No Association Between Polygenic Risk Scores for Cancer and Development of Radiation Therapy Toxicity.
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Barnett Gillian C, Kerns Sarah L, Dorling Leila, Fachal Laura, Aguado-Barrera Miguel E, Martínez-Calvo Laura, Jandu Harkeran K, Welsh Ceilidh, Tyrer Jonathan, Coles Charlotte E, Haviland Joanne S, Parker Christopher, Gómez-Caamaño Antonio, Calvo-Crespo Patricia, Sosa-Fajardo Paloma, Burnet Neil G, Summersgill Holly, Webb Adam, De Ruysscher Dirk, Seibold Petra, Chang-Claude Jenny, Talbot Christopher J, Rattay Tim, Parliament Matthew, De Ruyck Kim, Rosenstein Barry S, Pharoah Paul D P, Dunning Alison M, Vega Ana, West Catharine M L, RGC and REQUITE Consortia
Аннотация
METHODS AND MATERIALS: Analyses included 9,717 patients with breast (n=3,078), prostate (n=5,748) or lung (n=891) cancer from Radiogenomics and REQUITE Consortia cohorts. Patients underwent potentially curative radiation therapy and were assessed prospectively for toxicity. Germline genotyping involved genome-wide single nucleotide polymorphism (SNP) arrays with nontyped SNPs imputed. PRS for each cancer were generated by summing literature-identified cancer susceptibility risk alleles: 352 breast, 136 prostate, and 24 lung. Weighted PRS were generated using log odds ratio (ORs) for cancer susceptibility. Standardized total average toxicity (STAT) scores at 2 and 5 years (breast, prostate) or 6 to 12 months (lung) quantified toxicity. Primary analysis tested late STAT, secondary analyses investigated acute STAT, and individual endpoints and SNPs using multivariable regression.
RESULTS: Increasing PRS did not increase risk of late toxicity in patients with breast (OR, 1.000; 95% confidence interval [CI], 0.997-1.002), prostate (OR, 0.99; 95% CI, 0.98-1.00; weighted PRS OR, 0.93; 95% CI, 0.83-1.03), or lung (OR, 0.93; 95% CI, 0.87-1.00; weighted PRS OR, 0.68; 95% CI, 0.45-1.03) cancer. Similar results were seen for acute toxicity. Secondary analyses identified rs138944387 associated with breast pain (OR, 3.05; 95% CI, 1.86-5.01; P = 1.09 × 10-5) and rs17513613 with breast edema (OR, 0.94; 95% CI, 0.92-0.97; P = 1.08 × 10-5).
CONCLUSIONS: Patients with increased polygenic predisposition to breast, prostate, or lung cancer can safely undergo radiation therapy with no anticipated excess toxicity risk. Some individual SNPs increase the likelihood of a specific toxicity endpoint, warranting validation in independent cohorts and functional studies to elucidate biologic mechanisms.