Abstract 5092: Variants at 6q21 implicate PRDM1 in the etiology of therapy-induced second malignancies after Hodgkin's lymphoma
Bibliographic record
Abstract
Abstract Survivors of Hodgkin's lymphoma (HL) are at increased risk for second malignant neoplasms (SMNs) induced by exposure to radiation therapy (RT). Although SMNs are a leading cause of death in survivors of HL, it is not possible to identify those patients at greatest risk. We performed a genome-wide association study (GWAS) of 99 HL survivors who developed SMNs and 86 who did not, all of whom were treated for HL with RT. We then tested three SNPs in a replication set of 120 RT-treated HL patients with SMNs and 112 without SMNs. The functional effects of risk-associated variants on gene expression were assessed in lymphoblastoid cell lines before and after exposure to radiation. Two variants at 6q21 between PRDM1 and ATG5 were associated with SMNs in younger but not older HL patients treated with RT [rs4946728: P = 1.26×10-9, and rs1040411: P = 4.68×10-8]; individuals homozygous for the rs4946728 risk allele comprise 50% of the general population and were found to be at an eleven-fold increased risk for SMNs as compared to those homozygous for the protective allele. The risk variants comprise a haplotype that was associated with decreased PRDM1 expression (p=0.03) and protein levels. Furthermore, the risk variants were associated with a marked attenuation in the induction of PRDM1 following radiation exposure (p=0.002). Thus, we identified a new risk locus for SMNs following radiation treatment for HL at 6q21. This locus is associated with both basal and radiation-induced expression of PRDM1. These findings demonstrate a novel gene-exposure interaction associated with radiation-induced carcinogenesis and suggest that patients homozygous for the risk variants may benefit from early cancer screening. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5092. doi:10.1158/1538-7445.AM2011-5092
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.015 | 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 teacher head, 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".