Prevalence of mutations associated with NCCN criteria for hereditary prostate cancer testing in an Indian population.
Bibliographic record
Abstract
e17087 Background: Germline mutations in various genes increase the risk of lethal metastatic prostate cancer (PCa). It is well established that mutations including BRCA1, BRCA2, ATM, and CHEK2 are known to increase the risk of developing metastatic PCa, as 1 in 8 men with this disease are likely to harbour such mutations. The majority of research has focused on the role of DNA-repair genes in PCa risk, but more work is needed to clarify the distribution and frequency of mutations in different populations and genes. The primary aim of this study is to determine the germline genetic mutations in a northern Indian cohort of patients with high-risk PCa. Methods: We recruited 287 men that meet NCCN criteria for hereditary PCa testing. Five millilitres of blood was collected in EDTA tubes. Subsequently, DNA was extracted from the samples utilizing isolation kits and stored at -80°C until sequencing. The DNA extracted was sent for Whole Exome Sequencing genetic testing. The presence of germline mutations in genes known to be associated with prostate and other cancers was determined using established bioinformatic pipelines. Results: In our study involving 287 patients, pathogenic mutations were detected in 79 individuals. The total count of gene mutations observed was 43, with 13 patients exhibiting more than one mutation.These mutations spanned across 44 genes, with varying frequencies. Notably, BRCA2 mutations were found in 12 men (4.2%), ATM mutations in 5 individuals (1.7%), and CUBN mutations in 4 patients (1.4%). Additionally, ATR, LZTR1, PALB2, and RASA2 mutations were each observed in 3 patients (1.1%), while ADA2, BUB1B, CLCN7, ERCC2, FANCA, HNF1A, MSH2, PIEZO1, and VPS13B mutations were identified in 2 patients (0.69% of the cohort). Among the mutations detected, several were related to DNA repair genes. Specifically, BRCA2 mutations were observed in 12 cases (4.2%), ATM mutations in 5 cases (1.7%), PALB2 mutations in 3 cases (1.04%), ERCC2 mutations in 2 cases (0.7%), and BRCA1, ERCC5, and RAD51D mutations each in 1 case (0.35%). Overall, 25 (8.7%) of the total patients displayed alterations in DNA repair genes. Regarding variants of uncertain significance (VUS), the distribution among patients was as follows: 64 patients (22.3%) showed 3 VUS, 54 patients (18.8%) had 2 VUS, 46 patients (16.0%) had 4 VUS, 37 patients (12.9%) had 5 VUS, 28 patients (9.75%) had 1 VUS, and 19 patients (6.6%) had either 0 or 6 VUS. Conclusions: In our study, the incidence of germline mutations in genes mediating DNA-repair processes among men that meet NCCN criteria for hereditary PCa was 8.7% in this population in Northern India. This is 3.1% lower when comparing to the incidence reporting by Pritchard for metastatic PCa. Additional insights into the genetic risk of PCs are provided by this study which can be used to guide genetic testing.
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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 | 0.001 | 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) | 0.003 | 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".