Development of a method for generating SNP interaction-aware polygenic risk scores for radiotherapy toxicity
AuthorsFranco, N. R.
Massi, M. C.
Paganoni, A. M.
Talbot, C. J.
De Meerleer, G.
De Ruysscher, D
Van Limbergen, E.
Elliott, Rebecca M
Veldwijk, M. R.
Noris Chiorda, B.
Farcy-Jacquet, M. P.
Rosenstein, B. S.
Stock, R. G.
Aguado-Barrera, M. E.
Dunning, A. M.
Kerns, S. L.
West, Catharine M L
AffiliationMOX, Department of Mathematics, Politecnico di Milano, Italy.
MetadataShow full item record
AbstractAim: 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.
CitationFranco NR, Massi MC, Ieva F, Manzoni A, Paganoni AM, Zunino P, et al. Development of a method for generating SNP interaction-aware polygenic risk scores for radiotherapy toxicity. Radiotherapy and Oncology. 2021 Jun;159:241–8.
JournalRadiotherapy and Oncology
- A Deep Learning Approach Validates Genetic Risk Factors for Late Toxicity After Prostate Cancer Radiotherapy in a REQUITE Multi-National Cohort.
- Authors: Massi MC, Gasperoni F, Ieva F, Paganoni AM, Zunino P, Manzoni A, Franco NR, Veldeman L, Ost P, Fonteyne V, Talbot CJ, Rattay T, Webb A, Symonds PR, Johnson K, Lambrecht M, Haustermans K, De Meerleer G, de Ruysscher D, Vanneste B, Van Limbergen E, Choudhury A, Elliott RM, Sperk E, Herskind C, Veldwijk MR, Avuzzi B, Giandini T, Valdagni R, Cicchetti A, Azria D, Jacquet MF, Rosenstein BS, Stock RG, Collado K, Vega A, Aguado-Barrera ME, Calvo P, Dunning AM, Fachal L, Kerns SL, Payne D, Chang-Claude J, Seibold P, West CML, Rancati T
- Issue date: 2020
- Multivariate normal tissue complication probability modeling of gastrointestinal toxicity after external beam radiotherapy for localized prostate cancer.
- Authors: Cella L, D'Avino V, Liuzzi R, Conson M, Doria F, Faiella A, Loffredo F, Salvatore M, Pacelli R
- Issue date: 2013 Sep 23
- Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer.
- Authors: Kerns SL, Dorling L, Fachal L, Bentzen S, Pharoah PD, Barnes DR, Gómez-Caamaño A, Carballo AM, Dearnaley DP, Peleteiro P, Gulliford SL, Hall E, Michailidou K, Carracedo Á, Sia M, Stock R, Stone NN, Sydes MR, Tyrer JP, Ahmed S, Parliament M, Ostrer H, Rosenstein BS, Vega A, Burnet NG, Dunning AM, Barnett GC, West CM, Radiogenomics Consortium
- Issue date: 2016 Aug
- Integrated models for the prediction of late genitourinary complaints after high-dose intensity modulated radiotherapy for prostate cancer: making informed decisions.
- Authors: De Langhe S, De Meerleer G, De Ruyck K, Ost P, Fonteyne V, De Neve W, Thierens H
- Issue date: 2014 Jul
- Individual patient data meta-analysis shows a significant association between the ATM rs1801516 SNP and toxicity after radiotherapy in 5456 breast and prostate cancer patients.
- Authors: Andreassen CN, Rosenstein BS, Kerns SL, Ostrer H, De Ruysscher D, Cesaretti JA, Barnett GC, Dunning AM, Dorling L, West CML, Burnet NG, Elliott R, Coles C, Hall E, Fachal L, Vega A, Gómez-Caamaño A, Talbot CJ, Symonds RP, De Ruyck K, Thierens H, Ost P, Chang-Claude J, Seibold P, Popanda O, Overgaard M, Dearnaley D, Sydes MR, Azria D, Koch CA, Parliament M, Blackshaw M, Sia M, Fuentes-Raspall MJ, Ramon Y Cajal T, Barnadas A, Vesprini D, Gutiérrez-Enríquez S, Mollà M, Díez O, Yarnold JR, Overgaard J, Bentzen SM, Alsner J, International Radiogenomics Consortium (RgC)
- Issue date: 2016 Dec