Abstract 35: Novel genetic and clinical determinants of Constitutional Mismatch Repair Deficiency syndrome: Report from the CMMRD consortium
Bibliographic record
Abstract
Abstract Purpose: Constitutional mismatch repair deficiency (CMMRD) is a devastating cancer predisposition syndrome affecting children born with two mutated alleles in one of four mismatch repair genes. Data regarding clinical manifestations, molecular screening tools and management are limited. Patients and methods: We established an international CMMRD consortium and collected comprehensive clinical and genetic data. Molecular diagnosis of tumor and germline biospecimens were performed. A surveillance protocol was developed and implemented. Results: Overall, 27/30 (90%) of children with CMMR-D developed 48 different tumors. While childhood CMMR-D related tumors were observed in all families, Lynch related tumors in adults were observed in only 2/17 families (p<0.0001). All children with CMMR-D had cafe-au-lait spots and 14/17 families were consanguineous. We detected 17 different germline MMR mutations. These included mutations in PMS2(8), MSH6(7) and MLH1(2). Importantly 7/17 mutations were previously unreported. Brain tumors were the most common cancers reported (44%) followed by gastrointestinal (33%) and hematological malignancies (17%). Importantly, 14 (29%) of these were low grade and respectable cancers. Tumor immunohistochemistry was 100% sensitive and specific in diagnosing MMR deficiency of the corresponding gene while microsatellite instability was neither sensitive nor specific as a diagnostic tool (p<0.0001). Furthermore, screening of normal tissue by immunohistochemistry correlated with genetic confirmation of CMMR-D. The surveillance protocol detected 43 lesions which included asymptomatic malignant gliomas and gastrointestinal carcinomas. All tumors were amenable to complete resection and all patients undergoing surveillance are alive. Conclusion: CMMR-D is a highly penetrant syndrome where family history of cancer may not be contributory. Screening tumors and normal tissues using immunohistochemistry for abnormal expression of MMR gene products helps in diagnosis and early implementation of surveillance for these children. Citation Format: Doua Bakry, Brittany Campbell, Carol Durno, Melyssa Aronson, Qasim Alharbi, Musa Alharbi, Shlomi Constantini, Aaron Pollett, Shay Ben-Shachar, Jordan Lerner-Ellis, Steven Gallinger, Ronit Elhasid, Roula Farah, Ibrahim Qaddoumi, Matthew Mistry, Ramyar Lily, Steve Keiles, Rina Dvir, Derek Stephens, David Malkin, Eric Bouffet, Cynthia Hawkins, Uri Tabori. Novel genetic and clinical determinants of Constitutional Mismatch Repair Deficiency syndrome: Report from the CMMRD consortium. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 35. doi:10.1158/1538-7445.CANSUSC14-35
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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 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| 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".