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Advances in genetic technologies result in improved diagnosis of mismatch repair deficiency in colorectal and endometrial cancers.
J Med Genet. 2022 04; 59(4):328-334.JM

Abstract

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.

Authors+Show Affiliations

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.Clinical Genetics Service, Manchester Centre for Genomic Medicine, North-West Genomics Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK.Division of Cancer Sciences, The University of Manchester, Manchester, UK. Department of Obstetrics and Gynaecology, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK.Clinical Genetics Service, Manchester Centre for Genomic Medicine, North-West Genomics Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK.Clinical Genetics Service, Manchester Centre for Genomic Medicine, North-West Genomics Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK.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.Clinical Genetics Service, Manchester Centre for Genomic Medicine, North-West Genomics Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK.Department of Pathology, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK.Department of Pathology, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK.Clinical Genetics Service, Manchester Centre for Genomic Medicine, North-West Genomics Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK.Department of Surgery, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK.Department of Surgery, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK.Department of Pathology, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33452216

Citation

Evans, D Gareth, et al. "Advances in Genetic Technologies Result in Improved Diagnosis of Mismatch Repair Deficiency in Colorectal and Endometrial Cancers." Journal of Medical Genetics, vol. 59, no. 4, 2022, pp. 328-334.
Evans DG, Lalloo F, Ryan NA, et al. Advances in genetic technologies result in improved diagnosis of mismatch repair deficiency in colorectal and endometrial cancers. J Med Genet. 2022;59(4):328-334.
Evans, D. G., Lalloo, F., Ryan, N. A., Bowers, N., Green, K., Woodward, E. R., Clancy, T., Bolton, J., McVey, R. J., Wallace, A. J., Newton, K., Hill, J., McMahon, R., & Crosbie, E. J. (2022). Advances in genetic technologies result in improved diagnosis of mismatch repair deficiency in colorectal and endometrial cancers. Journal of Medical Genetics, 59(4), 328-334. https://doi.org/10.1136/jmedgenet-2020-107542
Evans DG, et al. Advances in Genetic Technologies Result in Improved Diagnosis of Mismatch Repair Deficiency in Colorectal and Endometrial Cancers. J Med Genet. 2022;59(4):328-334. PubMed PMID: 33452216.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Advances in genetic technologies result in improved diagnosis of mismatch repair deficiency in colorectal and endometrial cancers. AU - Evans,D Gareth, AU - Lalloo,Fiona, AU - Ryan,Neil Aj, AU - Bowers,Naomi, AU - Green,Kate, AU - Woodward,Emma R, AU - Clancy,Tara, AU - Bolton,James, AU - McVey,Rhona J, AU - Wallace,Andrew J, AU - Newton,Katy, AU - Hill,James, AU - McMahon,Raymond, AU - Crosbie,Emma J, Y1 - 2021/01/15/ PY - 2020/10/25/received PY - 2020/12/17/revised PY - 2020/12/23/accepted PY - 2021/1/17/pubmed PY - 2022/4/15/medline PY - 2021/1/16/entrez KW - genetic predisposition to disease KW - genetic testing KW - surgical oncology SP - 328 EP - 334 JF - Journal of medical genetics JO - J Med Genet VL - 59 IS - 4 N2 - 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. SN - 1468-6244 UR - https://www.unboundmedicine.com/medline/citation/33452216/Advances_in_genetic_technologies_result_in_improved_diagnosis_of_mismatch_repair_deficiency_in_colorectal_and_endometrial_cancers_ L2 - http://jmg.bmj.com/lookup/pmidlookup?view=long&amp;pmid=33452216 DB - PRIME DP - Unbound Medicine ER -