A tumor focused approach to resolving the etiology of DNA mismatch repair deficient tumors classified as suspected Lynch syndrome.

Humans Colorectal Neoplasms, Hereditary Nonpolyposis / genetics DNA Mismatch Repair / genetics Colorectal Neoplasms / genetics Neoplastic Syndromes, Hereditary / genetics MutL Protein Homolog 1 / genetics DNA Methylation / genetics Microsatellite Instability
Colorectal cancer DNA mismatch repair deficiency Endometrial cancer Lynch syndrome MLH1 methylation Muir-Torre syndrome Sebaceous skin tumor Suspected Lynch syndrome

Journal

Journal of translational medicine
ISSN: 1479-5876
Titre abrégé: J Transl Med
Pays: England
ID NLM: 101190741

Informations de publication

Date de publication:
26 04 2023
Historique:
received: 09 02 2023
accepted: 19 04 2023
medline: 28 4 2023
pubmed: 27 4 2023
entrez: 26 4 2023
Statut: epublish

Résumé

Routine screening of tumors for DNA mismatch repair (MMR) deficiency (dMMR) in colorectal (CRC), endometrial (EC) and sebaceous skin (SST) tumors leads to a significant proportion of unresolved cases classified as suspected Lynch syndrome (SLS). SLS cases (n = 135) were recruited from Family Cancer Clinics across Australia and New Zealand. Targeted panel sequencing was performed on tumor (n = 137; 80×CRCs, 33×ECs and 24xSSTs) and matched blood-derived DNA to assess for microsatellite instability status, tumor mutation burden, COSMIC tumor mutational signatures and to identify germline and somatic MMR gene variants. MMR immunohistochemistry (IHC) and MLH1 promoter methylation were repeated. In total, 86.9% of the 137 SLS tumors could be resolved into established subtypes. For 22.6% of these resolved SLS cases, primary MLH1 epimutations (2.2%) as well as previously undetected germline MMR pathogenic variants (1.5%), tumor MLH1 methylation (13.1%) or false positive dMMR IHC (5.8%) results were identified. Double somatic MMR gene mutations were the major cause of dMMR identified across each tumor type (73.9% of resolved cases, 64.2% overall, 70% of CRC, 45.5% of ECs and 70.8% of SSTs). The unresolved SLS tumors (13.1%) comprised tumors with only a single somatic (7.3%) or no somatic (5.8%) MMR gene mutations. A tumor-focused testing approach reclassified 86.9% of SLS into Lynch syndrome, sporadic dMMR or MMR-proficient cases. These findings support the incorporation of tumor sequencing and alternate MLH1 methylation assays into clinical diagnostics to reduce the number of SLS patients and provide more appropriate surveillance and screening recommendations.

Identifiants

DOI: 10.1186/s12967-023-04143-1 PMID: 37101184 PMC: PMC10134620
pubmed: 37101184
doi: 10.1186/s12967-023-04143-1
pii: 10.1186/s12967-023-04143-1
pmc: PMC10134620
doi:

Substances chimiques

MutL Protein Homolog 1 EC 3.6.1.3

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

282

Subventions

Organisme : NCI NIH HHS
ID : U24 CA074800
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA074794
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA097735
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA074799
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA167551
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA074800
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA074783
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA074783
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA074806
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA074794
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA074806
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA097735
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA074799
Pays : United States

Commentaires et corrections

Type : UpdateOf

Informations de copyright

© 2023. The Author(s).

Références

Hum Mutat. 2015 Mar;36(3):292-5
pubmed: 25504677
Eur J Hum Genet. 2020 Nov;28(11):1624-1628
pubmed: 32678338
Hered Cancer Clin Pract. 2021 Oct 16;19(1):43
pubmed: 34656160
Eur J Hum Genet. 2021 Mar;29(3):482-488
pubmed: 33279946
Am J Surg Pathol. 2019 May;43(5):591-600
pubmed: 30864976
J Med Genet. 2011 Aug;48(8):513-9
pubmed: 21712435
J Pathol. 2014 Dec;234(4):548-59
pubmed: 25111426
Genet Med. 2013 Jan;15(1):25-35
pubmed: 22878509
Fam Cancer. 2020 Apr;19(2):161-167
pubmed: 32002723
Nat Commun. 2022 Jun 6;13(1):3254
pubmed: 35668106
Hered Cancer Clin Pract. 2022 Jul 15;20(1):27
pubmed: 35840994
Nucleic Acids Res. 2007;35(6):e41
pubmed: 17289753
Eur J Hum Genet. 2014 May;22(5):617-24
pubmed: 24084575
Genet Med. 2019 Oct;21(10):2167-2180
pubmed: 31086306
J Cancer Res Clin Oncol. 2023 Jan;149(1):25-46
pubmed: 36251064
Cancer Prev Res (Phila). 2012 Feb;5(2):320-7
pubmed: 22086678
J Clin Oncol. 2014 Jan 10;32(2):90-100
pubmed: 24323032
J Mol Diagn. 2016 Nov;18(6):923-932
pubmed: 27720647
Gastroenterology. 2022 Dec;163(6):1691-1694.e7
pubmed: 36037994
JCO Precis Oncol. 2017;2017:
pubmed: 29850653
Eur J Hum Genet. 2015 Aug;23(8):1080-4
pubmed: 25370038
Eur J Hum Genet. 2020 May;28(5):597-608
pubmed: 31822864
J Med Genet. 2019 Jul;56(7):462-470
pubmed: 30877237
Eur J Hum Genet. 2014 Nov;22(11):1334-7
pubmed: 24518836
J Gastroenterol Hepatol. 2017 Feb;32(2):427-438
pubmed: 27273229
Gastroenterology. 2014 Mar;146(3):643-646.e8
pubmed: 24333619
JCO Precis Oncol. 2021 May 05;5:
pubmed: 34250417
J Mol Diagn. 2021 Feb;23(2):242-252
pubmed: 33259954
Genet Med. 2009 Jan;11(1):35-41
pubmed: 19125126
Fam Cancer. 2013 Mar;12(1):27-33
pubmed: 22987205
Fam Cancer. 2021 Jul;20(3):223-230
pubmed: 33215268
Gastroenterology. 2021 Mar;160(4):1414-1416.e3
pubmed: 33253688
Gut. 2021 Nov;70(11):2138-2149
pubmed: 33414168
J Mol Diagn. 2021 Mar;23(3):358-371
pubmed: 33383211
J Mol Diagn. 2023 Feb;25(2):94-109
pubmed: 36396080
Fam Cancer. 2017 Oct;16(4):491-500
pubmed: 28528517
Am J Surg Pathol. 2016 Jun;40(6):770-6
pubmed: 26848797
Fam Cancer. 2014 Jun;13(2):219-25
pubmed: 24114314
Gut. 2015 Jan;64(1):101-10
pubmed: 24615377
Gynecol Oncol. 2021 Jan;160(1):161-168
pubmed: 33393477
Cancer Cell. 2011 Aug 16;20(2):200-13
pubmed: 21840485
Nat Commun. 2020 Jul 20;11(1):3644
pubmed: 32686686
Australas J Dermatol. 2019 May;60(2):126-133
pubmed: 30506759
BMJ Open. 2016 Feb 19;6(2):e010293
pubmed: 26895986
Gastroenterology. 2014 Dec;147(6):1308-1316.e1
pubmed: 25194673
Appl Clin Genet. 2014 Oct 06;7:183-93
pubmed: 25328415
Fam Cancer. 2011 Jun;10(2):297-301
pubmed: 21360204
Nat Genet. 2009 Jan;41(1):112-7
pubmed: 19098912

Auteurs

Romy Walker (R)

Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, VIC, 3010, Australia.
ORCID: 0000-0001-8948-8417

Khalid Mahmood (K)

Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, VIC, 3010, Australia.
Melbourne Bioinformatics, The University of Melbourne, Melbourne, VIC, 3051, Australia.

Jihoon E Joo (JE)

Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, VIC, 3010, Australia.

Mark Clendenning (M)

Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, VIC, 3010, Australia.

Peter Georgeson (P)

Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, VIC, 3010, Australia.

Julia Como (J)

Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, VIC, 3010, Australia.

Sharelle Joseland (S)

Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, VIC, 3010, Australia.

Susan G Preston (SG)

Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, VIC, 3010, Australia.

Yoland Antill (Y)

Familial Cancer Centre, Royal Melbourne Hospital, Parkville, VIC, 3050, Australia.
Familial Cancer Centre, Cabrini Health, Malvern, VIC, 3144, Australia.
Familial Cancer Centre, Monash Health, Clayton, VIC, 3168, Australia.
Faculty of Medicine, Dentistry and Health Sciences, Monash University, Melbourne, VIC, 3800, Australia.

Rachel Austin (R)

Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, 4029, Australia.

Alex Boussioutas (A)

Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia.
Department of Gastroenterology, The Alfred Hospital, Melbourne, VIC, 3004, Australia.
Department of Medicine, The Royal Melbourne Hospital, Melbourne, VIC, 3010, Australia.
Familial Cancer Centre, Peter MacCallum Cancer Centre, Parkville, VIC, 3000, Australia.

Michelle Bowman (M)

Familial Cancer Service, Westmead Hospital, Sydney, NSW, 2145, Australia.

Jo Burke (J)

Tasmanian Clinical Genetics Service, Royal Hobart Hospital, Hobart, TAS, 7000, Australia.
School of Medicine, University of Tasmania, Sandy Bay, TAS, 7005, Australia.

Ainsley Campbell (A)

Clinical Genetics Unit, Austin Health, Melbourne, VIC, 3084, Australia.

Simin Daneshvar (S)

Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, VIC, 3010, Australia.

Emma Edwards (E)

Familial Cancer Service, Westmead Hospital, Sydney, NSW, 2145, Australia.

Margaret Gleeson (M)

Hunter Family Cancer Service, Newcastle, NSW, 2298, Australia.

Annabel Goodwin (A)

Cancer Genetics Department, Royal Prince Alfred Hospital, Camperdown, NSW, 2050, Australia.
University of Sydney, Sydney, NSW, 2050, Australia.

Marion T Harris (MT)

Monash Health Familial Cancer Centre, Clayton, VIC, 3168, Australia.

Alex Henderson (A)

Genetic Health Service, Wellington, Greater Wellington, 6242, New Zealand.
Wellington Hospital, Newtown, Greater Wellington, 6021, New Zealand.

Megan Higgins (M)

Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, 4029, Australia.
University of Queensland, St Lucia, QLD, 4067, Australia.

John L Hopper (JL)

Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, VIC, 3010, Australia.

Ryan A Hutchinson (RA)

Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, VIC, 3010, Australia.

Emilia Ip (E)

Cancer Genetics Service, Liverpool Hospital, Liverpool, NSW, 2170, Australia.

Joanne Isbister (J)

Genomic Medicine and Familial Cancer Centre, Royal Melbourne Hospital, Parkville, VIC, 3000, Australia.
Department of Medicine, The University of Melbourne, Melbourne, VIC, 3000, Australia.
Parkville Familial Cancer Centre, Peter McCallum Cancer Centre, Melbourne, VIC, 3000, Australia.

Kais Kasem (K)

Department of Clinical Pathology, Medicine Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, Australia.

Helen Marfan (H)

Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, 4029, Australia.

Di Milnes (D)

Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, 4029, Australia.
Royal Brisbane and Women's Hospital, Herston, QLD, 4029, Australia.

Annabelle Ng (A)

Cancer Genetics Department, Royal Prince Alfred Hospital, Camperdown, NSW, 2050, Australia.

Cassandra Nichols (C)

Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, WA, 6008, Australia.

Shona O'Connell (S)

Monash Health Familial Cancer Centre, Clayton, VIC, 3168, Australia.

Nicholas 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.

Bernard J Pope (BJ)

Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Melbourne Bioinformatics, The University of Melbourne, Melbourne, VIC, 3051, Australia.

Nicola Poplawski (N)

Adult Genetics Unit, Royal Adelaide Hospital, Adelaide, SA, 5000, Australia.
Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA, 5000, Australia.

Abiramy Ragunathan (A)

Familial Cancer Service, Westmead Hospital, Sydney, NSW, 2145, Australia.

Courtney Smyth (C)

Familial Cancer Centre, Monash Health, Clayton, VIC, 3168, Australia.

Allan Spigelman (A)

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.

Kirsty Storey (K)

Parkville Familial Cancer Centre, Peter McCallum Cancer Centre, Melbourne, VIC, 3000, Australia.

Rachel Susman (R)

Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, 4029, Australia.

Jessica A Taylor (JA)

Genomic Medicine and Familial Cancer Centre, Royal Melbourne Hospital, Parkville, VIC, 3000, Australia.

Linda Warwick (L)

ACT Genetic Service, The Canberra Hospital, Woden, ACT, 2606, Australia.

Mathilda Wilding (M)

Familial Cancer Service, Royal North Shore Hospital, St Leonards, NSW, 2065, Australia.

Rachel Williams (R)

Prince of Wales Clinical School, UNSW Medicine and Health, UNSW Sydney, Kensington, NSW, 2052, Australia.
Prince of Wales Hereditary Cancer Centre, Prince of Wales Hospital, Randwick, NSW, 2031, Australia.

Aung K Win (AK)

Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, VIC, 3010, Australia.
Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, VIC, 3010, Australia.
Genomic Medicine and Familial Cancer Centre, Royal Melbourne Hospital, Parkville, VIC, 3000, Australia.

Michael D Walsh (MD)

Sullivan Nicolaides Pathology, Bowen Hills, QLD, 4006, Australia.
School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, 4072, Australia.

Finlay A Macrae (FA)

Genomic Medicine and Familial Cancer Centre, Royal Melbourne Hospital, Parkville, VIC, 3000, Australia.
Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Parkville, VIC, Australia.

Mark A Jenkins (MA)

Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, VIC, 3010, Australia.
Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, VIC, 3010, Australia.

Christophe Rosty (C)

Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia.
Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, VIC, 3010, Australia.
Envoi Specialist Pathologists, Brisbane, QLD, 4059, Australia.
University of Queensland, Brisbane, QLD, 4072, Australia.

Ingrid M Winship (IM)

Genomic Medicine and Familial Cancer Centre, Royal Melbourne Hospital, Parkville, VIC, 3000, Australia.
Department of Medicine, The University of Melbourne, Melbourne, VIC, 3000, Australia.

Daniel D Buchanan (DD)

Colorectal Oncogenomics Group, Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, 305 Grattan Street, Parkville, VIC, 3010, Australia. daniel.buchanan@unimelb.edu.au.
Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, VIC, 3010, Australia. daniel.buchanan@unimelb.edu.au.
Genomic Medicine and Familial Cancer Centre, Royal Melbourne Hospital, Parkville, VIC, 3000, Australia. daniel.buchanan@unimelb.edu.au.
ORCID: 0000-0003-2225-6675

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › A tumor focused approach to resolving the...
questionsmedicales.fr › Maladies métaboliques et nutritionnelles › Maladies métaboliques › Troubles dus à un défaut de réparation de l'ADN › Tumeurs colorectales héréditaires sans polypose › A tumor focused approach to resolving the...
questionsmedicales.fr › Phénomènes génétiques › Réparation de l'ADN › Réparation de mésappariement de l'ADN › A tumor focused approach to resolving the...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies gastro-intestinales › Maladies intestinales › Maladies du rectum › Tumeurs colorectales › A tumor focused approach to resolving the...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Maladies génétiques congénitales › Syndromes néoplasiques héréditaires › A tumor focused approach to resolving the...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de liaison à l'ADN › Protéines MutL › Protéine-1 homologue de MutL › A tumor focused approach to resolving the...
questionsmedicales.fr › Phénomènes génétiques › Méthylation de l'ADN › A tumor focused approach to resolving the...
questionsmedicales.fr › Phénomènes génétiques › Instabilité du génome › Instabilité des microsatellites › A tumor focused approach to resolving the...