Genome sequencing of multiple primary tumors to reveal underlying germline cancer susceptibility.
Bibliographic record
Abstract
1552 Background: Apart from germline mutations in BRCA1 and BRCA2, the basis for genetic susceptibility to breast and ovarian cancer is heterogeneous, and can necessitate sequential or multiplex genetic testing. In addition, examination of germline DNA alone may not be conclusive. Information regarding both primary and secondary genetic events can be obtained from genomic analysis of tumors in conjunction with germline DNA. Methods: To determine the underlying cause of multiple primary malignancies in an Ashkenazi Jewish individual, whole genome sequencing was performed on DNA from the patient’s germline, invasive ductal carcinoma of the breast, and ovarian high-grade serous carcinoma. After identifying a structural variant of interest in this patient, germline DNA of 1846 Ashkenazi Jewish individuals who had a personal history of either breast, pancreatic, or ovarian cancer or a history of both breast and/or ovarian cancer and a similar family history, were screened using a TaqMan copy number assay or a specific PCR breakpoint assay to determine if this structural variant is a founder mutation. Results: A novel germline complex structural variant of PALB2 creating a 3790 base-pair deletion encompassing exon 11 associated with a 68 base-pair insertion was identified and confirmed by Sanger sequencing and a TaqMan copy number assay. The germline deletion was retained in both tumors. In addition, both tumors acquired second hits that led to inactivation of the wild-type allele of PALB2. The germline PALB2 structural variant was not identified in any of the additional 1846 Ashkenazi Jewish individuals genotyped. Conclusions: Whole genome sequencing of multiple primary tumors enabled identification and characterization of a novel germline structural variant in PALB2 as the basis for the individual’s susceptibility to breast and ovarian cancer. The variant does not appear to be a founder mutation in Ashkenazim.
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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) | 0.004 | 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".