Abstract 3007: Monogenic and polygenic associations with subsequent breast cancer risk in survivors of childhood cancer: The St. Jude Lifetime Cohort Study (SJLIFE)
Notice bibliographique
Résumé
Abstract The allelic spectrum of the genetic architecture of breast cancer (BC) susceptibility includes at least 172 common variants with small effect sizes (per-allele odds ratio range: 1.03-1.31), plus rare variants with high (BRCA1, BRCA2, CHD1, PTEN, STK11, TP53) or moderate penetrance (ATM, CHEK2, NBN, NF1, PALB2). While these common variants confer modest risk individually, their combined effect in the form of a polygenic risk score (PRS) may be substantial. The SJLIFE whole-genome sequencing (WGS) data provide a unique opportunity to evaluate common and rare sets of genetic variants jointly, along with treatment exposures, for their contributions to subsequent BC risk in adult survivors of childhood cancer. This analysis utilized WGS data from 1131 females of European ancestry [median age at last follow-up: 34.9 years (range: 6.2-68.6)] of whom 47 were diagnosed with a subsequent BC (median age at BC 40.3 years, range: 25.5-53.0). The PRS (mean, 10.1; range, 8.3-12.2) was calculated using a weighted sum of the number of risk alleles and their log per-allele odds ratio from Michailidou et al. (Nature, Nov. 2017). A total of 34 (3.0%) survivors were carriers of pathogenic or likely pathogenic (P/LP) variants in the 11 BC predisposition genes (listed above). The standardized incidence ratio (SIR) for BC was 6.7 (95% CI, 5.0-8.9) for survivors relative to the SEER population. The SIR varied from 3.7 (95% CI, 1.4-8.1) for survivors with PRS in the 1st quintile to 3.6 (95% CI, 1.2-8.3), 7.3 (95% CI, 3.8-12.7), 7.6 (95% CI, 3.6-14.0), and 11.4 (95% CI, 6.8-18.1) in the 2nd, 3rd, 4th, and 5th quintiles, respectively. In the multivariable model adjusting for age at diagnosis, chest irradiation, alkylating agents, anthracyclines, attained age, and significant genotype eigenvectors, the relative rates (RR) of BC were 16.5 (95% CI, 6.4 - 42.6), 11.5 (95% CI, 4.4-29.9), and 47.8 (95% CI, 8.2-278.3) for carriers vs. non-carriers of the P/LP variants among all survivors, and survivors with and without chest irradiation, respectively. The RR per one standard deviation of PRS were 1.5 (95% CI, 1.1-1.9), 1.6 (95% CI, 1.2-2.0) and 1.3 (95% CI, 0.7-2.2), respectively, for the same three groups. Importantly, PRS was significantly associated with the rate of subsequent BC under the age of 45 (RR, 1.7; 95% CI, 1.3-2.2) but not over 45 (RR, 0.9; 95% CI, 0.6-1.5). To our knowledge, this is the first assessment of the joint effects of rare and common genetic variations implicated in the etiology of BC in the general population, among long-term survivors of childhood cancer. Clinically, we anticipate that an individual genetic profile utilizing common susceptibility loci in combination with rare P/LP variants will inform an improved strategy for personalized BC risk stratification and management for childhood cancer survivors. Further replication studies are warranted to confirm and refine our findings. Citation Format: Zhaoming Wang, Carmen L. Wilson, Qi Liu, John Easton, Heather L. Mulder, Michael Rusch, Michael Edmonson, Shawn Levy, Aman Patel, Ying Shao, Ti-Cheng Chang, Stephen V. Rice, Yadav Sapkota, Russell J. Brooke, Wonjong Moon, Evadnie Rampersaud, Xiaotu Ma, Cynthia Pepper, Xin Zhou, Xiang Chen, Wenan Chen, Angela Jones, Braden Boone, Matthew J. Ehrhardt, Rebecca M. Howell, Nicholas Phillips, Courtney Lewis, Chimene A. Kesserwan, Gang Wu, Kim E. Nichols, James R. Downing, Melissa M. Hudson, Jinghui Zhang, Yutaka Yasui, Leslie L. Robison. Monogenic and polygenic associations with subsequent breast cancer risk in survivors of childhood cancer: The St. Jude Lifetime Cohort Study (SJLIFE) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3007.
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 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| 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 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 ».