Unselected germline screening in pancreatic adenocarcinoma yields high rates of pathogenic and likely pathogenic variants (PV) in hereditary cancer susceptibility genes.
Bibliographic record
Abstract
1582 Background: Recent literature cites a germline mutation rate of 3.9-15.1% in patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) depending on breadth of genes tested, pre-selection of high-risk history and population substructure. True incidence of germline mutations in PDAC is unknown in unselected population. Methods: All patients (pts) diagnosed with PDAC in the province of British Columbia, Canada and referred to the Hereditary Cancer Program, were eligible to undergo 30 gene Color saliva kit testing under a research protocol, or clinical multigene testing if they met existing local criteria regardless of whether they signed on to the protocol. Any healthcare provider or patients themselves could refer. Results: 243 pts were referred between August 2016 and October 2018 but 25.1% (61) declined and 9.1% (22) died before testing. Of the 141 pts who consented to research protocol and completed germline testing, median age was 64 (46.1-81.0), 68.8% were European, 1.4% Ashkenazi Jewish heritage, 42% male, 61% non-smoker, 24.1% had personal history of a second cancer and 39% had metastatic disease. Baseline characteristics were similar between the PV positive and uninformative group. 20/25 PV were in known PDAC susceptibility genes with cascade screening implications (ATM (9), BRCA2 (4), BRCA2/ATM (1), CDKN2A (4), and MSH2 (2)). Excluding the 3 PV identified through carrier testing (1) and prior research identification (2), the rate of PV in unselected, unrelated PDAC cohort is 22/138 (15.9%). Utilizing previous NCCN criteria for BRCA1/BRCA2 testing or for familial pancreatic cancer did not appear to select for patients with higher risk of PV positive (12/65 (18.4%) PV positive rate versus 13/76 (17.1%) in those that didn’t meet criteria). Previous criteria would have missed 52% (13/25) PV in ATM (6), BRCA2/ATM (1), BRCA2 (2), MSH2 (2), NBN (1), CHEK2 (1). To date, a third of families with PV identified have accessed cascade testing in 38 relatives. Conclusions: Given the high incidence of 15.9% PV in hereditary cancer susceptibility genes, our data support recommendations for universal germline genetic testing of PDAC pts.
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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 | 0.001 | 0.008 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".