Germline hMLH1 promoter mutation in a Newfoundland HNPCC kindred
Bibliographic record
Abstract
Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant form of inherited predisposition to colorectal and other malignancies. It is associated with mutations in DNA mismatch-repair genes, especially hMSH2 and hMLH1. Management of HNPCC families is improved if the underlying mutation in each family can be discovered. We describe a Newfoundland kindred, meeting the Amsterdam Criteria for HNPCC, in which a mutation in the promoter region of the hMLH1 gene co-segregates with the disease phenotype. The -42C > T mutation is within a putative Myb proto-oncogene binding site. Using electrophoretic mobility shift assays, we demonstrated that the mutated Myb binding sequence is less effective in binding nuclear proteins than the wild-type promoter sequence. Using in vivo transfection experiments in HeLa cells, we further demonstrated that the mutated promoter has only 37% of the activity of the wild-type promoter in driving the expression of a reporter gene. The average age of onset in six family members affected with colorectal cancer is 62 years, which is substantially later than the typical age of onset in HNPCC families. This is consistent with a substantial decrease, but not total elimination, of mismatch repair function in affected members of this family. This is the first report of a heritable hMLH1 promoter mutation in any HNPCC family.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 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) | 0.000 | 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 teacher head, 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".