A multicenter whole-genome sequencing cohort of bleomycin-induced pneumonitis in predominantly clinically low-risk patients.
19 affiliations
- 1Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia. [email protected].
- 2Department of Oncology, The University of Melbourne, Melbourne, Australia. [email protected].
- 3The Kinghorn Cancer Centre, St Vincent's Hospital, Darlinghurst, NSW, Australia.
- 4School of Medicine and Psychology, Australian National University, Acton, ACT, Australia.
- 5Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
- 6School of Clinical Medicine, St Vincent's Healthcare Clinical Campus, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.
- 7Chris O'Brien Lifehouse, Camperdown, NSW, Australia.
- 8Western Cancer Centre, Dubbo, NSW, Australia.
- 9The University of Sydney- School of Rural Health Dubbo, Dubbo, NSW, Australia.
- 10Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.
- 11Department of Oncology, The University of Melbourne, Melbourne, Australia.
- 12Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Barangaroo, Australia.
- 13Department of Haematology, Liverpool Hospital, Liverpool, NSW, UK.
- 14Fiona Stanley Hospital, Murdoch, WA, Australia.
- 15University of Western Australia, Crawley, UK.
- 16Sydney Adventist Hospital, Wahroonga, NSW, Australia.
- 17Macquarie University Hospital, Macquarie Park, NSW 10.Barwon Health, Geelong, Australia.
- 18Barwon Health, Geelong, Australia.
- 19Deakin University, Victoria, Australia.
Abstract
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.
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BibTeX
@article{hitchen2026multicenter,
title = {{A multicenter whole-genome sequencing cohort of bleomycin-induced pneumonitis in predominantly clinically low-risk patients.}},
author = {Nadia Hitchen and Eleanor E Handel and Claudia Leslie and Pietro R Di Ciaccio and Anthony Joshua and Luke Ardolino and Peter Grimison and Florian Honeyball and Ben Tran and Linda McCarthy and Samuel Milliken and Nicholas Viiala and Shane Gangatharan and Ian Bilmon and Alison Y Zhang and Jeremy Lewin and Garvin Marx and Caitlin Murphy and Anne Trinh and Nicola Wong and Leonard Goldstein and Sarah Kummerfeld and Matthew Hobbs and Megan B Barnet},
journal = {Molecular genetics and genomics : MGG},
year = {2026},
month = oct,
doi = {10.1007/s00438-026-02534-9},
url = {https://europepmc.org/article/MED/42957900},
note = {CC BY},
}
RIS
TY - JOUR
TI - A multicenter whole-genome sequencing cohort of bleomycin-induced pneumonitis in predominantly clinically low-risk patients.
AU - Nadia Hitchen
AU - Eleanor E Handel
AU - Claudia Leslie
AU - Pietro R Di Ciaccio
AU - Anthony Joshua
AU - Luke Ardolino
AU - Peter Grimison
AU - Florian Honeyball
AU - Ben Tran
AU - Linda McCarthy
AU - Samuel Milliken
AU - Nicholas Viiala
AU - Shane Gangatharan
AU - Ian Bilmon
AU - Alison Y Zhang
AU - Jeremy Lewin
AU - Garvin Marx
AU - Caitlin Murphy
AU - Anne Trinh
AU - Nicola Wong
AU - Leonard Goldstein
AU - Sarah Kummerfeld
AU - Matthew Hobbs
AU - Megan B Barnet
PY - 2026
DA - 2026/10/30
JO - Molecular genetics and genomics : MGG
DO - 10.1007/s00438-026-02534-9
UR - https://europepmc.org/article/MED/42957900
AB - 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.
SN - 1617-4615
SN - 1617-4623
ER -