Comprehensive molecular assessment of mismatch repair deficiency in Lynch-associated ovarian cancers using next-generation sequencing (NGS) panel.
Bibliographic record
Abstract
1523 Background: Abnormalities in mismatch repair (MMR) gene may be the result of pathogenic germline (Lynch syndrome) and somatic mutations as well as epigenetic events. Abnormalities in MMR have been described in non-serous/non-mucinous ovarian cancer (OC) but few studies have examined the causes of these MMR defects (MMRd). To address this, we have completed targeted mutational and methylation sequencing on MMRd OC cases. Methods: Women with newly diagnosed non-serous/mucinous OC (N = 215) were prospectively recruited from three cancer centers in Ontario, Canada between 2015-18. Tumors were reflexively assessed for MMR protein expression by immunohistochemistry. Tumor DNA was extracted from macrodissected MMRd cases and MMR-intact (MMRi) controls following pathology review. Matched tumor-normal samples were run on a custom NGS panel to identify germline and somatic mutations, copy number variants, rearrangements and promoter methylation in MMR and associated genes. Results: Of the 215 women enrolled in our study, 185 (86%) had OC alone and 30 (14%) had synchronous OC and endometrial cancer. Twenty-eight (13%) cases were MMRd, 11 of which were synchronous. The MMRd cohort had median age of 52.5 years, with mostly stage I (N = 14; 50%), grade 1 or 2 disease (N = 18; 64%) with endometrioid histotype (N = 18; 64%). One patient had recurrence after median follow-up of 33.6 months (13.2-93.6). There was no significant difference in overall/progression-free survival between the MMRd and MMRi patients. Using the NGS panel, Lynch syndrome (LS) was detected in 39% of MMRd cases (11/28; 7 OC and 4 synchronous): 7 MSH6, 2 MLH1, 1 PMS2, and 1 MSH2. Clinical germline sequencing was performed on all cases and verified panel findings. An explanation for the observed MMR phenotype was available for 18/20 deficient cases, including 9/10 MLH1−/PMS2− (7 somatic methylation, 1 bi-allelic somatic deletion, 1 germline mutation), 0/1 PMS2−, 6/7 MSH6− (6 germline mutations) and 2/2 MSH2−/MSH6− (1 germline mutation, 1 bi-allelic somatic mutation). Concordance between clinical and research panel sequencing results was 90%. None of the germline mutations were missed by the panel. Conclusions: Use of our custom NGS panel allows for the streamlined assessment of hereditary and somatic causes of MMR deficiency in OC and may be an attractive screening strategy for LS in this population.
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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 | 0.001 |
| 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".