Abstract B113: Prevalence of germline BRCA and mismatch repair (MMR) gene mutations in pancreatic cancer
Notice bibliographique
Résumé
Abstract Background: Germline mutations of BRCA1, BRCA2, MLH1, MSH2, and MSH6 are known to increase risk of pancreatic cancer. However, the prevalence of pathogenic germline mutations of these genes among pancreatic cancer patients is unknown. Accurately characterizing the frequencies of mutations of these genes will inform patient selection for future gene discovery studies and, clinically, foster screening strategies and tailored treatments. Objective: To determine the prevalence of pathogenic germline mutations of BRCA1, BRCA2, MLH1, MSH2, and MSH6 in a cohort of pancreatic cancer patients, and to determine the association between mutation carrier status and personal and family history of cancer. Methods: The Ontario Pancreas Cancer Study (OPCS) enrolls all consenting participants with a diagnosis of pancreatic cancer into a province-wide electronic pathology database. A cross-sectional sample of 300 patients from 715 OPCS probands enrolled between April 2003 and August 2012 were randomly selected from three strata based on a family history of pancreatic, breast, and ovarian cancer. Targeted next-generation sequencing was successfully performed on germline DNA from 291 of the 300 selected probands. Mutations were classified as benign, of unknown significance, or pathogenic by literature and database review. Pathogenic mutations were confirmed with Sanger sequencing. Prevalence estimates representing the whole OPCS were estimated using the Horvitz-Thompson estimator. Univariate analysis determined association between carrier status and clinical covariates, and regression analysis for overall survival. Results: A total of 7 pathogenic germline mutations were identified: 1 BRCA1, 2 BRCA2, 1 MLH1, 2 MSH2, and 1 MSH6. The estimated prevalence of pathogenic mutations in BRCA1 and BRCA2 among probands in this OPCS series was 1.1% (95% confidence interval: 0.1-2.0%); in the mismatch repair genes MLH1, MSH2, and MSH6 it was 1.5% (0.3-2.6%). Both a personal history of colorectal cancer and a first-degree relative with colorectal cancer, breast cancer, or melanoma were significantly associated (p<0.001 and p<0.01, respectively) with MMR mutations. There were no significant differences in tumor location within the pancreas (head/uncinate versus body/tail), clinical nodal status, rates of resection, age at diagnosis, BMI, history of smoking, history of pancreatitis, family history of pancreatic cancer, family history of colorectal cancer, or differences in survival between the MMR or sporadic cohorts. Conclusion: This study is the first to quantify population-based prevalences of germline mutations of BRCA1, BRCA2, MLH1, MSH2, and MSH6 in pancreatic cancer. Surprisingly, the prevalence of pathogenic germline mutations of the MMR genes in pancreatic cancer is higher than expected, and is comparable to that of BRCA1 and BRCA2. The prevalence of the MMR germline mutations is also comparable to the prevalence of MMR germline mutations in colorectal cancer cohorts. Relatives who carry MMR gene mutations can benefit from tailored cancer prevention strategies; thus mutational analysis of MLH1, MSH2, and MSH6 should be included in molecular genetic testing and counseling strategies for pancreatic cancer patients, especially those with a family history of malignancy. Translational studies will follow to determine if stratifying pancreatic cancer risk by familial susceptibility genes, as in colorectal cancer, fosters tailored and cost-effective primary and secondary prevention strategies for carriers. Moreover, unique chemotherapy sensitivity and resistance patterns would be expected for MMR-associated pancreatic cancer, as is emerging for BRCA-associated pancreatic cancer. Citation Format: Iris Selander, Robert Grant, Ashton Connor, Shamini Selvarajah, Ayelet Borgida, Laurent Briollais, Jordan Lerner-Ellis, Spring Holter, Steven Gallinger. Prevalence of germline BRCA and mismatch repair (MMR) gene mutations in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B113.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,003 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,002 | 0,003 |
| Études des sciences et des technologies | 0,001 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».