||7R21CA261833-02 Interpret this number
||University Of Minnesota
||Treatment-Specific Genetic Risk Scores for Late Effects Prediction in Childhood,adolescent, and Young Adult Cancer Survivors
PROJECT SUMMARY OR ABSTRACT
There is growing evidence that polygenic risk scores (PRS), or aggregate measures of genetic risk for disease
based on findings from genome-wide association studies (GWAS), may be useful in predicting risks for a wide
array of chronic health conditions (CHCs) in the general population. But are PRS useful for predicting late
effects risks in survivors of childhood, adolescent, and young adult (CAYA) cancer? Recently, we have shown
that PRS based on GWAS conducted in the general population are relatively poor predictors of risks for
various CHCs in survivors, in part because they do not consider the modifying effects of specific curative
therapies for cancer on genetic risks for CHCs, i.e., treatment-specific genetic effects. To date, no existing
analytic method bridges this research gap: this project is innovative because it aims to develop a new method
for PRS that can also incorporate treatment-specific genetic effects. The overall objective of the proposed
project is to create novel genetic risk predictors that combine established genetic risk signals identified in
general population GWAS with treatment-specific genetic effects to equitably predict CHC risks in CAYA
cancer survivors. We will investigate this approach using a preliminary set of ten CHCs and complex traits,
including subsequent cancers and cardiovascular and endocrine diseases. The long-term goal of this project is
to apply these newly developed treatment-specific genetic risk predictors to inform personalized follow-up care
programs for survivors, which responds to RFA-CA-20-028 application domains 5 (development of risk
predictors of late effects) and 6 (development of targeted interventions to reduce the burden of cancer).
Utilizing existing genetic/phenotype data from ~13,000 survivors, the proposed study will pursue the following
specific aims: (1) compile a comprehensive catalog of treatment-specific genetic effects for each of the
selected phenotypes; (2) develop and evaluate corresponding “survivor-enriched” PRS that incorporate these
treatment-specific genetic effects; and (3) assess whether survivor-enriched PRS can decrease disparities in
late effects risk prediction in survivors from racial/ethnic minority populations. To accomplish the first aim, we
will perform strategic genome-wide association analyses to identify genetic variants whose risk associations
with CHCs are modified by therapeutic exposures. We then intend to adapt existing methods shown to improve
the cross-population generalizability of PRS to combine discoveries from general population GWAS with
results from genetic analyses in survivors. The relative predictive ability of these survivor-enriched PRS will be
evaluated in an independent survivor sample. Lastly, given that treatment-specific genetic effects may be
trans-ethnic, we will assess survivor-enriched PRS in racial/ethnic minority survivor subgroups that have been
traditionally excluded from Eurocentric GWAS. The proposed research is significant in its potential to help
identify survivors at high risk for adverse health outcomes with treatment-specific genetic risk scores, which
would represent an important advance over current guidelines for survivorship care.
Leveraging Therapy-Specific Polygenic Risk Scores to Predict Restrictive Lung Defects in Childhood Cancer Survivors.
, Yuan Y.
, Austin E.D.
, Stokes D.C.
, Krasin M.J.
, Davidoff A.M.
, Sapkota Y.
, Wang Z.
, Ness K.K.
, Wilson C.L.
, et al.
Cancer research, 2022-08-16; 82(16), p. 2940-2950.