Student Sage Hill School Irvine, California, United States
Introduction: Lung cancer is the leading cause of cancer-related deaths in both men and women. 85% of all lung cancer cases fall under non-small-cell lung cancer (NSCLC) and within NSCLCs, there are two types: lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). As the gene profiles of these different cancer types differ, it is important to study them separately. Since LUAD is the more common of the two, my research looks only at the genetic profiles of LUAD tissue. Understanding which genes have major roles in LUAD can provide insight into the development of new targeted therapies. The current treatments for lung cancer include radiation therapy, chemotherapy, and immunotherapy. They typically have unpleasant side effects and can increase the risk of developing other diseases or cancers. Therefore, personalized medicine is taking a larger role in treating diseases by specifically targeting genes that are found to be the main drivers of cancer. They can also avoid healthy cells by manipulating the expression of the gene to minimize the cause of the disease while also minimizing side effects. In this research, the transcriptome profiles of normal lung tissue were compared to those of LUAD to identify novel differentially expressed genes and sex-specific genes that can be further analyzed in future research to determine their impact on the disease.
Materials and
Methods: Acquisition of the transcriptome profile data, differential gene analysis, and visualization of volcano plots were carried out using RStudio 2023.12.0 with the TCGABiolinks library. 539 primary tumor samples and 59 solid normal tissue samples were pulled from TCGA and upon being downloaded onto RStudio, were preprocessed and analyzed. With the same data extraction and data analysis methods as the differential gene analysis, the female analysis used 50 female primary tumor samples and the 59 solid tissue normal samples. The male analysis used 50 male primary tumor samples and the 59 solid tissue normal samples. To visualize the differentially expressed genes, a volcano plot was generated with an x-axis cutoff at 0 and a y-axis cutoff at 0.01. The gene ontology terms were generated using the top 100 dysregulated genes, based on log fold change with p-value < 0.05 using the platform, Metascape. The Human Protein Atlas was accessed to identify the survival plots of the top 100 up- and down-regulated genes were identified. The Venn diagram was created using the edgeR library on R to compare the DEGs of females and males with LUAD
Results, Conclusions, and Discussions: After a cutoff of logFC > 1.5 and p-value < 0.05, there were 6592 differentially expressed genes, including 5438 up-regulated genes and 1154 down-regulated genes. There is a contrasting pattern of down-regulated and up-regulated genes in LUAD based on the volcano plot (Figure 1). This could be because many normal functions are consistently down-regulated in cancer, so it is more significant. On the other hand, the up-regulated genes have a wider range of expression but are also less consistent and therefore, less significant in cancer cells.
The gene ontology (Figure 2) reveals insights into LUAD pathogenesis. Among the up-regulated pathways, the HNF3B pathway is the protein network for FOXA2 and FOXA3, found to increase fatty acid metabolism, which provides energy and resources for cancer cell survival and metastasis. In the down-regulated pathways, the compromised oxygen transport and suppressed immune response via the cellular response to the tumor necrosis factor may contribute to tumorigenesis.
Certain genes (Figure 3) are found to be potential prognostic indicators for LUAD. SFTPC and AGER are among the top 10 down-regulated genes. SFTPC maintains lung stability, while AGER is involved in various processes including development and inflammation. Meanwhile, in the down-regulated genes, FGF19 plays a role in cell survival, tissue repair, and tumor growth. Higher SFTPC expression and higher AGER expression align with higher survival probability while patients with lower FGF19 expression are found to increase their chances of survival. These genes can act as potential prognostic markers for predicting the progression of the disease.
Sex-specific analysis of lung adenocarcinoma (Figure 4) identified unexpected gene expression patterns and potential involvement of microtubules in metastasis. Members of the MAGE-A family, typically expressed in male germ cells, were unexpectedly up-regulated in both males and females with lung adenocarcinoma, suggesting further research into their role in females. Some of the top dysregulated genes encode microtubules or their assisting proteins, which may promote metastasis by influencing cell structure and promoting cell movement away from their original location.
This research can be used to help select specific genes and pathways that can act as targets for the development of targeted therapies.
Acknowledgements (Optional): I am deeply grateful to my mentor, Dr. James Marchant, for his constant guidance throughout my research process, from offering advice while developing my research question to reviewing the paper. I would also like to send a heartfelt thanks to my TA, Garth Fisher, who was there whenever I ran across an issue and would help me resolve it. Additionally, I want to express my gratitude toward everyone involved in the Southern California Academy of Sciences Research Training Program, led by Dr. Kimo Morris. It’s been a privilege participating in the program and the numerous opportunities provided by this program, including the chance to participate in this conference, have been invaluable. Finally, I would like to thank my parents for constantly supporting me every day and encouraging me to push my boundaries and reach beyond what I thought I was capable of.
References (Optional): al Zeyadi, M., Dimova, I., Ranchich, V., Rukova, B., Nesheva, D., Hamude, Z., Georgiev, S., Petrov, D., & Toncheva, D. 2015. Whole genome microarray analysis in non-small cell lung cancer. Biotechnology & Biotechnological Equipment, 29(1), 111–118. Mižíková, I., & Thébaud, B. 2021. Looking at the developing lung in single-cell resolution. American Journal of Physiology-Lung Cellular and Molecular Physiology, 320(5), L680–L687. Wang, B.-Y., Huang, J.-Y., Chen, H.-C., Lin, C.-H., Lin, S.-H., Hung, W.-H., & Cheng, Y.-F. 2020. The comparison between adenocarcinoma and squamous cell carcinoma in lung cancer patients. Journal of Cancer Research and Clinical Oncology, 146(1), 43–52.
