From clinically tested to newly discovered: validation of breast and ovarian cancer predisposing variants
Bibliographic record
Abstract
Inherited germline pathogenic variants are responsible for ~5% of breast cancer and ~10% of ovarian cancer. BRCA1 and BRCA2 were established as breast cancer susceptibility genes over twenty-five years ago, and since then, several other genes have been seen to play a role in breast or ovarian cancer predisposition, such as PALB2 and RAD51C. Through rapid expansion and isolation since immigration in the early 17th century, French Canadians are a relatively genetically homogenous population due to genetic founder effects and therefore represent a unique demographic for genetic contributions to disease. To date, twenty variants in BRCA1, BRCA2, and PALB2 that likely predispose families to breast and ovarian cancer have been identified as recurring in French Canadians. The first objective of this thesis was to evaluate the clinical efficacy and validity of targeted genetic testing for these variants in Montreal French Canadians. A Sequenom genotyping assay identified a pathogenic variant in 0.2% (5 of 1940) of cancer-free controls, and 3.8% (21/555) of breast cancer cases unselected for age or family history. Of twenty variants tested, seven were identified in 12/113 (10%) of early onset cases. The option of providing this test as population-based screening is discussed. A proportion of high-risk patients remain without any known predisposing variants, and oftentimes gene panel testing results in variants of uncertain clinical significance. The second objective of this thesis was to characterize four variants of uncertain significance as likely benign or deleterious. One RAD51C (c.705G>T) variant was found to associate with ovarian cancer cases (3/888, 0.34%) in French Canadians (0/969 female controls). Initial functional analyses provide evidence that the variant is deleterious in vitro and may contribute to risk or progression of cancer. Taken together, the results of this thesis provide valuable information regarding both known and newly discovered breast and ovarian cancer predisposing variants in French Canadians
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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 | 0.004 | 0.010 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".