@article{8758729,
  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. (C) 2021 The Authors. Published by Elsevier B.V.}},
  author       = {{Franco, Nicola Rares and Massi, Michela Carlotta and Ieva, Francesca and Manzoni, Andrea and Paganoni, Anna Maria and Zunino, Paolo and Veldeman, Liv and Ost, Piet and Fonteyne, Valerie and Talbot, Christopher J. and Rattay, Tim and Webb, Adam and Johnson, Kerstie and Lambrecht, Maarten and Haustermans, Karin and De Meerleer, Gert and de Ruysscher, Dirk and Vanneste, Ben and Van Limbergen, Evert and Choudhury, Ananya and Elliott, Rebecca M. and Sperk, Elena and Veldwijk, Marlon R. and Herskind, Carsten and Avuzzi, Barbara and Noris Chiorda, Barbara and Valdagni, Riccardo and Azria, David and Farcy-Jacquet, Marie-Pierre and Brengues, Muriel and Rosenstein, Barry S. and Stock, Richard G. and Vega, Ana and Aguado-Barrera, Miguel E. and Sosa-Fajardo, Paloma and Dunning, Alison M. and Fachal, Laura and Kerns, Sarah L. and Payne, Debbie and Chang-Claude, Jenny and Seibold, Petra and West, Catharine M.L. and Rancati, Tiziana and Lievens, Yolande and Van Eijkeren, Marc and Monten, Christel and De Neve, Wilfried and Peeters, Stephanie and Weltens, Caroline and Defraene, Gilles and van Limberghen, Erik and Briers, Erik and Bourgier, Celine and Draghici, Roxana and Bons, Francoise and Blaschke, Thomas and Weiß, Christian and Helmbold, Irmgard and Weißenberger, Christian and Stegmaier, Petra and Claßen, Johannes and Giesche, Ulrich and Sautter-Bihl, Marie-Luise and Neu, Burkhard and Schnabel, Thomas and Ehmann, Michael and Gauter-Fleckenstein, Benjamin and Schäfer, Jörg and Giandini, Tommaso and Franceschini, Marzia and Sangalli, Claudia and Morlino, Sara and Lozza, Laura and De Santis, Maria C. and Pietro, Gabriele and Delmastro, Elena and Garibaldi, Elisabetta and Cicchetti, Alessandro and Piqué-Leiva, Bibiana and Molla, Meritxel and Giraldo, Alexandra and Ramos, Monica and Lobato-Busto, Ramon and Torrado Moya, Laura and Dominguez-Rios, Isabel and Fajardo-Paneque, Irene and Calvo-Crespo, Patricia and Carballo, Ana and Peleteiro, Paula and Olivia-Fuentes-Rios, [missing] and Gomez-Caamano, Antonio and Harrop, Victoria and Payne, Debbie and Keni, Manjusha and Symonds, Paul R. and Lavers, Samuel and Wright, Simon and Thiagarajan, Sridhar and Aznar-Garcia, Luis and Kancherla, Kiran and Kent, Christopher and Vasanthan, Subramaniam and Appleton, Donna and Kaushik, Monika and Kenny, Frances and Khout, Hazem and Krupa, Jaroslaw and Lambert, Kelly V. and Pilgrim, Simon and Shokuhi, Sheila and Valassiadou, Kalliope and Bioangiu, Ion and Sampson, Kufre and Osman, Ahmed and Faivre-Finn, Corinne and Foweraker, Karen and Pascoe, Abigail and Esler, Claire P. and Ward, Tim and Higginson, Daniel S. and Green, Sheryl and Consortium, REQUITE}},
  issn         = {{0167-8140}},
  journal      = {{RADIOTHERAPY AND ONCOLOGY}},
  keywords     = {{Radiology,Nuclear Medicine and imaging,Oncology,Hematology,Prostate cancer,Radiotherapy,Late toxicity,Genetic risk factors,SNPs,Epistasis,EPISTASIS,REQUITE}},
  language     = {{eng}},
  pages        = {{241--248}},
  title        = {{Development of a method for generating SNP interaction-aware polygenic risk scores for radiotherapy toxicity}},
  url          = {{http://doi.org/10.1016/j.radonc.2021.03.024}},
  volume       = {{159}},
  year         = {{2021}},
}

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