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.

Autor: Walker R; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, 3010, Australia., Joo JE; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, 3010, Australia., Mahmood K; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, 3010, Australia.; Melbourne Bioinformatics, The University of Melbourne, Melbourne, VIC, 3053, Australia., Clendenning M; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, 3010, Australia., Como J; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, 3010, Australia., Preston SG; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, 3010, Australia., Joseland S; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, 3010, Australia., Pope BJ; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.; Melbourne Bioinformatics, The University of Melbourne, Melbourne, VIC, 3053, Australia., Medeiros ABD; Clinical and Functional Genomics Group, International Research Centre/CIPE, A.C. Camargo Cancer Centre, Sao Paulo, 01508-010, Brazil., Murillo BV; Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, WA, 6008, Australia., Pachter N; Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, WA, 6008, Australia.; Medical School, University of Western Australia, Perth, WA, 6009, Australia.; School of Medicine, Curtin University, Perth, WA, 6845, Australia., Sweet K; Division of Human Genetics, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA., Spigelman AD; Hunter Family Cancer Service, Newcastle, NSW, 2298, Australia.; St Vincent's Cancer Genetics Unit, Sydney, NSW, 2290, Australia.; Surgical Professorial Unit, UNSW Clinical School of Clinical Medicine, Sydney, NSW, 2052, Australia., Groves A; Hunter Family Cancer Service, Newcastle, NSW, 2298, Australia., Gleeson M; Hunter Family Cancer Service, Newcastle, NSW, 2298, Australia., Bernatowicz K; Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA 5000, Australia., Poplawski N; Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA 5000, Australia.; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia., Andrews L; Hereditary Cancer Centre, Prince of Wales Hospital, Randwick, New South Wales, Australia.; School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, Australia., Healey E; Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Randwick, New South Wales 2031 Australia.; Illawarra Cancer Care Centre, Wollongong Hospital, Wollongong, New South Wales 2500 Australia., Gallinger S; Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada., Grant RC; Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada., Win AK; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, 3010, Australia.; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, VIC, 3053, Australia., Hopper JL; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, VIC, 3053, Australia., Jenkins MA; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, 3010, Australia.; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, VIC, 3053, Australia., Torrezan GT; Clinical and Functional Genomics Group, International Research Centre/CIPE, A.C. Camargo Cancer Centre, Sao Paulo, 01508-010, Brazil.; National Institute of Science and Technology in Oncogenomics and Therapeutic Innovation, Sao Paulo 01508-010, Brazil., Rosty C; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, 3010, Australia.; Envoi Specialist Pathologists, Brisbane, QLD, 4059, Australia.; University of Queensland, Brisbane, QLD, 4072, Australia., Macrae FA; Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, 3000, Australia.; Department of Medicine, The University of Melbourne, Parkville, VIC, 3000, Australia.; Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Parkville, VIC, 3000, Australia., Winship IM; Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, 3000, Australia.; Department of Medicine, The University of Melbourne, Parkville, VIC, 3000, Australia., Buchanan DD; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, 3010, Australia.; Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, 3000, Australia., Georgeson P; Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia.; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, VIC, 3010, Australia.
Jazyk: angličtina
Zdroj: MedRxiv : the preprint server for health sciences [medRxiv] 2024 Aug 09. Date of Electronic Publication: 2024 Aug 09.
DOI: 10.1101/2024.08.08.24311713
Abstrakt: 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.
Competing Interests: Robert C. Grant received a scholarship from Pfizer and provided consulting or advisory roles for Astrazeneca, Tempus, Eisai, Incyte, Knight Therapeutics, Guardant Health, and Ipsen. All other authors have no relevant financial or non-financial interests to disclose.
Databáze: MEDLINE
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