Cancer Research and Treatment

Original Articles

Genetic Variant at 6p21.1 Impairs APOBEC2 in Hypoxic Mitophagy via HIF-1α/BNIP3 in Gastric Cancer: Zhonghua Zheng, Qian Li, Yuanliang Gu, Xinxiang Gao, Xinya Wang, Yan Zhang, Fangmei An, Qiang Zhan, Shuangshuang Yin, Yun Gao, Rui Peng, Li Liu, Erbao Zhang, Meng Zhu, Xiaofeng Chen, Gang Li, Hao Xu, Guangfu Jin, Caiwang Yan; Received October 30, 2025 Accepted May 8, 2026 Published online May 12, 2026; DOI: https://doi.org/10.4143/crt.2025.1194 [Accepted]

Abstract PDF: Purpose
Genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms (SNPs) at the 6p21.1 locus associated with gastric cancer (GC) risk. However, the underlying biological mechanisms remain poorly understood.
Materials and Methods
We conducted fine-mapping analysis of the 6p21.1 region using large-scale GC GWAS data (10,254 cases and 10,914 controls). Functional annotation, luciferase reporter assays, Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) experiments were performed to identify functional variants. The eQTL and colocalization analyses were used to determine the susceptibility gene. Mechanistic investigations included phenotypic assays under normoxic and hypoxic conditions, along with seahorse, immunofluorescence and ATP assays to assess mitochondrial function.
Results
We identified rs9381024 as the independent association signal at 6p21.1, with rs2235679, in strong linkage disequilibrium with rs9381024, emerging as a potential causative SNP. The T risk allele of rs2235679 reduced APOBEC2 expression by enhancing the binding of transcriptional repressor MZF1, thereby suppressing promoter activity. Expression analysis revealed a progressive decrease in APOBEC2 levels with gastric lesions severity, becoming nearly undetectable in GC tissues. Functionally, reduced APOBEC2 expression significantly promoted the proliferation of GC cells under hypoxic conditions but not under normoxia. Mechanistically, downregulation of APOBEC2 activated mitophagy to maintain mitochondria homeostasis via HIF-1α/BNIP3 pathway under hypoxia, ultimately driving tumor growth.
Conclusion
Our findings provide novel mechanistic insights into how genetic variants at 6p21.1 contribute to GC risk and progression, highlighting the tumor-suppressive role of APOBEC2.

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Lung and Thoracic cancer

Genomic Landscape of Pulmonary Sarcomatoid Carcinoma: Hyun Jung Kwon, Sejoon Lee, Yeon Bi Han, Jeonghyo Lee, Soohyeon Kwon, Hyojin Kim, Jin-Haeng Chung; Cancer Res Treat. 2024;56(2):442-454. Published online November 14, 2023; DOI: https://doi.org/10.4143/crt.2023.764

Abstract PDF Supplementary Material PubReader ePub

Purpose
Pulmonary sarcomatoid carcinoma (PSC) is a rare aggressive subtype of non–small cell lung cancer (NSCLC) with limited therapeutic strategies. We attempted to elucidate the evolutionary trajectories of PSC using multiregional and longitudinal tumor samples.
Materials and Methods
A total of 31 patients were enrolled in this study and 11 longitudinal samples were available from them. Using whole exome sequencing data, we analyzed the mutational signatures in both carcinomatous and sarcomatous areas in primary tumors of the 31 patients and longitudinal samples obtained from 11 patients. Furthermore, digital droplet polymerase chain reaction (ddPCR), and programmed death-ligand 1 (PD-L1) immunohistochemistry using the Ventana SP263 assay were performed.
Results
TP53 was identified as the most frequently altered gene in the primary (74%) and metastatic (73%) samples. MET exon 14 skipping mutations, confirmed by ddPCR, and TP53 mutations were mutually exclusive; whereas, MET exon 14 skipping mutations frequently co-occurred with MDM2 amplification. Metastatic tumors showed dissimilar genetic profiles from either primary component. During metastasis, the signatures of APOBEC decreased in metastatic lesions compared with that in primary lesions. PSC showed higher MET and KEAP1 mutations and stronger PD-L1 protein expression compared with that recorded in other NSCLCs.
Conclusion
Decreased APOBEC signatures and subclonal diversity were detected during malignant progression in PSC. Frequent MET mutations and strong PD-L1 expression distinguished PSC from other NSCLCs. The aggressiveness and therapeutic difficulties of PSC were possibly attributable to profound intratumoral and intertumoral genetic diversity. Next-generation sequencing could suggest the appropriate treatment strategy for PSC.

Citations

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