No Association Between Polygenic Risk Scores for Cancer and Development of Radiation Therapy Toxicity

Gillian C. Barnett; Sarah L. Kerns; RGC and REQUITE Consortia; Leila Dorling; Laura Fachal; Miguel E. Aguado-Barrera; Laura Martínez-Calvo; Harkeran K. Jandu; Ceilidh Welsh; Jonathan Tyrer; Charlotte E. Coles; Joanne S. Haviland; Christopher Parker; Antonio Gómez-Caamaño; Patricia Calvo-Crespo; Paloma Sosa-Fajardo; Neil G. Burnet; Holly Summersgill; Adam Webb; Dirk De Ruysscher; Petra Seibold; Jenny Chang-Claude; Christopher J. Talbot; Tim Rattay; Matthew Parliament; Kim De Ruyck; Barry S. Rosenstein; Paul D.P. Pharoah; Alison M. Dunning; Ana Vega; Catharine M.L. West

doi:10.1016/j.ijrobp.2022.06.098

No Association Between Polygenic Risk Scores for Cancer and Development of Radiation Therapy Toxicity

Gillian C. Barnett^*, Sarah L. Kerns, RGC and REQUITE Consortia, Leila Dorling, Laura Fachal, Miguel E. Aguado-Barrera, Laura Martínez-Calvo, Harkeran K. Jandu, Ceilidh Welsh, Jonathan Tyrer, Charlotte E. Coles, Joanne S. Haviland, Christopher Parker, Antonio Gómez-Caamaño, Patricia Calvo-Crespo, Paloma Sosa-Fajardo, Neil G. Burnet, Holly Summersgill, Adam Webb, Dirk De RuysscherPetra Seibold, Jenny Chang-Claude, Christopher J. Talbot, Tim Rattay, Matthew Parliament, Kim De Ruyck, Barry S. Rosenstein, Paul D.P. Pharoah, Alison M. Dunning, Ana Vega, Catharine M.L. West

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

3 Citations (Scopus)

9 Downloads (Pure)

Abstract

Purpose: Our aim was to test whether updated polygenic risk scores (PRS) for susceptibility to cancer affect risk of radiation therapy toxicity. Methods and Materials: Analyses included 9,717 patients with breast (n=3,078), prostate (n=5,748) or lung (n=891) cancer from Radiogenomics and REQUITE Consortia cohorts. Patients underwent potentially curative radiation therapy and were assessed prospectively for toxicity. Germline genotyping involved genome-wide single nucleotide polymorphism (SNP) arrays with nontyped SNPs imputed. PRS for each cancer were generated by summing literature-identified cancer susceptibility risk alleles: 352 breast, 136 prostate, and 24 lung. Weighted PRS were generated using log odds ratio (ORs) for cancer susceptibility. Standardized total average toxicity (STAT) scores at 2 and 5 years (breast, prostate) or 6 to 12 months (lung) quantified toxicity. Primary analysis tested late STAT, secondary analyses investigated acute STAT, and individual endpoints and SNPs using multivariable regression. Results: Increasing PRS did not increase risk of late toxicity in patients with breast (OR, 1.000; 95% confidence interval [CI], 0.997-1.002), prostate (OR, 0.99; 95% CI, 0.98-1.00; weighted PRS OR, 0.93; 95% CI, 0.83-1.03), or lung (OR, 0.93; 95% CI, 0.87-1.00; weighted PRS OR, 0.68; 95% CI, 0.45-1.03) cancer. Similar results were seen for acute toxicity. Secondary analyses identified rs138944387 associated with breast pain (OR, 3.05; 95% CI, 1.86-5.01; P = 1.09 × 10^–5) and rs17513613 with breast edema (OR, 0.94; 95% CI, 0.92-0.97; P = 1.08 × 10^–5). Conclusions: Patients with increased polygenic predisposition to breast, prostate, or lung cancer can safely undergo radiation therapy with no anticipated excess toxicity risk. Some individual SNPs increase the likelihood of a specific toxicity endpoint, warranting validation in independent cohorts and functional studies to elucidate biologic mechanisms.

Original language	English
Pages (from-to)	494-501
Number of pages	8
Journal	International Journal of Radiation Oncology Biology Physics
Volume	114
Issue number	3
DOIs	https://doi.org/10.1016/j.ijrobp.2022.06.098
Publication status	Published - 1 Nov 2022
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by Cancer Research UK RadNet Cambridge (C17918/A28870) and Cancer Research UK Manchester Major Centre (C147/A25254). This project was funded in part by the National Cancer Institute, National Institutes of Health K07 CA187546 (principal investigator: S.L.K), supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds (INT15/00070, INT16/00154, INT17/00133, INT20/00071; PI19/01424; PI16/00046; PI13/02030; PI10/00164), and through the Autonomous Government of Galicia (consolidation and structuring program: IN607B) (principal investigator: A.V.). RADIOGEN genotyping was carried out at CEGEN-PRB3-ISCIII; it is supported by grant PT17/0019, of the PE I+D+i 2013-2016, funded by ISCIII and ERDF. The REQUITE (principal investigator: C.M.L.W.) study received funding from the European Union's seventh Framework Programme for research, technological development, and demonstration under grant agreement No. 601826. L.F. was supported by the European Union's Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement No. 656144. T.R. is a National Institute of Health Research (NIHR) Academic Clinical Lecturer (CL 2017-11-002). He was previously funded by a NIHR Doctoral Research Fellowship (DRF 2014-07-079). This publication presents independent research funded by NIHR. The views expressed are those of the authors and not necessarily those of NHS, NIHR, or the UK Department of Health. C.M.L.W. (principal investigator of RAPPER) is supported by the NIHR Manchester Biomedical Research Centre. RAPPER was supported by Cancer Research UK grants C1094/A18504, C147/A25254, and C147/A25254. The PRACTICAL consortium was supported by Cancer Research UK grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, and C16913/A6135.

Publisher Copyright:
© 2022 The Authors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ijrobp.2022.06.098Licence: CC BY

No Association Between Polygenic Risk Scores for Cancer and Development of Radiation Therapy ToxicityFinal published version, 604 KBLicence: CC BY

Cite this

Barnett, G. C., Kerns, S. L., RGC and REQUITE Consortia, Dorling, L., Fachal, L., Aguado-Barrera, M. E., Martínez-Calvo, L., Jandu, H. K., Welsh, C., Tyrer, J., Coles, C. E., Haviland, J. S., Parker, C., Gómez-Caamaño, A., Calvo-Crespo, P., Sosa-Fajardo, P., Burnet, N. G., Summersgill, H., Webb, A., ... West, C. M. L. (2022). No Association Between Polygenic Risk Scores for Cancer and Development of Radiation Therapy Toxicity. International Journal of Radiation Oncology Biology Physics, 114(3), 494-501. https://doi.org/10.1016/j.ijrobp.2022.06.098

@article{2bb9a5feb7a843a099b05b23e5c037bd,

title = "No Association Between Polygenic Risk Scores for Cancer and Development of Radiation Therapy Toxicity",

abstract = "Purpose: Our aim was to test whether updated polygenic risk scores (PRS) for susceptibility to cancer affect risk of radiation therapy toxicity. Methods and Materials: Analyses included 9,717 patients with breast (n=3,078), prostate (n=5,748) or lung (n=891) cancer from Radiogenomics and REQUITE Consortia cohorts. Patients underwent potentially curative radiation therapy and were assessed prospectively for toxicity. Germline genotyping involved genome-wide single nucleotide polymorphism (SNP) arrays with nontyped SNPs imputed. PRS for each cancer were generated by summing literature-identified cancer susceptibility risk alleles: 352 breast, 136 prostate, and 24 lung. Weighted PRS were generated using log odds ratio (ORs) for cancer susceptibility. Standardized total average toxicity (STAT) scores at 2 and 5 years (breast, prostate) or 6 to 12 months (lung) quantified toxicity. Primary analysis tested late STAT, secondary analyses investigated acute STAT, and individual endpoints and SNPs using multivariable regression. Results: Increasing PRS did not increase risk of late toxicity in patients with breast (OR, 1.000; 95% confidence interval [CI], 0.997-1.002), prostate (OR, 0.99; 95% CI, 0.98-1.00; weighted PRS OR, 0.93; 95% CI, 0.83-1.03), or lung (OR, 0.93; 95% CI, 0.87-1.00; weighted PRS OR, 0.68; 95% CI, 0.45-1.03) cancer. Similar results were seen for acute toxicity. Secondary analyses identified rs138944387 associated with breast pain (OR, 3.05; 95% CI, 1.86-5.01; P = 1.09 × 10–5) and rs17513613 with breast edema (OR, 0.94; 95% CI, 0.92-0.97; P = 1.08 × 10–5). Conclusions: Patients with increased polygenic predisposition to breast, prostate, or lung cancer can safely undergo radiation therapy with no anticipated excess toxicity risk. Some individual SNPs increase the likelihood of a specific toxicity endpoint, warranting validation in independent cohorts and functional studies to elucidate biologic mechanisms.",

author = "Barnett, {Gillian C.} and Kerns, {Sarah L.} and {RGC and REQUITE Consortia} and Leila Dorling and Laura Fachal and Aguado-Barrera, {Miguel E.} and Laura Mart{\'i}nez-Calvo and Jandu, {Harkeran K.} and Ceilidh Welsh and Jonathan Tyrer and Coles, {Charlotte E.} and Haviland, {Joanne S.} and Christopher Parker and Antonio G{\'o}mez-Caama{\~n}o and Patricia Calvo-Crespo and Paloma Sosa-Fajardo and Burnet, {Neil G.} and Holly Summersgill and Adam Webb and {De Ruysscher}, Dirk and Petra Seibold and Jenny Chang-Claude and Talbot, {Christopher J.} and Tim Rattay and Matthew Parliament and {De Ruyck}, Kim and Rosenstein, {Barry S.} and Pharoah, {Paul D.P.} and Dunning, {Alison M.} and Ana Vega and West, {Catharine M.L.}",

note = "Funding Information: This work was supported by Cancer Research UK RadNet Cambridge (C17918/A28870) and Cancer Research UK Manchester Major Centre (C147/A25254). This project was funded in part by the National Cancer Institute, National Institutes of Health K07 CA187546 (principal investigator: S.L.K), supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds (INT15/00070, INT16/00154, INT17/00133, INT20/00071; PI19/01424; PI16/00046; PI13/02030; PI10/00164), and through the Autonomous Government of Galicia (consolidation and structuring program: IN607B) (principal investigator: A.V.). RADIOGEN genotyping was carried out at CEGEN-PRB3-ISCIII; it is supported by grant PT17/0019, of the PE I+D+i 2013-2016, funded by ISCIII and ERDF. The REQUITE (principal investigator: C.M.L.W.) study received funding from the European Union's seventh Framework Programme for research, technological development, and demonstration under grant agreement No. 601826. L.F. was supported by the European Union's Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement No. 656144. T.R. is a National Institute of Health Research (NIHR) Academic Clinical Lecturer (CL 2017-11-002). He was previously funded by a NIHR Doctoral Research Fellowship (DRF 2014-07-079). This publication presents independent research funded by NIHR. The views expressed are those of the authors and not necessarily those of NHS, NIHR, or the UK Department of Health. C.M.L.W. (principal investigator of RAPPER) is supported by the NIHR Manchester Biomedical Research Centre. RAPPER was supported by Cancer Research UK grants C1094/A18504, C147/A25254, and C147/A25254. The PRACTICAL consortium was supported by Cancer Research UK grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, and C16913/A6135. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = nov,

day = "1",

doi = "10.1016/j.ijrobp.2022.06.098",

language = "English",

volume = "114",

pages = "494--501",

journal = "International Journal of Radiation Oncology Biology Physics",

issn = "0360-3016",

publisher = "Elsevier Inc.",

number = "3",

}

Barnett, GC, Kerns, SL, RGC and REQUITE Consortia, Dorling, L, Fachal, L, Aguado-Barrera, ME, Martínez-Calvo, L, Jandu, HK, Welsh, C, Tyrer, J, Coles, CE, Haviland, JS, Parker, C, Gómez-Caamaño, A, Calvo-Crespo, P, Sosa-Fajardo, P, Burnet, NG, Summersgill, H, Webb, A, De Ruysscher, D, Seibold, P, Chang-Claude, J, Talbot, CJ, Rattay, T, Parliament, M, De Ruyck, K, Rosenstein, BS, Pharoah, PDP, Dunning, AM, Vega, A & West, CML 2022, 'No Association Between Polygenic Risk Scores for Cancer and Development of Radiation Therapy Toxicity', International Journal of Radiation Oncology Biology Physics, vol. 114, no. 3, pp. 494-501. https://doi.org/10.1016/j.ijrobp.2022.06.098

TY - JOUR

T1 - No Association Between Polygenic Risk Scores for Cancer and Development of Radiation Therapy Toxicity

AU - Barnett, Gillian C.

AU - Kerns, Sarah L.

AU - RGC and REQUITE Consortia

AU - Dorling, Leila

AU - Fachal, Laura

AU - Aguado-Barrera, Miguel E.

AU - Martínez-Calvo, Laura

AU - Jandu, Harkeran K.

AU - Welsh, Ceilidh

AU - Tyrer, Jonathan

AU - Coles, Charlotte E.

AU - Haviland, Joanne S.

AU - Parker, Christopher

AU - Gómez-Caamaño, Antonio

AU - Calvo-Crespo, Patricia

AU - Sosa-Fajardo, Paloma

AU - Burnet, Neil G.

AU - Summersgill, Holly

AU - Webb, Adam

AU - De Ruysscher, Dirk

AU - Seibold, Petra

AU - Chang-Claude, Jenny

AU - Talbot, Christopher J.

AU - Rattay, Tim

AU - Parliament, Matthew

AU - De Ruyck, Kim

AU - Rosenstein, Barry S.

AU - Pharoah, Paul D.P.

AU - Dunning, Alison M.

AU - Vega, Ana

AU - West, Catharine M.L.

N1 - Funding Information: This work was supported by Cancer Research UK RadNet Cambridge (C17918/A28870) and Cancer Research UK Manchester Major Centre (C147/A25254). This project was funded in part by the National Cancer Institute, National Institutes of Health K07 CA187546 (principal investigator: S.L.K), supported by Spanish Instituto de Salud Carlos III (ISCIII) funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds (INT15/00070, INT16/00154, INT17/00133, INT20/00071; PI19/01424; PI16/00046; PI13/02030; PI10/00164), and through the Autonomous Government of Galicia (consolidation and structuring program: IN607B) (principal investigator: A.V.). RADIOGEN genotyping was carried out at CEGEN-PRB3-ISCIII; it is supported by grant PT17/0019, of the PE I+D+i 2013-2016, funded by ISCIII and ERDF. The REQUITE (principal investigator: C.M.L.W.) study received funding from the European Union's seventh Framework Programme for research, technological development, and demonstration under grant agreement No. 601826. L.F. was supported by the European Union's Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement No. 656144. T.R. is a National Institute of Health Research (NIHR) Academic Clinical Lecturer (CL 2017-11-002). He was previously funded by a NIHR Doctoral Research Fellowship (DRF 2014-07-079). This publication presents independent research funded by NIHR. The views expressed are those of the authors and not necessarily those of NHS, NIHR, or the UK Department of Health. C.M.L.W. (principal investigator of RAPPER) is supported by the NIHR Manchester Biomedical Research Centre. RAPPER was supported by Cancer Research UK grants C1094/A18504, C147/A25254, and C147/A25254. The PRACTICAL consortium was supported by Cancer Research UK grants C5047/A7357, C1287/A10118, C1287/A16563, C5047/A3354, C5047/A10692, and C16913/A6135. Publisher Copyright: © 2022 The Authors

PY - 2022/11/1

Y1 - 2022/11/1

N2 - Purpose: Our aim was to test whether updated polygenic risk scores (PRS) for susceptibility to cancer affect risk of radiation therapy toxicity. Methods and Materials: Analyses included 9,717 patients with breast (n=3,078), prostate (n=5,748) or lung (n=891) cancer from Radiogenomics and REQUITE Consortia cohorts. Patients underwent potentially curative radiation therapy and were assessed prospectively for toxicity. Germline genotyping involved genome-wide single nucleotide polymorphism (SNP) arrays with nontyped SNPs imputed. PRS for each cancer were generated by summing literature-identified cancer susceptibility risk alleles: 352 breast, 136 prostate, and 24 lung. Weighted PRS were generated using log odds ratio (ORs) for cancer susceptibility. Standardized total average toxicity (STAT) scores at 2 and 5 years (breast, prostate) or 6 to 12 months (lung) quantified toxicity. Primary analysis tested late STAT, secondary analyses investigated acute STAT, and individual endpoints and SNPs using multivariable regression. Results: Increasing PRS did not increase risk of late toxicity in patients with breast (OR, 1.000; 95% confidence interval [CI], 0.997-1.002), prostate (OR, 0.99; 95% CI, 0.98-1.00; weighted PRS OR, 0.93; 95% CI, 0.83-1.03), or lung (OR, 0.93; 95% CI, 0.87-1.00; weighted PRS OR, 0.68; 95% CI, 0.45-1.03) cancer. Similar results were seen for acute toxicity. Secondary analyses identified rs138944387 associated with breast pain (OR, 3.05; 95% CI, 1.86-5.01; P = 1.09 × 10–5) and rs17513613 with breast edema (OR, 0.94; 95% CI, 0.92-0.97; P = 1.08 × 10–5). Conclusions: Patients with increased polygenic predisposition to breast, prostate, or lung cancer can safely undergo radiation therapy with no anticipated excess toxicity risk. Some individual SNPs increase the likelihood of a specific toxicity endpoint, warranting validation in independent cohorts and functional studies to elucidate biologic mechanisms.

AB - Purpose: Our aim was to test whether updated polygenic risk scores (PRS) for susceptibility to cancer affect risk of radiation therapy toxicity. Methods and Materials: Analyses included 9,717 patients with breast (n=3,078), prostate (n=5,748) or lung (n=891) cancer from Radiogenomics and REQUITE Consortia cohorts. Patients underwent potentially curative radiation therapy and were assessed prospectively for toxicity. Germline genotyping involved genome-wide single nucleotide polymorphism (SNP) arrays with nontyped SNPs imputed. PRS for each cancer were generated by summing literature-identified cancer susceptibility risk alleles: 352 breast, 136 prostate, and 24 lung. Weighted PRS were generated using log odds ratio (ORs) for cancer susceptibility. Standardized total average toxicity (STAT) scores at 2 and 5 years (breast, prostate) or 6 to 12 months (lung) quantified toxicity. Primary analysis tested late STAT, secondary analyses investigated acute STAT, and individual endpoints and SNPs using multivariable regression. Results: Increasing PRS did not increase risk of late toxicity in patients with breast (OR, 1.000; 95% confidence interval [CI], 0.997-1.002), prostate (OR, 0.99; 95% CI, 0.98-1.00; weighted PRS OR, 0.93; 95% CI, 0.83-1.03), or lung (OR, 0.93; 95% CI, 0.87-1.00; weighted PRS OR, 0.68; 95% CI, 0.45-1.03) cancer. Similar results were seen for acute toxicity. Secondary analyses identified rs138944387 associated with breast pain (OR, 3.05; 95% CI, 1.86-5.01; P = 1.09 × 10–5) and rs17513613 with breast edema (OR, 0.94; 95% CI, 0.92-0.97; P = 1.08 × 10–5). Conclusions: Patients with increased polygenic predisposition to breast, prostate, or lung cancer can safely undergo radiation therapy with no anticipated excess toxicity risk. Some individual SNPs increase the likelihood of a specific toxicity endpoint, warranting validation in independent cohorts and functional studies to elucidate biologic mechanisms.

UR - http://www.scopus.com/inward/record.url?scp=85138029152&partnerID=8YFLogxK

U2 - 10.1016/j.ijrobp.2022.06.098

DO - 10.1016/j.ijrobp.2022.06.098

M3 - Article

C2 - 35840111

AN - SCOPUS:85138029152

SN - 0360-3016

VL - 114

SP - 494

EP - 501

JO - International Journal of Radiation Oncology Biology Physics

JF - International Journal of Radiation Oncology Biology Physics

IS - 3

ER -

No Association Between Polygenic Risk Scores for Cancer and Development of Radiation Therapy Toxicity

Abstract

Bibliographical note

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this