Journal Article

DKFZ-2021-00835

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Development of a method for generating SNP interaction-aware polygenic risk scores for radiotherapy toxicity.

Rares Franco, N. ; Carlotta Massi, M. ; Ieva, F. ; Manzoni, A. ; Maria Paganoni, A. ; Zunino, P. ; Veldeman, L. ; Ost, P. ; Fonteyne, V. ; Talbot, C. J. ; Rattay, T. ; Webb, A. ; Johnson, K. ; Lambrecht, M. ; Haustermans, K. ; De Meerleer, G. ; de Ruysscher, D. ; Vanneste, B. ; Van Limbergen, E. ; Choudhury, A. ; Elliott, R. M. ; Sperk, E. ; Veldwijk, M. ; Herskind, C. ; Avuzzi, B. ; Noris Chiorda, B. ; Valdagni, R. ; Azria, D. ; Farcy-Jacquet, M.-P. ; Brengues, M. ; Rosenstein, B. S. ; Stock, R. G. ; Vega, A. ; Elías Aguado-Barrera, M. ; Sosa-Fajardo, P. ; Dunning, A. M. ; Fachal, L. ; Kerns, S. L. ; Payne, D. ; Chang-Claude, J.DKFZ* ; Seibold, P.DKFZ* ; Ml West, C. ; Rancati, T. ; Consortium, R. (Collaboration Author) ; Lievens, Y. ; van Eijkeren, M. ; Monten, C. ; De Neve, W. ; Peeters, S. ; Weltens, C. ; Defraene, G. ; van Limberghen, E. ; Briers, E. ; Bourgier, C. ; Draghici, R. ; Bons, F. ; Blaschke, T. ; Weiß, C. ; Helmbold, I. ; Weißenberger, C. ; Stegmaier, P. ; Claßen, J. ; Giesche, U. ; Sautter-Bihl, M.-L. ; Neu, B. ; Schnabel, T. ; Ehmann, M. ; Gauter-Fleckenstein, B. ; Schäfer, J. ; Giandini, T. ; Franceschini, M. ; Sangalli, C. ; Morlino, S. ; Lozza, L. ; De Santis, M. C. ; Pietro, G. ; Delmastro, E. ; Garibaldi, E. ; Cicchetti, A. ; Piqué-Leiva, B. ; Molla, M. ; Giraldo, A. ; Ramos, M. ; Lobato-Busto, R. ; Torrado Moya, L. ; Dominguez-Rios, I. ; Fajardo-Paneque, I. ; Calvo-Crespo, P. ; Carballo, A. ; Peleteiro, P. ; Olivia-Fuentes-Rios ; Gomez-Caamano, A. ; Harrop, V. ; Payne, D. ; Keni, M. ; Symonds, P. R. ; Lavers, S. ; Wright, S. ; Thiagarajan, S. ; Aznar-Garcia, L. ; Kancherla, K. ; Kent, C. ; Vasanthan, S. ; Appleton, D. ; Kaushik, M. ; Kenny, F. ; Khout, H. ; Krupa, J. ; Lambert, K. V. ; Pilgrim, S. ; Shokuhi, S. ; Valassiadou, K. ; Bioangiu, I. ; Sampson, K. ; Osman, A. ; Faivre-Finn, C. ; Foweraker, K. ; Pascoe, A. ; Esler, C. P. ; Ward, T. ; Higginson, D. S. ; Green, S.

2021
Elsevier Science Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.radonc.2021.03.024

Abstract: 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).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).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.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.

Keyword(s): SNPs ; epistasis ; genetic risk factors ; late toxicity ; prostate cancer ; radiotherapy

Note: 2021 Apr 8;159:241-248

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Contributing Institute(s):

1. C020 Epidemiologie von Krebs (C020)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2021

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Ebsco Academic Search ; Essential Science Indicators ; IF < 5 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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