Do polygenic risk scores for cancer susceptibility associate with risk of radiotherapy toxicity
Kerns, S. L. Barnett, G. Dorling, L. Fachal, L. Martinez-Calvo, L. Aguado-Barrera, M. E. Dearnaley, D Coles, C. E. Burnet, Neil G Webb, A.
Kerns, S. L.
Barnett, G.
Dorling, L.
Fachal, L.
Martinez-Calvo, L.
Aguado-Barrera, M. E.
Dearnaley, D
Coles, C. E.
Burnet, Neil G
Webb, A.
Citations
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Abstract
Purpose/Objective(s): Single nucleotide polymorphisms (SNPs) associated
with increased susceptibility to cancer frequently lie in genes that
might also modulate response to radiation. The purpose of this study is to
evaluate whether individuals at increased genetic risk of developing cancer
are also more likely to develop late radiotherapy-induced toxicities. We
test the hypothesis that polygenic risk scores (PRS) for cancer susceptibility
alter toxicity risk among cancer patients who received radiotherapy.
Materials/Methods: Analysis included 1,134 breast, 3,521 prostate, and
610 lung cancer patients from radiotherapy cohorts from the Radiogenomics
and REQUITE Consortia. All patients received radiotherapy
alone or as part of combination treatment and were followed prospectively for development of toxicity in relevant tissues. Germline DNA was genotyped
using a genome-wide SNP array with non-typed SNPs imputed
using the 1000 Genomes reference data. A PRS was generated for each
patient by summing risk alleles from cancer susceptibility SNPs identified
in the literature - 352 for breast, 147 for prostate, 24 for lung cancer. A
weighted PRS was similarly generated for prostate and lung cancer in
which each SNP was first weighted by its odds ratio for cancer susceptibility;
such a score was not available for breast cancer as the odds ratios
vary by estrogen receptor status. Toxicity was quantified for each patient
using STAT score, which is a previously validated measure of overall
radiotherapy toxicity that combines multiple individual endpoints. Multivariable
logistic regression tested association between PRS and toxicity
STAT score (dichotomized at the mean plus one standard deviation) at 2
years after treatment for breast and prostate and up to 1 year for lung
cancer patients, controlling for clinical covariates. Individual SNPs
comprising the PRS were tested in a secondary analysis.
Results: No association was found between PRS and development of late
radiotherapy toxicity among breast (PRS OR Z 1.01, 95% CI Z 1.00 to
1.02), prostate (PRS OR Z 1.01, 95% CI Z 1.00 to 1.03; weighted PRS
OR Z 1.10, 95%CI Z 0.94 to 1.28) or lung cancer patients (PRS OR Z
0.95, 95% CI Z 0.88 to 1.02; weighted PRS OR Z 0.77, 95% CI Z 0.51
to 1.14). On multivariable analysis of individual SNPs, rs138944387 was
associated with breast pain (beta Z 1.12; 95% CI Z 0.62 to 1.61; p Z
1.09x10-5) and rs17513613 was associated with risk of breast edema (beta
Z -0.21; 95% CI Z -0.31 to -0.12; p Z 2.01x10-5).
Conclusion: Cancer patients with a high polygenic predisposition to breast,
prostate or lung cancer show no evidence of an increased risk of late
radiotherapy toxicity. Thus, these patients can undergo standard treatment
without an anticipated excess toxicity risk. The association between individual
SNPs and late toxicity requires validation in independent cohorts
and functional studies to elucidate the biologic mechanism underlying this
shared risk.
Description
Date
2020
Publisher
Collections
Keywords
Type
Meetings and Proceedings
Citation
Kerns SL, Barnett G, Dorling L, Fachal L, Martinez-Calvo L, Aguado-Barrera M, et al. Do polygenic risk scores for cancer susceptibility associate with risk of radiotherapy toxicity. International Journal of Radiation Oncology Biology Physics. 2020;108(3):E513-E