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

Authors
  • Franco, Nicola Rares1
  • Massi, Michela Carlotta2
  • Ieva, Francesca3
  • Manzoni, Andrea4
  • Paganoni, Anna Maria5
  • Zunino, Paolo6
  • Veldeman, Liv7
  • Ost, Piet8
  • Fonteyne, Valérie9
  • Talbot, Christopher J10
  • Rattay, Tim11
  • Webb, Adam12
  • Johnson, Kerstie13
  • Lambrecht, Maarten14
  • Haustermans, Karin15
  • De Meerleer, Gert16
  • de Ruysscher, Dirk17
  • Vanneste, Ben18
  • Van Limbergen, Evert19
  • Choudhury, Ananya20
    • And 23 more
  • 1 MOX, Department of Mathematics, Politecnico di Milano, Italy. Electronic address: [email protected]. , (Italy)
  • 2 MOX, Department of Mathematics, Politecnico di Milano, Italy; CADS-Center for Analysis, Decisions and Society, Human Technopole, Milan, Italy. Electronic address: [email protected]. , (Italy)
  • 3 MOX, Department of Mathematics, Politecnico di Milano, Italy; CADS-Center for Analysis, Decisions and Society, Human Technopole, Milan, Italy; CHRP-National Center for Healthcare Research and Pharmacoepidemiology, University of Milano-Bicocca, Milan, Italy. Electronic address: [email protected]. , (France)
  • 4 MOX, Department of Mathematics, Politecnico di Milano, Italy. Electronic address: [email protected]. , (Italy)
  • 5 MOX, Department of Mathematics, Politecnico di Milano, Italy; CADS-Center for Analysis, Decisions and Society, Human Technopole, Milan, Italy; CHRP-National Center for Healthcare Research and Pharmacoepidemiology, University of Milano-Bicocca, Milan, Italy. Electronic address: [email protected]. , (Italy)
  • 6 MOX, Department of Mathematics, Politecnico di Milano, Italy. Electronic address: [email protected]. , (Italy)
  • 7 Department of Human Structure and Repair, Ghent University, Belgium; Department of Radiation Oncology, Ghent University Hospital, Belgium. Electronic address: [email protected]. , (Belgium)
  • 8 Department of Human Structure and Repair, Ghent University, Belgium; Department of Radiation Oncology, Ghent University Hospital, Belgium. Electronic address: [email protected]. , (Belgium)
  • 9 Department of Human Structure and Repair, Ghent University, Belgium; Department of Radiation Oncology, Ghent University Hospital, Belgium. Electronic address: [email protected]. , (Belgium)
  • 10 Leicester Cancer Research Centre, Department of Genetics and Genome Biology, University of Leicester, United Kingdom. Electronic address: [email protected]. , (United Kingdom)
  • 11 Leicester Cancer Research Centre, Department of Genetics and Genome Biology, University of Leicester, United Kingdom. Electronic address: [email protected]. , (United Kingdom)
  • 12 Leicester Cancer Research Centre, Department of Genetics and Genome Biology, University of Leicester, United Kingdom. Electronic address: [email protected]. , (United Kingdom)
  • 13 Leicester Cancer Research Centre, Department of Genetics and Genome Biology, University of Leicester, United Kingdom. Electronic address: [email protected]. , (United Kingdom)
  • 14 Department of Radiation Oncology, University Hospitals Leuven, Belgium. Electronic address: [email protected]. , (Belgium)
  • 15 Department of Radiation Oncology, University Hospitals Leuven, Belgium. Electronic address: [email protected]. , (Belgium)
  • 16 Department of Radiation Oncology, University Hospitals Leuven, Belgium. Electronic address: [email protected]. , (Belgium)
  • 17 Maastricht University Medical Center, the Netherlands; Department of Radiation Oncology (Maastro), GROW Institute for Oncology and Developmental Biology, Maastricht, the Netherlands. Electronic address: [email protected]. , (Netherlands)
  • 18 Department of Radiation Oncology (Maastro), GROW Institute for Oncology and Developmental Biology, Maastricht, the Netherlands. Electronic address: [email protected]. , (Netherlands)
  • 19 Maastricht University Medical Center, the Netherlands; Department of Radiation Oncology (Maastro), GROW Institute for Oncology and Developmental Biology, Maastricht, the Netherlands. Electronic address: [email protected]. , (Netherlands)
  • 20 Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, UK. Electronic address: [email protected].
  • 21 Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, UK. Electronic address: [email protected].
  • 22 Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Germany. Electronic address: [email protected]. , (Germany)
  • 23 Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Germany. Electronic address: [email protected]. , (Germany)
  • 24 Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Germany. Electronic address: [email protected]. , (Germany)
  • 25 Department of Radiation Oncology 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: [email protected]. , (Italy)
  • 26 Department of Radiation Oncology 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: [email protected]. , (Italy)
  • 27 Department of Radiation Oncology 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Oncology and Haemato-Oncology, Università degli Studi di Milano, Milan, Italy; Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: [email protected]. , (Italy)
  • 28 Department of Radiation Oncology, University Federation of Radiation Oncology, Montpellier Cancer Institute, Univ Montpellier MUSE, France. Electronic address: [email protected]. , (France)
  • 29 Department of Radiation Oncology, University Federation of Radiation Oncology, Institut de Cancérologie du Gard, Nimes, France. Electronic address: [email protected]. , (France)
  • 30 Department of Radiation Oncology, University Federation of Radiation Oncology, Montpellier Cancer Institute, Univ Montpellier MUSE, France. Electronic address: [email protected]. , (France)
  • 31 Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, USA. Electronic address: [email protected].
  • 32 Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, USA. Electronic address: [email protected].
  • 33 Grupo de Medicina Xenómica (USC), Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain; Instituto de Investigación Sanitaria de Santiago de Compostela, Spain; Biomedical Network on Rare Diseases (CIBERER), Spain. Electronic address: [email protected]. , (Spain)
  • 34 Grupo de Medicina Xenómica (USC), Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain; Instituto de Investigación Sanitaria de Santiago de Compostela, Spain. Electronic address: [email protected]. , (Spain)
  • 35 Grupo de Medicina Xenómica (USC), Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain; Instituto de Investigación Sanitaria de Santiago de Compostela, Spain; Department of Radiation Oncology, Complexo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain. Electronic address: [email protected]. , (Spain)
  • 36 Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Labs, UK. Electronic address: [email protected].
  • 37 Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Strangeways Research Labs, UK; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK. Electronic address: [email protected].
  • 38 Departments of Radiation Oncology and Surgery, University of Rochester Medical Center, Rochester, USA. Electronic address: [email protected].
  • 39 Centre for Integrated Genomic Medical Research (CIGMR), University of Manchester, UK. Electronic address: [email protected].
  • 40 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Germany. Electronic address: [email protected]. , (Germany)
  • 41 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: [email protected]. , (Germany)
  • 42 Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, UK. Electronic address: [email protected].
  • 43 Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: [email protected]. , (Italy)
Type
Published Article
Journal
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology
Publication Date
Jun 01, 2021
Volume
159
Pages
241–248
Identifiers
DOI: 10.1016/j.radonc.2021.03.024
PMID: 33838170
Source
Medline
Keywords
Language
English
License
Unknown

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. Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. This record was last updated on 01/24/2022 and may not reflect the most current and accurate biomedical/scientific data available from NLM. The corresponding record at NLM can be accessed at https://www.ncbi.nlm.nih.gov/pubmed/33838170
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