Deciphering Age-Associated Gene Expression Patterns in Colon Cancer: Implications for Older Patients' Risk and Survival

Abstract

In recent years, there has been a concerning trend of increasing colorectal cancer incidence rates among young adults. Colorectal cancer, which has historically been linked to aging, is currently the primary cause of cancer-related deaths among men aged 29 to 49 in the United States. Furthermore, it stands as the third leading cause of cancer-related mortality globally. This concerning shift highlights the need for further research and increased awareness of the disease in relation to age. The majority of colorectal cancer cases are colon adenocarcinomas (COAD, more commonly referred to as colon cancer), arising from dysregulatory genetic or epigenetic mutations in colon epithelial cells that confer them a selective advantage in their environments. While risk factors such as family history, inflammatory bowel diseases, smoking, poor diet, obesity, and lack of exercise have been identified, the precise reasons for the surge in young adult cases remain unclear.  The primary objective of this study is to explore and comprehend the significant gene expression patterns and biological pathways linked to colon cancer. The particular emphasis is on distinguishing these patterns between younger and older patients to investigate whether age might have a potential association with these gene expression trends. By examining age-related differences in gene expression, the research aimed to shed light on potential age-related factors contributing to colon cancer development and progression. To this end, transcriptomic data and clinical data from The Cancer Genome Atlas database was retrieved and then analyzed for differentially expressed (DE) genes by comparing 473 colon cancer tissues with 41 adjacent normal tissues. In addition, tissues of colon cancer patients aged < 50 years and those aged ≥ 50 years were evaluated for signature biological pathways, hub genes, and the survivability associated with these hub genes. It was found that in colon cancer patients, genes such as matrix metallopeptidase 7 (MMP7), cystatin SN (CST1), and kallikrein related peptidase 6 (KLK6) are highly upregulated, whilst carbonic anhydrase 1 (CA1), otopeptrin 2 (OTOP2, and aquaporin 8 (AQP8) are highly downregulated. Additionally, it was shown that the genes COL1A1, SPP1, TIMP1, BGN, COL10A1, THBS2SIX1, GABRD, SLC4A4, P4HA3, TNNI3, COL4A6, CBLN2, FAP, ZG16, B3GNT6, AQP8, and SFRP4 are associated with the poor survival rate of colon cancer patients. Notably, it was also found that in colon cancer patients aged ≥ 50 years, claudin 18 (CLDN18), beta-1,4-N-acetyl-galactosaminyltransferase 4 (B4GALNT4), and desmocollin 3 (DSC3) are markedly downregulated. In contrast, it was found that colon cancer patients aged < 50 years showed no significant differential gene expression compared to adjacent normal tissues. The findings from this research significantly contribute to a deeper comprehension of age-related factors in the development of colon cancer and provide valuable insights into the roles certain genes may play in shaping the outcomes of colon cancer patients, especially for older patients. By identifying and elucidating these associations, this study enhances our knowledge of the disease's pathogenesis, potentially paving the way for improved diagnostics, targeted therapies, and more personalized treatment strategies for colon cancer patients, particularly for higher-risk, older patients.