Development of a method for generating SNP interaction-aware polygenic risk scores for radiotherapy toxicity.

Rares Franco, Nicola, Carlotta Massi, Michela, Ieva, Francesca, Manzoni, Andrea, Maria Paganoni, Anna, Zunino, Paolo, Veldeman, Liv, Ost, Piet, Fonteyne, Valérie, Talbot, Christopher J, Rattay, Tim, Webb, Adam, Johnson, Kerstie, Lambrecht, Maarten, Haustermans, Karin, De Meerleer, Gert, de Ruysscher, Dirk, Vanneste, Ben, Van Limbergen, Evert, Choudhury, Ananya, Elliott, Rebecca M, Sperk, Elena, Veldwijk, Marlon, Herskind, Carsten, Avuzzi, Barbara, Noris Chiorda, Barbara, Valdagni, Riccardo, Azria, David, Farcy-Jacquet, Marie-Pierre, Brengues, Muriel, Rosenstein, Barry S, Stock, Richard G, Vega, Ana, Elías Aguado-Barrera, Miguel, Sosa-Fajardo, Paloma, Dunning, Alison M, Fachal, Laura, Kerns, Sarah L, Payne, Debbie, Chang-Claude, Jenny, Seibold, Petra, Ml West, Catharine and Rancati, Tiziana (2021) Development of a method for generating SNP interaction-aware polygenic risk scores for radiotherapy toxicity. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. ISSN 1879-0887. This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs

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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.

Item Type: Article
Additional Information: This article is available to all UHB staff and students via ASK Discovery tool http://tinyurl.com/z795c8c by using their UHB Athens login IDs
Subjects: QZ Pathology. Oncology
WC Communicabable diseases
WJ Urogenital system. Urology
WN Medical imaging. Radiology
Divisions: Clinical Support > Radiology
Related URLs:
Depositing User: Jamie Edgar
Date Deposited: 21 Apr 2021 10:43
Last Modified: 21 Apr 2021 10:43
URI: http://www.repository.uhblibrary.co.uk/id/eprint/4225

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