The Association of Hyperhomocysteinemia (HHCY) with Cancer Risk: An Updated Systematic Review and Meta-analysis of Case-Control Studies (2013-2024)

Abstract: Cancer continues to be one of the leading causes of morbidity and mortality globally, influenced by a complex interplay of genetic, environmental, and nutritional factors. Among these, the metabolism of homocysteine (HCY), a sulfur-containing amino acid derived from dietary methionine, has attracted growing attention due to its involvement in one-carbon metabolism and its potential link to cancer. Elevated HCY levels, a condition known as hyperhomocysteinemia (HHCY), have been shown to disrupt crucial cellular processes such as DNA methylation and promote oxidative stress (OS)—both of which contribute to genomic instability and cancer progression. Disruptions in the folate and methionine cycles, as well as genetic polymorphisms like MTHFR C677T, can exacerbate HHCY and increase cancer susceptibility. This study aimed to explore the relationship between HCY levels and cancer risk through a systematic review and meta-analysis of case-control studies, with the goal of elucidating the role of HHCY in cancer development. A comprehensive literature search identified 1880 studies, of which 31 met the inclusion criteria. A total of 4937 cancer cases and 6053 controls were included in the analysis. The results indicated a significant association between elevated HCY levels and increased cancer risk, with a pooled odds ratio (OR) of 1.18 (95% CI [1.04, 1.33]). Additionally, a meta-analysis of mean differences revealed significantly higher HCY levels in cancer cases compared to controls (pooled standardized mean difference = 1.56, 95% CI [0.11, 3.01]). These findings highlight the potential role of HCY as a biomarker for cancer risk, though significant heterogeneity across studies suggests the need for further research to understand the underlying mechanisms and the impact on different cancer types.