Genomic Microsatellite Signatures Identify Germline Mismatch Repair Deficiency and Risk of Cancer Onset-Reference-Cited by-同舟云学术

Genomic Microsatellite Signatures Identify Germline Mismatch Repair Deficiency and Risk of Cancer Onset

Published:2023-02-01 Issue:4 Volume:41 Page:766-777
ISSN:0732-183X
Container-title:Journal of Clinical Oncology
language:en
Short-container-title:JCO

Author:

Chung Jiil¹²^ORCID,Negm Logine¹²³,Bianchi Vanessa²,Stengs Lucie²,Das Anirban¹²⁴⁵^ORCID,Liu Zhihui Amy⁶⁷,Sudhaman Sumedha¹²,Aronson Melyssa⁸^ORCID,Brunga Ledia¹⁹,Edwards Melissa¹,Forster Victoria²^ORCID,Komosa Martin²,Davidson Scott¹⁹^ORCID,Lees Jodi¹,Tomboc Patrick¹⁰^ORCID,Samuel David¹¹,Farah Roula¹²,Bendel Anne¹³,Knipstein Jeffrey¹⁴^ORCID,Schneider Kami Wolfe¹⁵^ORCID,Reschke Agnes¹⁶^ORCID,Zelcer Shayna¹⁷,Zorzi Alexandra¹⁸,McWilliams Robert¹⁹^ORCID,Foulkes William D.²⁰^ORCID,Bedgood Raymond²¹^ORCID,Peterson Lindsay²²^ORCID,Rhode Sara²³,Van Damme An²⁴^ORCID,Scheers Isabelle²⁵,Gardner Sharon²⁶,Robbins Gabriel²⁶^ORCID,Vanan Magimairajan Issai²⁷²⁸^ORCID,Meyn M. Stephen²⁹³⁰^ORCID,Auer Rebecca³¹^ORCID,Leach Brandie³²^ORCID,Burke Carol³²,Villani Anita⁴^ORCID,Malkin David⁴^ORCID,Bouffet Eric⁴^ORCID,Huang Annie²⁴³³,Taylor Michael D.²³⁴,Durno Carol⁸³⁵,Shlien Adam¹⁹³³,Hawkins Cynthia²⁹³⁶^ORCID,Getz Gad³⁷³⁸³⁹⁴⁰,Maruvka Yosef E.⁴¹^ORCID,Tabori Uri¹²⁴^ORCID,

Affiliation:

1. Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada

2. The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada

3. Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

4. Division of Hematology/Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, ON, Canada

5. Department of Pediatric Hematology/Oncology, Tata Medical Centre, Kolkata, India

6. Department of Biostatistics, Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada

7. Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada

8. Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, ON, Canada

9. Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada

10. Department of Pediatrics, West Virginia University, Morgantown, WV

11. Valley Children's Hospital, Madera, CA

12. Lebanese American University Medical Center-Rizk, Beirut, Lebanon

13. Department of Pediatric Hematology-Oncology, Children's Minnesota, Minneapolis, MN

14. Division of Pediatric Hematology/Oncology/BMT, Medical College of Wisconsin, Milwaukee, WI

15. Department of Pediatric Hematology-Oncology, Children's Hospital Colorado, Aurora, CO

16. Department of Pediatric Hematology/Oncology, Stanford University, Palo Alto, CA

17. Department of Pediatrics, London Health Sciences Centre, London, ON, Canada

18. Division of Haematology/Oncology, Western University, London, ON, Canada

19. Department of Oncology, Mayo Clinic, Rochester, MN

20. Departments of Oncology and Human Genetics, McGill University Health Centre, Cancer Genetics Program, Montreal, QC, Canada

21. Coliseum Medical Centers, Macon, GA

22. Division of Medical Oncology, Washington University, St Louis, MO

23. Department of Hematology and Oncology, Cleveland Clinic, Cleveland, OH

24. Pediatric Gastroenterology and Hepatology Unit, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium

25. Universite Catholique de Louvain La Faculte de Medecine, Bruxelles, Belgium

26. Department of Pediatric Hematology-Oncology, NYU Langone Health, New York, NY

27. Department of Pediatric Hematology-Oncology, CancerCare Manitoba, Winnipeg, MB, Canada

28. Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada

29. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada

30. Center for Human Genomics and Precision Medicine, School of Medicine and Public Health, University of Wisconsin, Madison, WI

31. Centre for Innovative Cancer Research, Ottawa Hospital Research Institute, Ottawa, ON, Canada

32. Department of Gastroenterology, Hepatology, and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH

33. Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

34. Department of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada

35. Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada

36. Division of Pathology, The Hospital for Sick Children, Toronto, ON, Canada

37. The Broad Institute of MIT and Harvard, Cambridge, MA

38. Center for Cancer Research, Massachusetts General Hospital, Boston, MA

39. Harvard Medical School, 250 Longwood Avenue, Boston, MA

40. Department of Pathology, Massachusetts General Hospital, Boston, MA

41. Faculty of Biotechnology and Food Engineering, The Lokey Center for Life Science and Engineering, TECHNION – Israel Institute of Technology, Haifa, Israel

Abstract

PURPOSE Diagnosis of Mismatch Repair Deficiency (MMRD) is crucial for tumor management and early detection in patients with the cancer predisposition syndrome constitutional mismatch repair deficiency (CMMRD). Current diagnostic tools are cumbersome and inconsistent both in childhood cancers and in determining germline MMRD. PATIENTS AND METHODS We developed and analyzed a functional Low-pass Genomic Instability Characterization (LOGIC) assay to detect MMRD. The diagnostic performance of LOGIC was compared with that of current established assays including tumor mutational burden, immunohistochemistry, and the microsatellite instability panel. LOGIC was then applied to various normal tissues of patients with CMMRD with comprehensive clinical data including age of cancer presentation. RESULTS Overall, LOGIC was 100% sensitive and specific in detecting MMRD in childhood cancers (N = 376). It was more sensitive than the microsatellite instability panel (14%, P = 4.3 × 10−12), immunohistochemistry (86%, P = 4.6 × 10−3), or tumor mutational burden (80%, P = 9.1 × 10−4). LOGIC was able to distinguish CMMRD from other cancer predisposition syndromes using blood and saliva DNA ( P < .0001, n = 277). In normal cells, MMRDness scores differed between tissues (GI > blood > brain), increased over time in the same individual, and revealed genotype-phenotype associations within the mismatch repair genes. Importantly, increased MMRDness score was associated with younger age of first cancer presentation in individuals with CMMRD ( P = 2.2 × 10−5). CONCLUSION LOGIC was a robust tool for the diagnosis of MMRD in multiple cancer types and in normal tissues. LOGIC may inform therapeutic cancer decisions, provide rapid diagnosis of germline MMRD, and support tailored surveillance for individuals with CMMRD.

Publisher

American Society of Clinical Oncology (ASCO)

Subject

Cancer Research,Oncology

Link

https://ascopubs.org/doi/pdfdirect/10.1200/JCO.21.02873

Reference45 articles.

1. Comprehensive Analysis of Hypermutation in Human Cancer

2. Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers

3. Immune Checkpoint Inhibition for Hypermutant Glioblastoma Multiforme Resulting From Germline Biallelic Mismatch Repair Deficiency

4. Comprehensive molecular characterization of human colon and rectal cancer

5. Integrated genomic characterization of endometrial carcinoma

Cited by 8 articles. 订阅此论文施引文献订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献

1. Genetic predisposition to gastrointestinal polyposis: syndromes, tumour features, genetic testing, and clinical management;The Lancet Gastroenterology & Hepatology;2024-01

2. Data-driven decision-making for precision diagnosis of digestive diseases;BioMedical Engineering OnLine;2023-09-01

3. Constitutional mismatch repair deficiency syndrome with atypical features caused by a homozygous MLH1 missense variant (c.1918C>A, p.(Pro640Thr)): a case report;Frontiers in Oncology;2023-08-17

4. Efficacy of Nivolumab in Pediatric Cancers with High Mutation Burden and Mismatch Repair Deficiency;Clinical Cancer Research;2023-05-01

5. Constitutional Microsatellite Instability, Genotype, and Phenotype Correlations in Constitutional Mismatch Repair Deficiency;Gastroenterology;2023-04