A rare germline mutation reverses the suppressive effect of GPC5 thereby promoting lung adenocarcinoma development and tumorigenesis

Zhifa Zheng^1,2,3,4Lina Zhao^1,2,3,4Sen Zhao⁵Zhihong Wu^1,3,4*NAN WU^2,3,4*

• ¹Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
• ²Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
• ³Beijing Key Laboratory of Big Data Innovation and Application for Skeletal Health Medical Care, Beijing, China
• ⁴Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China
• ⁵Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States

Lung adenocarcinoma is the most common subtype of primary lung cancer. LUAD has a substantial genetic predisposition, with around 8% of patients having a positive family history. A few germline mutations have been reported to be associated with familial lung cancer. We recruited a Chinese family with four members affected by LUAD. Exome sequencing was performed on peripheral blood DNA from three affected members and one healthy member in the pedigree. We prioritized a heterozygous missense variant c.776C>T (p. Pro259Leu) in GPC5, a known tumor-suppressor gene for lung cancer. This variant is not carried by the healthy family member and is extremely rare in the Genome Aggregation Database. We performed in vitro experiments to explore the effect of c.776C>T on GPC5 function and found c.776C>T mutation diminished the suppressive effect of GPC5 on tumor growth, while promoting tumor migration and invasion through epithelial-mesenchymal transition. Taken together, our findings underscore GPC5 as a genetic susceptibility hub connecting genomic instability to tumor microenvironment remodeling, offering insights into precision immunotherapy strategies.