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.

Development of a method for generating SNP interaction-aware polygenic risk scores for radiotherapy toxicity / N.R. Franco, M.C. Massi, F. Ieva, A. Manzoni, A.M. Paganoni, P. Zunino, L. Veldeman, P. Ost, V. Fonteyne, C.J. Talbot, T. Rattay, A. Webb, K. Johnson, M. Lambrecht, K. Haustermans, G. De Meerleer, D. de Ruysscher, B. Vanneste, E. Van Limbergen, A. Choudhury, R.M. Elliott, E. Sperk, M.R. Veldwijk, C. Herskind, B. Avuzzi, B. Noris Chiorda, R. Valdagni, D. Azria, M.-. Farcy-Jacquet, M. Brengues, B.S. Rosenstein, R.G. Stock, A. Vega, M.E. Aguado-Barrera, P. Sosa-Fajardo, A.M. Dunning, L. Fachal, S.L. Kerns, D. Payne, J. Chang-Claude, P. Seibold, C.M.L. West, T. Rancati. - In: RADIOTHERAPY AND ONCOLOGY. - ISSN 0167-8140. - 159(2021 Jun), pp. 241-248. [10.1016/j.radonc.2021.03.024]

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

F. Ieva;A. Manzoni;B. Avuzzi;R. Valdagni;T. Rancati
2021

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.
Epistasis; Genetic risk factors; Late toxicity; Prostate cancer; Radiotherapy; SNPs; Area Under Curve; Humans; Male; Polymorphism, Single Nucleotide; Risk Factors; Prostatic Neoplasms; Radiation Injuries
Settore MED/36 - Diagnostica per Immagini e Radioterapia
Article (author)
File in questo prodotto:
File Dimensione Formato  
PMID 33838170.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 1.5 MB
Formato Adobe PDF
1.5 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/877830
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus 1
  • ???jsp.display-item.citation.isi??? 1
social impact