Development of a method for generating SNP interaction-aware polygenic risk scores for radiotherapy toxicity
Nicola Rares Franco, Michela Carlotta Massi, Francesca Ieva, Andrea Manzoni, Anna Maria Paganoni, Paolo Zunino, Liv Veldeman, Piet Ost, Valérie Fonteyne, Chris J. Talbot, Tim Rattay, Adam Webb, Kerstie Johnson, Maarten Lambrecht, Karin Haustermans, Gert De Meerleer, Dirk De Ruysscher, Ben Vanneste, Evert van Limbergen, Ananya Choudhury, Rebecca Elliott, Elena Sperk, Marlon R. Veldwijk, Carsten Herskind, B. Avuzzi, B. Noris Chiorda, R. Valdagni, D. Azria, Marie‐Pierre Farcy‐Jacquet, Muriel Brengues, Barry S. Rosenstein, Richard G. Stock, Ana Vega, Miguel E. Aguado‐Barrera, Paloma Sosa‐Fajardo, Alison M. Dunning, Laura Fachal, Sarah L. Kerns, Debbie Payne, Jenny Chang‐Claude, Petra Seibold, Catharine West, T. Rancati, Tiziana Rancati, Yolande Lievens, Marc van Eijkeren, Christel Monten, Wilfried De Neve, Stephanie Peeters, Caroline Weltens, Gilles Defraene, Erik van Limberghen, Erik Briers, Celine Bourgier, Roxana Draghici, Francoise Bons, Thomas Blaschke, Christian Weiß, Irmgard Helmbold, Christian Weißenberger, Petra Stegmaier, Johannes Claßen, Ulrich Giesche, Marie-Luise Sautter-Bihl, Burkhard Neu, Thomas Schnabel, Michael Ehmann, Benjamin Gauter-Fleckenstein, Jörg Schäfer, Tommaso Giandini, Marzia Franceschini, Claudia Sangalli, Sara Morlino, Laura Lozza, Maria C. De Santis, Gabriele Pietro, Elena Delmastro, Elisabetta Garibaldi, Alessandro Cicchetti, Bibiana Piqué-Leiva, Meritxel Molla, Alexandra Giraldo, Monica Ramos, Ramon Lobato-Busto, Laura Torrado Moya, Isabel Dominguez-Rios, Irene Fajardo-Paneque, Patricia Calvo-Crespo, Ana Carballo, Paula Peleteiro, Olivia-Fuentes-Rios, Antonio Gomez-Caamano, Victoria Harrop, Debbie Payne, Debbie Payne, Manjusha Keni, Paul R. Symonds, Samuel Lavers, Simon Wright, Sridhar Thiagarajan
Abstract
AIM: To identify the effect of single nucleotide polymorphism (SNP) interactions on the risk of toxicity following radiotherapy (RT) for prostate cancer (PCa) and propose a new method for polygenic risk score incorporating SNP-SNP interactions (PRSi). MATERIALS AND METHODS: Analysis included the REQUITE PCa cohort that received external beam RT and was followed for 2 years. Late toxicity endpoints were: rectal bleeding, urinary frequency, haematuria, nocturia, decreased urinary stream. Among 43 literature-identified SNPs, the 30% most strongly associated with each toxicity were tested. SNP-SNP combinations (named SNP-allele sets) seen in ≥10% of the cohort were condensed into risk (RS) and protection (PS) scores, respectively indicating increased or decreased toxicity risk. Performance of RS and PS was evaluated by logistic regression. RS and PS were then combined into a single PRSi evaluated by area under the receiver operating characteristic curve (AUC). RESULTS: Among 1,387 analysed patients, toxicity rates were 11.7% (rectal bleeding), 4.0% (urinary frequency), 5.5% (haematuria), 7.8% (nocturia) and 17.1% (decreased urinary stream). RS and PS combined 8 to 15 different SNP-allele sets, depending on the toxicity endpoint. Distributions of PRSi differed significantly in patients with/without toxicity with AUCs ranging from 0.61 to 0.78. PRSi was better than the classical summed PRS, particularly for the urinary frequency, haematuria and decreased urinary stream endpoints. CONCLUSIONS: Our method incorporates SNP-SNP interactions when calculating PRS for radiotherapy toxicity. Our approach is better than classical summation in discriminating patients with toxicity and should enable incorporating genetic information to improve normal tissue complication probability models.