دورية أكاديمية
أعرض في EDS

Advances in genetic technologies result in improved diagnosis of mismatch repair deficiency in colorectal and endometrial cancers.

التفاصيل البيبلوغرافية
العنوان: Advances in genetic technologies result in improved diagnosis of mismatch repair deficiency in colorectal and endometrial cancers.
المؤلفون: Evans DG; Division of Evolution and Genomic Medicine, The University of Manchester, Manchester, UK.; Clinical Genetics Service, Manchester Centre for Genomic Medicine, North-West Genomics Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK., Lalloo F; Clinical Genetics Service, Manchester Centre for Genomic Medicine, North-West Genomics Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK., Ryan NA; Division of Cancer Sciences, The University of Manchester, Manchester, UK.; Department of Obstetrics and Gynaecology, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK., Bowers N; Clinical Genetics Service, Manchester Centre for Genomic Medicine, North-West Genomics Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK., Green K; Clinical Genetics Service, Manchester Centre for Genomic Medicine, North-West Genomics Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK., Woodward ER; Division of Evolution and Genomic Medicine, The University of Manchester, Manchester, UK.; Clinical Genetics Service, Manchester Centre for Genomic Medicine, North-West Genomics Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK., Clancy T; Clinical Genetics Service, Manchester Centre for Genomic Medicine, North-West Genomics Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK., Bolton J; Department of Pathology, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK., McVey RJ; Department of Pathology, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK., Wallace AJ; Clinical Genetics Service, Manchester Centre for Genomic Medicine, North-West Genomics Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK., Newton K; Department of Surgery, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK., Hill J; Department of Surgery, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK., McMahon R; Department of Pathology, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK., Crosbie EJ; Division of Cancer Sciences, The University of Manchester, Manchester, UK emma.crosbie@manchester.ac.uk.; Department of Obstetrics and Gynaecology, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK.
المصدر: Journal of medical genetics [J Med Genet] 2022 Apr; Vol. 59 (4), pp. 328-334. Date of Electronic Publication: 2021 Jan 15.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: British Medical Association Country of Publication: England NLM ID: 2985087R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1468-6244 (Electronic) Linking ISSN: 00222593 NLM ISO Abbreviation: J Med Genet Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : British Medical Association
مواضيع طبية MeSH: Colorectal Neoplasms*/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis*/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis*/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis*/pathology , Endometrial Neoplasms*/diagnosis , Endometrial Neoplasms*/genetics , Endometrial Neoplasms*/pathology, Brain Neoplasms ; DNA Methylation/genetics ; DNA Mismatch Repair/genetics ; Female ; Germ-Line Mutation/genetics ; Humans ; Mismatch Repair Endonuclease PMS2/genetics ; MutL Protein Homolog 1/genetics ; MutS Homolog 2 Protein/genetics ; Neoplastic Syndromes, Hereditary ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins B-raf/metabolism
مستخلص: Background: Testing cancers for mismatch repair deficiency (dMMR) by immunohistochemistry (IHC) is a quick and inexpensive means of triaging individuals for germline Lynch syndrome testing. The aim of this study was to evaluate tumour dMMR and the prevalence of Lynch syndrome in patients referred to the Manchester Centre for Genomic Medicine, which serves a population of 5.6 million.
Methods: Tumour testing used IHC for MMR proteins with targeted BRAF and MLH1 promotor methylation testing followed by germline mutation and somatic testing as appropriate.
Results: In total, 3694 index tumours were tested by IHC (2204 colorectal cancers (CRCs), 739 endometrial cancers (ECs) and 761 other), of which 672/3694 (18.2%) had protein loss, including 348 (9.4%) with MLH1 loss. MLH1 loss was significantly higher for 739 ECs (15%) vs 2204 CRCs (10%) (p=0.0003) and was explained entirely by higher rates of somatic MLH1 promoter hypermethylation (87% vs 41%, p<0.0001). Overall, 65/134 (48.5%) patients with MLH1 loss and no MLH1 hypermethylation or BRAF c.1799T>A had constitutional MLH1 pathogenic variants. Of 456 patients with tumours showing loss of MSH2/MSH6, 216 (47.3%) had germline pathogenic variants in either gene. Isolated PMS2 loss was most suggestive of a germline MMR variant in 19/26 (73%). Of those with no germline pathogenic variant, somatic testing identified likely causal variants in 34/48 (71%) with MLH1 loss and in MSH2/MSH6 in 40/47 (85%) with MSH2/MSH6 loss.
Conclusions: Reflex testing of EC/CRC leads to uncertain diagnoses in many individuals with dMMR following IHC but without germline pathogenic variants or MLH1 hypermethylation. Tumour mutation testing is effective at decreasing this by identifying somatic dMMR in >75% of cases.
Competing Interests: Competing interests: None declared.
(© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)
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معلومات مُعتمدة: MR/M018431/1 United Kingdom MRC_ Medical Research Council; NIHR-CS-012-009 United Kingdom DH_ Department of Health
فهرسة مساهمة: Keywords: genetic predisposition to disease; genetic testing; surgical oncology
المشرفين على المادة: EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
EC 3.6.1.3 (Mismatch Repair Endonuclease PMS2)
EC 3.6.1.3 (MutL Protein Homolog 1)
EC 3.6.1.3 (MutS Homolog 2 Protein)
SCR Disease Name: Turcot syndrome
تواريخ الأحداث: Date Created: 20210116 Date Completed: 20220414 Latest Revision: 20220612
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC8961751
DOI: 10.1136/jmedgenet-2020-107542
PMID: 33452216
قاعدة البيانات: MEDLINE
الوصف
تدمد:1468-6244
DOI:10.1136/jmedgenet-2020-107542