Role of genetic modifiers on pulmonary consequences of cancer therapy in children

Abstract

Childhood cancer survivors (CCS) often face late-onset adverse effects, with pulmonary complications being particularly common. In this study, we analyzed 104 CCS with pulmonary issues post-treatment using a genome-wide association study (GWAS) to identify genetic susceptibility markers. Among the cohort, 20% were diagnosed with interstitial lung disease (ILD), while other complications included pulmonary fibrosis (3%) and bronchiolitis obliterans (3%). Pulmonary function test (PFT) impairments were present in 74% of patients, with symptoms such as exertional dyspnea (14%) and chronic cough (9%). Imaging revealed bronchiectasis in 7% of patients. Although no genome-wide significant loci were identified, several loci of suggestive significance were detected, including rs6804526 (P = 6.21 × 10-5) and rs117985268 (P = 2.98 × 10-5), which are previously associated with breast cancer and respiratory failure, respectively. Additionally, copy number variation (CNV) analysis identified a 21q22.3 deletion in one patient, a region linked to lung cancer. While no genome-wide significant loci were found, these suggestive loci and CNV findings highlight potential genetic modifiers of pulmonary risk in CCS, warranting further investigation in larger cohorts to confirm these associations.

Fig. 1

BAF and LRR plots of the 21q22.3 deletion. The upper panel shows the Log R Ratio (LRR), indicating copy number changes, with a clear reduction to −1.0 in the deleted region (CN = 1). The lower panel depicts the B Allele Frequency (BAF), illustrating the absence of heterozygosity (values clustering around 0.0 and 1.0) in the same region. These plots highlight a confirmed deletion spanning the 21q22.3 locus.

Fig. 2

GWAS results. (A) Manhattan plot displaying the −log₁₀(P-value) for genetic variants across the genome. Each dot represents a single nucleotide polymorphism (SNP), plotted by chromosomal position (x-axis) and statistical significance (y-axis). (B) quantile-quantile (Q-Q) plot comparing observed vs. expected −log₁₀(P-value) under the null hypothesis. The red dashed line represents the expected distribution, and the blue line represents the observed data. The genomic control factor (λ_GC = 0.95) is shown, indicating no significant genomic inflation. The shaded region represents the 95% confidence interval.