Abstract 2628: Genome-wide sequencing identifies <i>ATM</i> as a pancreatic cancer susceptibility gene
Bibliographic record
Abstract
Abstract Pancreatic ductal adenocarcinoma (PDA) affects over 44,000 people in the United States every year and carries a dismal prognosis, with a 5-year survival rate of just 5%. A subset of these patients (5-10%) report a familial history of the disease. The genetic etiology in these familial cases is poorly defined, with known susceptibility genes, such as: BRCA2, PALB2, CDKN2A, BRCA1, PRSS1 and STK11, accounting for only 10-15% of familial pancreatic cancer. In an effort to identify previously unappreciated pancreatic cancer susceptibility genes, we used next generation sequencing technology to evaluate the whole genome and whole exome sequences of 16 (6 families) and 22 individuals (10 families) respectively. All of these families enrolled into one of the familial pancreatic cancer registries participating in the Pancreatic Cancer Genetic Epidemiology (PacGene) Consortium, all had at least three members with PDA, and DNA was available from at least two affected members in each kindred. Using this approach, we identified heterozygous, inactivating, ATM mutations in two kindreds with familial pancreatic cancer (c.8266A>AT; p.K2756X and c.170G>GA; p.W57X). These mutations were previously reported as disease causing variants in patients with ataxia-telangiectasia, an autosomal recessive condition resulting from bi-allelic deleterious mutations of ATM. Interestingly, heterozygotes of deleterious ATM mutations have an increased risk of breast cancer. However, there have been no previous reports of deleterious ATM mutations in the germline of familial PDA patients. In our study, mutations segregated with disease in both kindreds and tumor analysis demonstrated Loss of heterozygosity (LOH) of the wild-type allele. Sequence analysis of the entire ATM gene in an additional 166 familial pancreatic cancer probands indentified four additional patients with deleterious mutations in the ATM gene (c.3214G>GT; p.E1072X, c.6095G>GA; p.R2032K, IVS41-1G>GT and c.3801delG), while no deleterious mutations were identified in 190 spouse controls (p=0.046). When considering only the mostly severely affected families, those with three or more pancreatic cancer cases, four deleterious mutations were found in 87 families (P=0.009). These results indicate that ATM mutations play an important role in familial pancreatic cancer predisposition and have significant implications in the management of affected individuals and the risk assessment of family members. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2628. doi:1538-7445.AM2012-2628
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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 | 0.000 |
| 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) | 0.003 | 0.001 |
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".