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.
| Original language | English |
|---|---|
| Pages (from-to) | 766-777 |
| Number of pages | 12 |
| Journal | Journal of Clinical Oncology |
| Volume | 41 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 1 Feb 2023 |
Bibliographical note
Funding Information:The SickKids Cancer Sequencing (KiCS) program was supported by the Garron Family Cancer Centre with funds from the SickKids Foundation. This research was supported by Meagan's Walk (MW-2014-10), b.r.a.i.n.child Canada, LivWise, SickKids Foundation donors—Harry and Agnieszka Hall, the Zane Cohen Center donors—The Mullin Family and Friends, the Canadian Institutes for Health Research (CIHR) grant (PJT-156006), the CIHR Joint Canada-Israel Health Research Program (MOP—137899), a Stand Up to Cancer (SU2C)—Bristol Myers Squibb Catalyst Research (SU2C-AACR-CT07-17) grant, a Genome Applications Partnership Program (GAPP) grant from Genome Canada, a COG NCORP Research Base Administrative Supplement Request: Landscape of somatic and inherited replication repair deficiency toward a childhood cancer vaccine (3UG1CA189955-08S2), CCS/CIHR/BC Spark Grants: Novel Technology Applications in Cancer Prevention and Early Detection (SPARK-21, 707089—funded by both CCS (Canadian Cancer Society) and BC (Brain Canada)), and St Baldrick's Foundation International Scholar Award (with generous support from the Team Campbell Foundation; Grant No.: 697257, A.D.). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C.
Publisher Copyright:
© American Society of Clinical Oncology.
Copyright:
Copyright 2023 Elsevier B.V., All rights reserved.
Keywords
- Humans
- Brain Neoplasms/diagnosis
- Colorectal Neoplasms/diagnosis
- DNA Mismatch Repair/genetics
- Genomics
- Germ Cells/pathology
- Microsatellite Instability
- Microsatellite Repeats
- Neoplastic Syndromes, Hereditary/diagnosis