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

Published on Apr 7, 2021in Radiotherapy and Oncology4.856
· DOI :10.1016/J.RADONC.2021.03.024
Nicola Rares Franco1
Estimated H-index: 1
(Ghent University Hospital),
Nicola Rares Franco (Ghent University Hospital)+ 40 AuthorsTiziana Rancati27
Estimated H-index: 27
Sources
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.
📖 Papers frequently viewed together
32 Citations
27 Citations
References22
Newest
#1Natalie Arnold (UHH: University of Hamburg)H-Index: 1
#1Natalie ArnoldH-Index: 9
Last. Wolfgang Koenig (TUM: Technische Universität München)H-Index: 32
view all 2 authors...
Improvement in risk prediction of atherosclerotic cardiovascular disease (ASCVD) using information on the genetic predisposition at an individual level might offer new possibilities for the successful management of such complex trait. Latest developments in genetic research with the conduction of genome-wide association studies have facilitated a broader utility of polygenic risk score (PRS) as a potent risk prognosticator, being strongly associated with future cardiovascular events. Although it...
2 CitationsSource
#1Michela Carlotta Massi (Polytechnic University of Milan)H-Index: 2
#2Francesca Gasperoni (Medical Research Council)
Last. Tiziana RancatiH-Index: 27
view all 46 authors...
Background: REQUITE (validating pREdictive models and biomarkers of radiotherapy toxicity to reduce side effects and improve QUalITy of lifE in cancer survivors) is an international prospective cohort study. The purpose of this project was to analyse a cohort of patients recruited into REQUITE using a deep learning algorithm to identify patient-specific features associated with the development of toxicity, and test the approach by attempting to validate previously published genetic risk factors....
2 CitationsSource
#1Sarah L. Kerns (URMC: University of Rochester Medical Center)H-Index: 27
#2Laura FachalH-Index: 24
Last. Catharine M L West (MAHSC: Manchester Academic Health Science Centre)H-Index: 77
view all 40 authors...
BACKGROUND: 10-20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies. METHODS: We conducted an individual patient data meta-analysis of six genome-wide association studies (n = 3,871) in men with European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequenc...
23 CitationsSource
: Polygenic risk scores (PRSs) have become the standard for quantifying genetic liability in the prediction of disease risks. PRSs are generally constructed as weighted sum scores of risk alleles using effect sizes from genome-wide association studies as their weights. The construction of PRSs is being improved with more appropriate selection of independent single-nucleotide polymorphisms (SNPs) and optimized estimation of their weights but is rarely reflected upon from a theoretical perspective...
19 CitationsSource
#1Petra Seibold (DKFZ: German Cancer Research Center)H-Index: 27
#2A Webb (University of Leicester)H-Index: 9
Last. William Li (The Queen's Medical Center)H-Index: 1
view all 128 authors...
Abstract Purpose REQUITE aimed to establish a resource for multi-national validation of models and biomarkers that predict risk of late toxicity following radiotherapy. The purpose of this article is to provide summary descriptive data. Methods An international, prospective cohort study recruited cancer patients in 26 hospitals in eight countries between April 2014 and March 2017. Target recruitment was 5300 patients. Eligible patients had breast, prostate or lung cancer and planned potentially ...
15 CitationsSource
#1Amit Khera (Harvard University)H-Index: 74
#2Mark Chaffin (Broad Institute)H-Index: 23
Last. Sekar KathiresanH-Index: 138
view all 11 authors...
A key public health need is to identify individuals at high risk for a given disease to enable enhanced screening or preventive therapies. Because most common diseases have a genetic component, one important approach is to stratify individuals based on inherited DNA variation1. Proposed clinical applications have largely focused on finding carriers of rare monogenic mutations at several-fold increased risk. Although most disease risk is polygenic in nature2–5, it has not yet been possible to use...
867 CitationsSource
#1Yvonka van Wijk (Maastricht University Medical Centre)H-Index: 4
#2Ben G. L. Vanneste (UM: Maastricht University)H-Index: 14
Last. Philippe Lambin (Maastricht University Medical Centre)H-Index: 111
view all 9 authors...
AbstractIntroduction: Previous studies revealed that dose escalated radiotherapy for prostate cancer patients leads to higher tumor control probabilities (TCP) but also to higher rectal toxicities. An isotoxic model was developed to maximize the given dose while controlling the toxicity level. This was applied to analyze the effect of an implantable rectum spacer (IRS) and extended with a genetic test of normal tissue radio-sensitivity. A virtual IRS (V-IRS) was tested using this method. We hypo...
5 CitationsSource
#1John Kang (URMC: University of Rochester Medical Center)H-Index: 7
#2Tiziana RancatiH-Index: 27
Last. Barry S. Rosenstein (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 35
view all 9 authors...
Due to the rapid increase in the availability of patient data, there is significant interest in precision medicine that could facilitate the development of a personalized treatment plan for each patient on an individual basis. Radiation oncology is particularly suited for predictive machine learning models due to the enormous amount of diagnostic data used as input and therapeutic data generated as output. An emerging field in precision radiation oncology that can take advantage of machine learn...
32 CitationsSource
#1María Correa-Rodríguez (UGR: University of Granada)H-Index: 11
#2Sebastien Viatte (MAHSC: Manchester Academic Health Science Centre)H-Index: 17
Last. Gisela Orozco (MAHSC: Manchester Academic Health Science Centre)H-Index: 31
view all 6 authors...
Osteoporosis individual susceptibility is determined by the interaction of multiple genetic variants and environmental factors. The aim of this study was to conduct SNP-SNP interaction analyses in candidate genes influencing heel quantitative ultrasound (QUS) parameter in early adulthood to identify novel insights into the mechanism of disease. The study population included 575 healthy subjects (mean age 20.41; SD 2.36). To assess bone mass QUS was performed to determine Broadband ultrasound att...
2 CitationsSource
#1Yvonka van WijkH-Index: 4
#2Ben G. L. Vanneste (UM: Maastricht University)H-Index: 14
Last. Philippe Lambin (UM: Maastricht University)H-Index: 111
view all 8 authors...
Abstract Introduction Previous studies have shown that the implantable rectum spacer (IRS) is not beneficial for all patients. A virtual IRS (V-IRS) was constructed to help identify the patients for whom it is cost-effective to implant an IRS, and its viability as a tool to tailor the decision of an IRS implantation to be beneficial for the specified patient was assessed. Please watch animation: ( https://www.youtube.com/watch?v=tDlagSXMKqw ) Materials and methods The V-IRS was tested on 16 pati...
10 CitationsSource
Cited By0
Newest