30; SBS36; adenoma; hereditary cancer predisposition; mutational signature; variant of uncertain clinical significance.

Publication types

Preprint

Grants and funding

U01 CA167551/CA/NCI NIH HHS/United States