Exploring the Role of Novel Candidate Genes in Susceptibility to Breast Cancer
Bibliographic record
Abstract
While several breast cancer susceptibility genes have been identified, more are likely to exist. Our research team recently identified ATRIP as a novel breast cancer susceptibility gene candidate through whole-exome sequencing (WES) of familial breast cancer patients and healthy controls from the Polish founder population. A recurrent rare mutation, ATRIP c.1152_1155del, was observed in 42 of 16,085 Polish breast cancer patients and in 11 of 9,285 controls (OR = 2.14, 95% CI = 1.13-4.28, p = 0.02). In another study among the Bahamian population, our research team identified three novel candidate genes, DCLRE1C, DDX19B, and XRCC3, with potential roles in susceptibility to breast cancer. To follow up with these findings, we conducted targeted full-gene sequencing on germline DNA from 1,021 familial breast cancer patients in Ontario, 1,390 French-Canadian patients in Quebec, and 421 Iranian patients. Controls included 930 healthy women from Ontario, 800 individuals from the Iranome database, and 450 from the Gen3G study. Additionally, we analyzed UK Biobank WES data from 15,643 Caucasian breast cancer cases and 157,943 matched controls. Gene-based association analysis revealed that of the four candidate genes under study, only ATRIP loss of function (LoF) variants were associated with a significantly increased risk of breast cancer among the British population. We identified ATRIP LoF carriers among 13 of 15,643 Caucasian breast cancer patients and 40 of 157,943 ethnicity-matched healthy individuals within the UK Biobank (UKB) cohort (age-adjusted OR = 3.28, 95% CI = 1.76-6.14, p < 0.001). As an exploratory aim, we also examined ATRIP in 1,488 unselected ovarian cancer patients from Ontario. We identified four LoF carriers, with none among 930 local controls (OR = 5.6, p = 0.14). Tumor DNA analysis of ten ATRIP-mutated breast tumors showed loss of heterozygosity (LOH) in at least four and homologous recombination deficiency (HRD) in seven tumors. Mutational signature analysis indicated defects in both homologous recombination repair (HRR) and mismatch repair pathways. ATRIP is essential for activating the ATR-mediated DNA damage checkpoint at stalled replication forks. Altogether, our findings support ATRIP as a breast cancer susceptibility gene linking DNA replication stress to hereditary breast cancer risk.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 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".