Studies of Microsatellite Instability Signatures in Replication Repair Deficient Malignant and Germline Tissues
Bibliographic record
Abstract
DNA replication errors are resolved by the mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, or PMS2) although pathogenic variants in MMR genes result in mismatch repair deficiency (MMRD). MMRD arises through primary causes (somatic or germline variants), or secondary causes (treatment-induced). Monoallelic germline variants in MMR genes causes Lynch Syndrome in adults who develop primarily gastrointestinal cancers. Biallelic germline MMR variants cause constitutional mismatch repair deficiency (CMMRD) in children who develop predominantly central nervous system malignancies. MMRD induces extreme genomic instability causing cancers characterized by hypermutation, microsatellite instability (MSI), and resistance to chemoradiation. The unique biology of MMRD tumors and high likelihood of cancer development means accurate diagnosis is crucial. MMRD diagnosis has relied on several methods which are insufficient in non-colorectal and childhood cancers. Fortunately, signatures of MSI provide highly specific diagnosis.Leveraging millions of microsatellites across the genome, this thesis resulted in creation of the functional assay LOw-pass Genomic Instability Characterization (LOGIC) for robust MMRD diagnosis in tumors. LOGIC additionally achieved diagnosis of CMMRD using germline tissues and MSI analysis revealed biological insights into MMRD mutagenesis. MSI correlated with specific MMR variants, tissues, and age at initial cancer diagnosis, enabling tailored screening protocols for the future. The capacity to reliably diagnose MMRD enabled determination of its prevalence in primary gliomas, which represent the leading cause of cancer-related mortality in children. A population-based screen of gliomas in children, adolescents, and young adults (CAYA, 0-40 years) from Toronto, St Jude Children’s Research Hospital, and the Children’s Brain Tumor Network revealed a significant prevalence in high-grade gliomas. MMRD was enriched in IDH- and H3-WT high-grade gliomas but was absent in gliomas with pediatric-type alterations, fusions, or copy number variants. Almost all MMRD gliomas were driven by primary causes, namely germline alterations in MMR genes causing Lynch Syndrome, redefining the cancer spectrum in Lynch Syndrome. Immunotherapy in a cohort from the International Replication Repair Deficiency Consortium revealed significantly improved overall survival in MMRD CAYA gliomas. We suggest increased MMRD screening in specific glioma subtypes, germline testing for patients and family members, and further studies of immunotherapies in CAYA.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".