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Leveraging Therapy-Specific Polygenic Risk Scores to Predict Restrictive Lung Defects in Childhood Cancer Survivors.

Cindy Im¹, Yan Yuan¹, Eric D Austin²

¹School of Public Health, University of Alberta, Edmonton, Alberta, Canada.

Cancer Research

|June 17, 2022

Summary

A new polygenic risk score (PRS) model accurately predicts restrictive ventilatory defects (RVD) in childhood cancer survivors. This therapy-specific approach improves risk stratification for pulmonary complications, enhancing long-term survivorship care.

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Area of Science:

Genomics
Oncology
Pulmonology

Background:

Therapy-related pulmonary complications are a major cause of morbidity in childhood cancer survivors.
Restrictive ventilatory defects (RVD) are common, particularly after chest radiotherapy and certain chemotherapies.

Purpose of the Study:

To develop and validate a therapy-specific polygenic risk prediction model for RVD in childhood cancer survivors.
To integrate clinical profiles with novel polygenic risk scores (PRS), including gene-by-treatment interactions.

Main Methods:

Utilized whole-genome sequencing data from 1,728 childhood cancer survivors.
Developed a composite RVD risk prediction model incorporating clinical data and PRSs.
Included a novel survivor-specific pharmaco/radiogenomic PRS (surPRS) reflecting gene-by-treatment (GxT) effects.

Main Results:

The novel surPRS was significantly associated with RVD risk in both training and validation datasets.
The composite model demonstrated superior discriminatory accuracy (AUC = 0.81) compared to clinical risk scores alone (AUC = 0.78).
Survivors in the highest risk quintile had a ~20-fold higher odds of RVD compared to those with lower predicted risk.

Conclusions:

A therapy-specific polygenic risk prediction model, leveraging GxT interactions, effectively identifies childhood cancer survivors at high risk for RVD.
This approach significantly improves risk stratification for pulmonary complications, potentially guiding personalized survivorship care.
The findings support the use of PRS in predicting late effects among childhood cancer survivors.