Incidental germline findings identified in a somatic genomic sequencing program for advanced cancer patients.
Bibliographic record
Abstract
1532 Background: Next generation sequencing (NGS) of tumor DNA is used to match precision cancer therapies. Germline DNA is often co-analyzed to aid in tumor variant interpretation, but may identify a previously unrecognized hereditary cancer syndrome (HCS). We reviewed germline variants and analyzed patients’ (pts) preferences in learning about HCSs discovered through an institutional somatic NGS program (NCT01505400). Methods: Advanced cancer pts with ECOG ≤ 1 were offered tumor-germline NGS using the Illumina TruSeq Amplicon Cancer Panel with 48 cancer genes designed specifically for somatic profiling. This also included the HCS genes: APC, ATM, CDH1, CDKN2A, KIT, MET, MLH1, PTEN, RB1, RET, SMAD4, SMARCB1, STK11, TP53, and VHL. All pts were provided with an optional IRB-approved consent for return of incidental germline pathogenic/likely pathogenic variants in HCS genes with appropriate genetic counselling. Results: From Aug/2013 to Nov/2015, 1937 pts were enrolled. Median age was 59, 67% were women and 18% had prior genetic testing. 1817 pts (94%) consented to be informed of incidental germline results and 103 pts (5%) declined, with no statistically significant differences based on age, sex, race or prior genetic testing. Of 1538 pts (85%) who successfully underwent NGS testing of tumor and germline, eight were found to have pathogenic germline variants in HCS genes. Three pts were previously clinically identified: one with Familial adenomatous polyposis (APC) and two with Li-Fraumeni syndrome (LFS, TP53). Five pts had previously unrecognized germline pathogenic variants: three in TP53 (LFS), of which only one fulfilled Chompret’s criteria, and one in SMARCB1 (schwannomatosis) in the absence of syndrome features. One harbored a TP53variant at 16% allele frequency suggesting an acquired event in blood, rather than LFS. Conclusions: Interest in the return of germline results is high among pts with advanced cancers who undergo somatic profiling. Despite not conducting comprehensive analysis of all potential germline variants, a number of HCSs were still incidentally identified, supporting the involvement of genetic counselling in somatic profiling programs.
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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 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 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) | 0.004 | 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".