A multicenter whole-genome sequencing cohort of bleomycin-induced pneumonitis in predominantly clinically low-risk patients

INTRODUCTION: Bleomycin is a key component of curative-intent chemotherapy for germ cell tumours (GCT) and Hodgkin Lymphoma (HL), but its use is limited by bleomycin-induced pneumonitis (BIP). Although established clinical risk factors predict some cases, BIP also occurs without these. Preclinical models and small human studies implicate a contribution of drug metabolism, oxidative stress, immune and fibrotic pathways that may contribute to susceptibility. We aimed to identify germline genetic contributors to BIP in predominantly clinically low-risk patients to improve risk stratification in GCT and HL. METHODS: We retrospectively identified 21 patients (13 GCT, 8 HL) who developed clinically significant BIP despite predominantly low clinical risk. Clinical data were collected and, where possible, blood samples were obtained for whole-genome sequencing (WGS). Analysis focused on a curated BIP-risk gene panel, derived from a literature review of genes/alleles implicated in BIP, alongside polygenic risk scores (PRS) for relevant lung and autoinflammatory/autoimmune pathology. RESULTS: Median age was 39 (GCT) and 49 (HL) years; 67% were life-time non-smokers. Most patients with BIP experienced CTCAE grade < 3 (76%), and 52% received corticosteroids. WGS was performed in 18 individuals. Missense variants with low general population allele frequency were observed in 9 genes within the curated panel, although the significance of these remains unknown. PRS analysis in 12 individuals of European ancestry showed no association of BIP with established PRS for lung disease or autoinflammatory/autoimmune disease. CONCLUSION: Biologically plausible candidate germline variants involved in lung surfactant biology and inflammatory signaling were identified. These exploratory findings provide candidate genes and pathways for future investigations into the genetic basis of BIP.