Penetrance of HNPCC-related cancers in a retrolective cohort of 12 large Newfoundland families carrying a MSH2 founder mutation: an evaluation using modified segregation models
Notice bibliographique
Résumé
BACKGROUND: Accurate risk (penetrance) estimates for associated phenotypes in carriers of a major disease gene are important for genetic counselling of at-risk individuals. Population-specific estimates of penetrance are often needed as well. Families ascertained from high-risk disease clinics provide substantial data to estimate penetrance of a disease gene, but these estimates must be adjusted for possible specific sources of bias. METHODS: A cohort of 12 independently ascertained HNPCC families harbouring a founder MSH2 mutation was identified from a cancer genetics clinic in St. John's, Newfoundland, Canada. Carrier status was known for 247 family members but phenotype information on up to 85 additional relatives with unknown carrier status was available; using modified segregation models these additional individuals could be included in the analyses. Three HNPCC-related phenotypes were evaluated as age at diagnosis of: any HNPCC cancer (first cancer), colorectal cancer (CRC), and endometrial cancer (EC) for females. RESULTS: Lifetime (age 70) risk estimates for male and female carriers were similar for developing any HNPCC cancer (Males = 98.2%, 95% Confidence Interval (CI) = (93.8%, 99.9%); Females = 92.8%, 95% CI = (82.4%, 99.1%)) but female carriers experienced substantially reduced lifetime risk for developing CRC compared to male carriers (Females = 38.9%, 95% CI = (24.2%, 62.1%); Males = 84.5%, 95% CI = (67.3%, 91.3%)). Female non-carriers had very low lifetime risk for these two outcomes while male non-carriers had lifetime risks intermediate to the female carriers and non-carriers. Female carriers had a lifetime risk of developing EC of 82.4%. Relative risks for developing any HNPCC cancer (carriers relative to non-carriers) were substantially greater for females compared to their male counterparts (Females = 54.8, 95%CI = (4.4, 379.8); Males = 9.7, 95% CI = (0.3, 23.8)). Relative risks for developing CRC at age 70 were substantially greater for females compared to their male counterparts (Females = 23.7, 95%CI = (5.6, 137.9); Males = 6.8%, 95% CI = (2.3, 66.2)). However, the risk of developing CRC decreased with age among both genders. CONCLUSION: The proposed modified segregation-based models used to estimate age-specific risks for HNPCC phenotypes can reduce bias due to ascertainment and missing genotype information as well as provide estimates of absolute and relative risks.
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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 | 0,004 | 0,003 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| 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) | 0,000 | 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 ».