Identification of new breast cancer predisposition genes via whole exome sequencing
Notice bibliographique
Résumé
The application of massively parallel sequencing (MPS) platforms has begun to revolutionize our understanding of the immense variation in the human genome and the complexity that can underlie genetic susceptibility to disease. The utility of exome capture MPS through the identification of genes for rare Mendelian disorders based on analysis of only a few individuals has been eloquently demonstrated. Common diseases such as breast cancer present substantially increased complexity in terms of locus, allelic and phenotypic heterogeneity, as well as complex relationships between genotype and phenotype (reduced penetrance, phenocopies etc.). With careful consideration of study design [1], thoughtful selection of families from our international resources (whole exome sequencing of two highly selected affected members of multiple-case breast cancer families), and a well-developed strategy (analytical pipeline) for distinguishing the few true breast cancer susceptibility genes from the many genes that have rare genetic variants that could plausibly alter protein function, we are advancing a large program of work aimed at identifying the majority of the “missing heritability” of breast cancer. Our early findings demonstrate that: 1) despite very plausible biological roles, some genetic variants in some genes predicted to be damaging by SIFT and Polyphen2 do not appear to be associated with breast cancer risk [2]. 2) application of our strategy can identify new breast cancer susceptibility genes. During the early conduct of this program, we identified a family with a protein truncating mutation in a gene involved in DNA repair. Follow-up has included mutation screening of: a) youngest affected members of 250 multiple-case breast cancer families, b) cases and controls participating in Australian population-based studies of breast cancer (ABCFS and MCCS) c) cases and controls in an international population-based case-control-family resource (BCFR) To date, these analyses have identified 6 families with frameshift or evolutionarily unlikely missense mutations in this gene. Features of these families include multiple-cases of early-onset female breast cancer with some potentially other interesting features such as early-onset male breast cancer and pancreatic cancer. These mutations have not been found in approximately 3000 unaffected population-based controls without a family history of breast cancer. We are continuing to expand our dataset to include the exome sequences of further families and coordinating the follow-up of candidate genes using appropriate MPS platforms and as founding partners of a newly formed international consortium of breast cancer exome sequencing researchers.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,001 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 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 tête enseignante, 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 ».