Functional Repair Assay for the Diagnosis of Constitutional Mismatch Repair Deficiency From Non-Neoplastic Tissue

Autor: Theodore W. Laetsch, Luis Alberto Pedroza, Brittany Campbell, Mark L. Bernstein, An Van Damme, Scott Lindhorst, Bruce Crooks, Melyssa Aronson, Jagadeesh Ramdas, Shlomi Constantini, Patrick Tomboc, Ashraf Shamvil, Ben George, Gary Mason, Vanan Magimairajan, Garth Nicholas, Uri Tabori, Kami Wolfe Schneider, William D. Foulkes, Lisa Yu, Kara Semotiuk, David Sumerauer, Cindy Zhang, Rebecca C. Luiten, Sara Carroll, Michal Zapotocky, Stella Lanni, Christopher E. Pearson, Laura Palma, Ariane Mandel, David Malkin, Daniel C. Bowers, Melissa Edwards, Andrew Y. Shuen, Nobuko Hijiya, Rina Dvir, Warren Mason, Gagan B. Panigrahi, Nataliya Zhukova, Roula Farah, Michael Yalon Oren, Oz Mordechai, Eric Bouffet, Helen Toledano, Naureen Mushtaq, Musa Alharbi, Margaret E. Wierman, Kristina A. Cole, Andrea H. Seeley, S. Gallinger, Yi Yen Lee, Valerie Larouche, Carol Durno, David Samuel
Přispěvatelé: UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, UCL - (SLuc) Service d'hématologie et d'oncologie pédiatrique
Rok vydání: 2019
Předmět:
0301 basic medicine
congenital
hereditary
and neonatal diseases and abnormalities
Cancer Research
Non neoplastic
DNA Mismatch Repair
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Neoplastic Syndromes
Hereditary
Predictive Value of Tests
Cell Line
Tumor
Biomarkers
Tumor
medicine
Humans
Genetic Predisposition to Disease
Genetic Testing
Mismatch Repair Endonuclease PMS2
Brain Neoplasms
business.industry
Cancer predisposition
Cancer
medicine.disease
digestive system diseases
DNA-Binding Proteins
DNA Repair Enzymes
MutS Homolog 2 Protein
Phenotype
030104 developmental biology
Oncology
chemistry
Case-Control Studies
030220 oncology & carcinogenesis
Mutation
Cancer research
MISMATCH REPAIR DEFICIENCY
DNA mismatch repair
Colorectal Neoplasms
MutL Protein Homolog 1
Penetrant (biochemical)
business
Zdroj: Journal of clinical oncology, Vol. 37, no.6, p. 461-470 (2019)
ISSN: 1527-7755
0732-183X
Popis: Purpose Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD. Patients and Methods In vitro MMR activity was quantified using a 3′-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus–transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome. Results All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days. Conclusion On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.
Databáze: OpenAIRE
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