July 9, 2025
National Cancer Center, National Research and Development Agency
Keio University School of Medicine
and others
[Key Findings]
We conducted whole-genome and whole-exome sequencing analysis on 1,773 cases of lung adenocarcinoma in Japanese patients to investigate the characteristics of early-onset cases (age 40 and under).
The analysis revealed that early-onset cases have a higher frequency of germline pathogenic variants (genetic changes present from birth) in the BRCA2 and TP53 genes compared to non-early-onset cases.
In tumors from cases with pathogenic variants in the BRCA2 gene, the homologous recombination repair mechanism, which accurately repairs broken DNA strands, was found to be deficient, suggesting that existing molecular targeted drugs (PARP inhibitors) may be effective.
Additionally, germline pathogenic variants in the ALKBH2 gene were identified as a new risk factor for early-onset lung adenocarcinoma cases.
This study demonstrated the need to share the challenges faced by patients with hereditary tumors and to build a new form of cancer care based on insights from medical genetics.
Koya Shiraishi, Unit Head, Takashi Kohno, Division Chief, and Meng-Lin Chang, Visiting Researcher, of the Division of Genome Biology, Research Institute, at the National Cancer Center (Chuo-ku, Tokyo; President: Hiroyuki Mano), National Research and Development Agency, and their colleagues formed a research consortium of eight institutions nationwide to conduct a large-scale analysis of lung adenocarcinoma in Japanese patients, investigating the causes of the disease in those who develop it at a young age (40 and under).
In this study, a comparison between early-onset and non-early-onset cases of lung adenocarcinoma revealed that early-onset cases more frequently have germline pathogenic variants, which are congenital mutations, in the TP53 and BRCA2 genes. Furthermore, in lung adenocarcinoma cases with variants in the BRCA2 gene, a deficiency in the homologous recombination repair mechanism, a characteristic also seen in breast and ovarian cancers, was observed. This suggests that existing molecular targeted drugs (PARP inhibitors) may be effective. Additionally, it was suggested that germline pathogenic variants in the DNA repair-related ALKBH2 gene may be a partial cause of early-onset lung adenocarcinoma.
Lung adenocarcinoma that develops in individuals aged 40 and under is often discovered at an advanced stage and is known to have a poor prognosis. This study highlights the need to share the challenges faced by patients with hereditary tumors and to establish a new form of cancer care based on insights from medical genetics.
The results of this research were published online in the international academic journal Journal of Thoracic Oncology on June 15, 2025 (U.S. Eastern Time).
For the full press release, please see below.