Population BRCA1 and BRCA2 Mutation Frequencies and Cancer Penetrances: A Kin–Cohort Study in Ontario, Canada
Bibliographic record
Abstract
BACKGROUND: BRCA1 and BRCA2 mutations in general populations and in various types of cancers have not been well characterized. We investigated the presence of these mutations in unselected patients with newly diagnosed incident ovarian cancer in Ontario, Canada, with respect to cancers reported among their relatives. METHODS: A population series of 1171 unselected patients with incident ovarian cancer diagnosed between January 1, 1995, and December 31, 1999, in Ontario, Canada, was screened for germline mutations throughout the BRCA1 and BRCA2 genes. Screening involved testing for common variants, then protein truncation testing of long exons, and then denaturing gradient gel electrophoresis or denaturing high-performance liquid chromatography for the remainder of BRCA1 and BRCA2, respectively. Cox regression analysis was used to examine cancer outcomes reported by the case probands for their 8680 first-degree relatives. Population allele frequencies and relative risks (RRs) were derived from the regression results by an extension of Saunders-Begg methods. Age-specific Ontario cancer incidence rates were used to estimate cumulative incidence of cancer to age 80 years by mutation status. RESULTS: Among 977 patients with invasive ovarian cancer, 75 had BRCA1 mutations and 54 had BRCA2 mutations, for a total mutation frequency of 13.2% (95% confidence interval [CI] = 11.2% to 15.5%). Higher risks for various cancer types in the general Ontario population were associated with BRCA1 mutation carriage than with noncarriage, including ovarian (RR = 21, 95% CI = 12 to 36), female breast (RR = 11, 95% CI = 7.5 to 15), and testis (RR = 17, 95% CI = 1.3 to 230) cancers. Higher risks were also associated with BRCA2 mutation carriage than with noncarriage, particularly for ovarian (RR = 7.0, 95% CI = 3.1 to 16), female and male breast (RR = 4.6, 95% CI = 2.7 to 7.8, and RR = 102, 95% CI = 9.9 to 1050, respectively), and pancreatic (RR = 6.6, 95% CI = 1.9 to 23) cancers. Cancer risks differed according to the mutation's position in the gene. Estimated cumulative incidence to age 80 years among women carrying BRCA1 mutations was 24% for ovarian cancer and 90% for breast cancer and among women carrying BRCA2 mutations was 8.4% for ovarian cancer and 41% for breast cancer. For the general Ontario population, estimated carrier frequencies of BRCA1 and BRCA2 mutations, respectively, were 0.32% (95% CI = 0.23% to 0.45%) and 0.69% (95% CI = 0.43% to 1.10%). CONCLUSIONS: BRCA1 and BRCA2 mutations may be more frequent in general populations than previously thought and may be associated with various types of cancers.
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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 | 0.002 |
| Science and technology studies | 0.002 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| 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".