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Updated: Jul 3, 2025

Visualizing DNA Damage Repair Proteins in Patient-Derived Ovarian Cancer Organoids via Immunofluorescence Assays
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Germline Mutations of Holliday Junction Resolvase Genes in Multiple Primary Malignancies Involving Lung Cancer Lead

Haoran Wang1,2,3, Yuping Chen4,5, Xinshu Wang5

  • 1Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|February 13, 2024
PubMed
Abstract

Insights

Multiple primary lung cancers are increasing. We found specific gene mutations in the homologous recombination repair pathway, suggesting new targeted therapies like PARP inhibitors for these patients.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • The incidence of multiple primary malignancies (MPM) involving lung cancer is rising.
  • Clarifying the genetic landscape of these patients is crucial for developing effective treatments.

Purpose of the Study:

  • To investigate the germline genetic profile of patients with MPM involving lung cancer.
  • To identify potential therapeutic targets for this patient population.

Main Methods:

  • Whole-exome sequencing (WES) of germline DNA from 71 MPM patients with lung cancer.
  • Pathway enrichment analysis to identify significantly mutated pathways.
  • In vitro and in vivo experiments to validate the functional impact of mutations and drug sensitivity.

Main Results:

  • Homologous recombination repair (HRR) pathway genes were frequently mutated in MPM lung cancer patients.
  • Specific mutations in Holliday junction resolvase (HJR) genes (GEN1, BLM, SXL4, RMI1) were identified.
  • These HJR mutations led to DNA repair deficiency and sensitivity to PARP inhibitors in lung cancer cells.

Conclusions:

  • This study provides the first comprehensive germline mutation profile for MPM involving lung cancer.
  • Identified HJR mutations and HRR pathway alterations may guide early prevention strategies.
  • Findings suggest potential for novel targeted therapies, including PARP inhibitors, for MPM lung cancer patients with HJR mutations.

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