Open Access
ARTICLE
Identification of BRCA2 Likely Germline Pathogenic Variants in Patients with Multiple Primary Lung Adenocarcinomas
Dat Quoc Tran1, Mayu Takeda2, Eiji Sugihara2, Tetsuya Tsukamoto2,3, Yasushi Hoshikawa4, Yasuyoshi Mizutani1, Kazuya Shiogama5, Naoya Asai6, Atsuko Niimi1, Makoto Sumitomo2, Hideyuki Saya2, Motoshi Suzuki1,*
1 Department of Molecular Oncology, Fujita Health University, Toyoake, Japan
2 Oncology Innovation Center, Fujita Health University, Toyoake, Japan
3 Department of Diagnostic Pathology, Fujita Health University, Toyoake, Japan
4 Department of Thoracic Surgery, Fujita Health University, Toyoake, Japan
5 Department of Pathology and Cytopathology, Fujita Health University, Toyoake, Japan
6 Department of Pathology, Fujita Health University, Toyoake, Japan
* Corresponding Author: Motoshi Suzuki. Email: 
(This article belongs to the Special Issue: Molecular Targeting Therapy for Anticancer Treatment)
Oncology Research https://doi.org/10.32604/or.2026.078309
Received 29 December 2025; Accepted 17 March 2026; Published online 13 April 2026
Abstract
Objectives: Genetic risk models have substantially advanced our understanding of germline pathogenic variants (GPVs) in some malignancies, whereas their clinical significance in lung cancer remains unclear. The present study aimed to better understand potential contribution of GPVs to lung cancer etiology. Methods: A targeted sequencing panel of 143 cancer-related genes was applied to analyze 26 distinct lung adenocarcinoma (LUAD) tumors from 11 patients histopathologically diagnosed with multiple primary lung cancers (MPLC). Tumor classification was performed through integrated evaluation of mutation profiles, and variants shared among tumor lesions were further validated as likely germline or somatic mutations using Sanger sequencing. Results: Mutation profiles were compared to reveal clonal relationships among lesions in each patient. Nine of the 11 cases (81.8%) were classified as MPLC, 1/11 (9.1%) as intrapulmonary metastasis (IM), and 1/11 (9.1%) exhibited features of both MPLC and IM. Among the nine MPLC cases, eight (88.9%) harbored matching variants across independent tumor lesions that were also detected in tumor-adjacent regions, suggesting classification as likely germline variants. Importantly, among the eight cases with shared variants, one possessed a novel truncating BRCA2 DNA repair associated (BRCA2) variant (p.N900IfsTer4), while the others harbored variants of uncertain significance (VUS) in the tumor protein p53 (TP53), caspase recruitment domain family member 11 (CARD11), platelet derived growth factor receptor beta (PDGFRB), lysine methyltransferase 2D (KMT2D), phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1), neuregulin 1 (NRG1), androgen receptor (AR), and KIT proto-oncogene, receptor tyrosine kinase (KIT) genes. To determine whether a similar BRCA2 variant was present in other lung cancer patients, 123 LUAD cases were analyzed, and one (0.81%) possessing a truncating BRCA2 variant (p.Q1429FfsTer20) without any typical driver mutations was identified. Conclusions: BRCA2 GPVs may represent putative pathogenic mutations, and thus be potential molecular targets for future treatment of LUAD.
Keywords
Multiple primary lung cancer; intrapulmonary metastasis; BRCA2 DNA repair associated; germline pathogenic variants; adenocarcinoma
Login
Register
Submit a Paper
Propose a Special lssue
Download PDF
Supplementary Material File
Downloads
Citation Tools
