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
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...
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Elsevier
2025-02-01
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| Series: | Translational Oncology |
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| author | 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 |
| author_facet | 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 |
| author_sort | Romy Walker |
| collection | DOAJ |
| description | 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 to those 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. |
| format | Article |
| id | doaj-art-98af4cff53ff4763aabf68562031e35c |
| institution | Kabale University |
| issn | 1936-5233 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj-art-98af4cff53ff4763aabf68562031e35c2025-01-22T05:41:33ZengElsevierTranslational Oncology1936-52332025-02-0152102266Adenomas 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 applicationsRomy Walker0Jihoon E. Joo1Khalid Mahmood2Mark Clendenning3Julia Como4Susan G. Preston5Sharelle Joseland6Bernard J. Pope7Ana B.D. Medeiros8Brenely V. Murillo9Nicholas Pachter10Kevin Sweet11Allan D. Spigelman12Alexandra Groves13Margaret Gleeson14Krzysztof Bernatowicz15Nicola Poplawski16Lesley Andrews17Emma Healey18Steven Gallinger19Robert C. Grant20Aung K. Win21John L. Hopper22Mark A. Jenkins23Giovana T. Torrezan24Christophe Rosty25Finlay A. Macrae26Ingrid M. Winship27Daniel D. Buchanan28Peter Georgeson29Colorectal 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; Corresponding author at: Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Victorian Comprehensive Cancer Centre, 305 Grattan Street, Parkville, Victoria, 3010 Australia.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, AustraliaColorectal 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, AustraliaColorectal 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, AustraliaColorectal 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, AustraliaColorectal 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, AustraliaColorectal 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, AustraliaColorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, VIC, 3010, Australia; Melbourne Bioinformatics, The University of Melbourne, Melbourne, VIC, 3053, AustraliaClinical and Functional Genomics Group, International Research Centre/CIPE, A.C. Camargo Cancer Centre, Sao Paulo, 01508-010, BrazilGenetic Services of Western Australia, King Edward Memorial Hospital, Perth, WA, 6008, AustraliaGenetic 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, AustraliaDivision of Human Genetics, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, 43210, USAHunter 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, AustraliaHunter Family Cancer Service, Newcastle, NSW, 2298, AustraliaHunter Family Cancer Service, Newcastle, NSW, 2298, AustraliaAdult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA 5000, AustraliaAdult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA 5000, Australia; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, AustraliaHereditary Cancer Centre, Prince of Wales Hospital, Randwick, New South Wales, Australia; School of Medicine and Public Health, University of Newcastle, Callaghan, New South Wales, AustraliaPrince 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 AustraliaLunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, CanadaDivision of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, CanadaUniversity 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, AustraliaCentre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, VIC, 3053, AustraliaUniversity 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, AustraliaClinical 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, BrazilColorectal 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, AustraliaGenomic 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, AustraliaGenomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, 3000, Australia; Department of Medicine, The University of Melbourne, Parkville, VIC, 3000, AustraliaColorectal 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, AustraliaColorectal 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, AustraliaBackground: 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 to those 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.http://www.sciencedirect.com/science/article/pii/S1936523324003929Mutational signatureAdenomaSBS36SBS30MUTYHNTHL1 |
| spellingShingle | 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 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 Translational Oncology Mutational signature Adenoma SBS36 SBS30 MUTYH NTHL1 |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Mutational signature Adenoma SBS36 SBS30 MUTYH NTHL1 |
| url | http://www.sciencedirect.com/science/article/pii/S1936523324003929 |
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