Abstract 3007: Monogenic and polygenic associations with subsequent breast cancer risk in survivors of childhood cancer: The St. Jude Lifetime Cohort Study (SJLIFE)
Bibliographic record
Abstract
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.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".