Abstract 2975: Two putative founder MSH6 mutations associated with inherited cancer susceptibility in Ashkenazi Jewish population
Bibliographic record
Abstract
Abstract Background Inherited mutations in DNA mismatch-repair genes are the cause of several cancers associated with Lynch syndrome. The most common mutations affect MLH1 and MSH2 genes, while the MSH6 gene is less commonly involved. Furthermore, MSH6 mutations have been observed to result in an attenuated form of the syndrome. We report here case-control studies of two putative MSH6 founder mutations in the Ashkenazi Jewish (AJ) population. Methods Case-control studies were performed using DNA extracted from the blood of individuals of AJ descent presenting cancers compatible with Lynch syndrome and AJ individuals unaffected by cancer as controls. The DNA samples were screened for the presence of the two mutations in exon 9. The frequency of the mutations and the range of malignancies were analyzed. Results Among 2104 population-based AJ colorectal cancer cases (CRC), 8 carried a 4 bp duplication mutation, c.3984_3987dupl (0.38%), and 3 carried a 4 bp deletion mutation, c.3959_3962del (0.14%), in the exon 9 of the MSH6 gene. In comparison, 1 duplication (0.06%) and no deletions were observed in 1813 control individuals. The odds ratio for the c.3984_3987dupl and the c.3959_3962del in this population are OR = 8.64 (exact 95%CI 1.23-375, Fisher's exact test two-sided P = 0.04) and OR = NA, P = 0.25, respectively. Notably, the one control found to carry the duplication was, during the course of follow-up, diagnosed with both cecal and endometrial cancer. In a hospital-based series of 78 CRC, one individual carried the deletion, but no duplications were seen. Among 136 hospital-based AJ endometrial cancer cases, 2 carried the duplication, leading to an OR of 27.0 (95%CI: 1.39-1596, P = 0.014) when compared with the 1813 controls. In a series of 61 hospital-based AJ pancreas cancer cases, no duplication carriers were seen, but 1 individual carried the deletion (OR NA, P = 0.033). Notably, this individual developed 3 independent primary cancers - pancreas cancer, CRC and rhabdomyosarcoma. Testing for microsatellite instability and loss of MSH6 protein is in progress in these samples. Conclusion These rare, probable founder, MSH6 truncating mutations reported here are of great importance for the screening, genetic counseling and follow-up of Ashkenazi Jewish families presenting malignant tumors compatible with Lynch syndrome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2975.
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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 | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".