In an analysis reported in the Journal of Clinical Oncology, Chung et al described the performance of a newly developed assay using genomic microsatellite signatures (LOGIC; low-pass genomic instability characterization) in detecting germline mismatch repair deficiency (MMRD) in patients with the cancer predisposition syndrome constitutional MMRD (CMMRD).
Study Details
The diagnostic performance of LOGIC in detecting MMRD was compared with that of a microsatellite instability panel, tumor mutational burden, and immunohistochemistry in cases of childhood cancer. Assessment of LOGIC MMRDness scores in normal tissue was performed.
Key Findings
In a cohort of 376 cases of childhood cancers:
- Sensitivity and specificity for MMRD was 100% and 100% with LOGIC (positive predictive value [PPV] = 100%, negative predictive value [NPV] = 100%), compared with 14.3% (P = 4.3 x 10-12 vs LOGIC) and 100% (PPV = 100%, NPV = 17.2%) for the microsatellite instability panel
- 80.4% (P = 9.1 x 10-4 vs LOGIC) and 100% (PPV = 100%, NPV = 47.6%) for tumor mutational burden
- 85.7% (P = 4.6 x 10-3 vs LOGIC) and 100% (PPV = 100%, NPV = 55.6%) for immunohistochemistry.
LOGIC distinguished CMMRD from other cancer predisposition syndromes using blood and saliva DNA (P < .0001).
In normal cells, LOGIC MMRDness scores differed among tissues. Analysis in gastrointestinal, hematopoietic, and brain systems, where tumors typically develop in CMMRD, found that the highest scores were in gastrointestinal tissue, followed by blood, then brain. Scores increased over time within the same individual. Further, MMRDness scores showed genotype-phenotype correlations within mismatch repair genes, identifying MMR gene variants that may confer lower mutagenicity vs the known pathogenic variants associated with CMMRD.
Increased MMRDness score was associated with younger age of first cancer presentation in patients with CMMRD (P = 2.2 x 10-5).
The investigators concluded, “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.”
Uri Tabori, MD, of The Hospital for Sick Children, Toronto, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the SickKids Foundation, Meagan’s Walk, Canadian Institutes for Health Research, and others. For full disclosures of the study authors, visit ascopubs.org.
