Background: The aim of this study was to investigate the association between plasma levels of homocysteine and the occurrence and progression of rectal cancer.

Material/Methods: The 320 study participants included healthy controls (n=80). and patients with rectal tumors (n=240), including 155 patients with rectal cancer, Stage I (n=32), Stage II (n=38), Stage III (n=50), and Stage IV (n=35), and patients with low-risk rectal adenomas (n=31), and high-risk rectal adenomas (n=54). All study participants had fasting blood samples taken, and plasma levels of homocysteine and carcinoembryonic antigen (CEA) were measured and compared. Receiver operating characteristic (ROC) curves were prepared to determine whether single, combined, or series levels of the two markers were diagnostic.

Results: A significantly increasing trend in the plasma levels of homocysteine from the healthy controls, to the individuals with low-risk rectal adenoma, high-risk rectal adenoma, and Stage I–IV rectal cancer were found. There were no statistically significant differences in the area under the curve (AUC) between the two single factors of plasma homocysteine and CEA. The AUC showed that the use of combined or parallel measurement of plasma CEA and homocysteine had the greatest diagnostic associations.

Conclusions: Plasma levels of homocysteine were significantly associated with occurrence and progression of rectal cancer. The combined use of measurement of plasma homocysteine and CEA levels might have the potential to increase the diagnostic efficiency of screening for early rectal cancer.

Hyperhomocysteinemia/Homocysteinuria is characterized by an increased level of toxic homocysteine in the plasma. The plasma concentration of homocysteine is 5-15 μmol/L in healthy individuals, while in hyperhomocysteinemic patients, it can be as high as 500 μmol/L. While increased homocysteine levels can cause symptoms such as osteoporosis and eye lens dislocation, high homocysteine levels are most closely associated with cardiovascular complications. Recent advances have shown that increased plasma Hcy is also a fundamental cause of neurodegenerative diseases (including Alzheimer's disease, Parkinson's disease, and dementia), diabetes, Down syndrome, and megaloblastic anemia, among others. In recent years, increased plasma homocysteine has also been shown to be closely related to cancer. In this review, we discuss the relation between elevated plasma Hcy levels and cancer, and we conclude that disturbed homocysteine metabolism is associated with cancer. Future clinical perspectives are also discussed.

Aim: Hyperhomocysteinemia has been associated with different pathologies, including cardiovascular diseases, hypertension, diabetes, and breast cancer (BC). To examine the differences in total homocysteine (tHcy) plasma levels, we compared healthy women to BC patients from a Mexican population.

Materials and methods: The tHcy plasma levels were measured using high-performance liquid chromatography with a fluorescence detector in 89 female controls and 261 BC patients.

Results: The observed plasma tHcy levels were significantly higher among the BC patients (11.1019 ± 5.9161 µmol/l) compared to the controls (9.1046 ± 1.3213 µmol/l) (p = 0.002), and these differences were evident when stratified by age (≥ 50 years old), menopause status, overweight and obesity, miscarriages, node metastases, progression, subtype classification (luminal, Her2 and triple negative) and nonresponse to chemotherapy.

Conclusions: The tHcy plasma levels could be a good marker for the progression and chemosensitivity of BC in the analyzed sample from a Mexican population.

Patients with malignancy have an increased risk of venous thromboembolic disease but the pathophysiology of this association has not been precisely defined. Hyperhomocysteinemia has become established as one of the commonest conditions associated with venous and arterial thrombosis. We examined the prevalence of hyperhomocysteinemia in women with early (group A, n = 31), metastatic breast cancer (group B, n = 41) and in a group of healthy females (group C, n = 29). Blood samples were collected at diagnosis or prior to treatment. We measured both total plasma homocysteine (tHcy) and red cell folate (RCF). The Mean (SD) tHcy were group A - 9.43 micromol/l (5.6), group B - 11.34 micromol/l (5.1) and group C - 7.9 micromol/l (1.5). A total of 39% of patients with metastatic and 22.6% with early breast cancer had tHcy concentrations above the upper limit of normal. Women with metastatic disease had significantly higher tHcy compared with controls (P < 0.01) but not when compared with women with early breast cancer. Also, no difference was observed when women with early disease were compared with controls. We found no correlation between age and tHcy. Lower RCF levels were identified in group B compared with group A, but this does not fully explain the increased tHcy levels seen within the same group. We conclude that hyperhomocysteinemia is common in women with advanced breast cancer. This observation could explain the high rate of venous thrombosis in women with metastatic breast malignancy.

Purpose: Accumulative evidence suggests that folate has a protective effect on gastric cancer. The methylenetetrahydrofolate dehydrogenase (MTHFD) plays an important role in folate and homocysteine metabolisms, and polymorphisms of MTHFD may result in disturbance of the folate-mediated homocysteine pathway. The aim of this study is to test the hypothesis that genetic variants of MTHFD and plasma homocysteine levels are associated with risk of gastric cancer and modulated by genotypes of methylenetetrahydrofolate reductase (MTHFR).

Experimental design: We genotyped G1958A and T401C in MTHFD and C677T in MTHFR and detected total plasma homocysteine (tHcy) levels in a case-control study of 589 gastric cancer cases and 635 cancer-free controls in a high-risk Chinese population.

Results: The variant genotypes of MTHFD 1958AA and 401CC were associated with a significantly increased risk of gastric cancer [adjusted odds ratio (OR), 2.05; 95% confidence interval (95% CI), 1.34-3.13 for 1958AA; adjusted OR, 1.43; 95% CI, 1.14-1.80 for 401CC] compared with 1958GG/GA and 401TT/TC genotypes, respectively. Both of the effects were more evident in the subjects carrying MTHFR 677CT/TT genotypes. The average tHcy level was significantly higher in gastric cancer cases than in controls (P < 0.01), and the upper quartile of tHcy (>13.6 micromol/L) was associated with an 82% significantly increased risk of gastric cancer, compared with the lowest quartile of tHcy (<or=8.0 micromol/L; adjusted OR, 1.82; 95% CI, 1.20-2.75).

Conclusions: The strong associations between MTHFD variants and the plasma tHcy levels and gastric cancer risk suggest, for the first time, a possible gene-environment interaction between genetic variants of folate-metabolizing genes and high tHcy levels in gastric carcinogenesis.

High blood homocysteine levels may risk gastric cancer. However, observational studies have been plagued by chance, bias, confounding, or reverse causality. In this study, we assessed the relationship between blood homocysteine levels and gastric cancer by using a Mendelian randomization method, which is independent of nongenetic confounding.We took 2 steps to perform Mendelian randomization analysis. First, we evaluated the methylenetetrahydrofolate reductase (MTHFR) C677T association with gastric cancer by a meta-analysis of case-control studies including 7566 patients with gastric cancer and 10 640 control subjects from 27 Case-Control studies. Second, MTHFR C677T polymorphism, which affects the blood homocysteine levels, was used as an instrumental variable to calculate the risk and estimate the association of gastric cancer with this single nucleotide polymorphism (SNP). We obtained an estimate to the association of blood total homocysteine levels with this SNP from a meta-analysis of Genome-Wide Association Studies (GWAS), which comprises a total of 44 147 individuals.In our Mendelian randomization analysis, we demonstrated a significant effect of the blood homocysteine levels on gastric cancer risk, representing an OR of 2.56 (95% CI = 2.41-2.72; P = 5.0×10) for gastric cancer per 1-SD increase in the natural log-transformed blood total homocysteine levels.We proved that there is a causal relationship between blood total homocysteine and risk of gastric cancer, and this study will add insight into the treatment and pathology research of gastric cancer.

Aim: Disorders in the metabolism of homocysteine and B vitamins, which are involved in a one-carbon transfer reaction and important for DNA synthesis and methylation, have been hypothesized to be associated with carcinogenesis. The purpose of this study is to evalu-ate the levels of homocysteine, vitamin B12 and folic acid in patients with newly diagnosed lung cancer and determines whether they might be used as an accurate tumor marker for monitoring the patients if they are found to be elevated in lung cancer.

Materials and methods: Forty male patients with lung cancer were included in this study. Age-matched forty healthy males who had not malignant disease or had not received any drug affecting plasma homocysteine levels were selected as control group. Homocysteine, vitamin B12 and folate levels were measured in the samples obtained from the patients and controls.

Results: Mean age of the patients with lung cancer was 58.7 ± 9.9 years. All the patients were cigarettes smokers. Mean daily consumption of cigarettes was 2.0±0.7 packs and mean duration of smoking was 30 ± 11 years. Histologic type of carcinoma was found to be squamous cell carcinoma in 55%, adenocarcinoma - in 35%, and small cell carcinoma - in 10% of the cases. Clinical stage was stage IA in 20%, stage IB - in 20%, stage IIA - in 2.5%, stage IIB - in 10%, stage IIIA - in 12.5%, stage IIIB - in 20%, and stage IV - in 15% of the cases. Mean homocysteine level was 15.3 ± 7.3 µmol/l in the patients with lung cancer while 9.8 ± 2.6 µmol/l in controls. Homocysteine level was significantly higher in the patients with lung cancer compared to control group (p < 0.001). Mean folate level was 4.3 ± 1.8 pg/ml in cancer cases while 6.1 ± 2.3 pg/ml in controls. That is to say, plasma folate levels were significantly lower in cases of lung cancer compared to controls (p < 0.001). There was no significantly difference between groups with regard to B12 levels (mean B12 level was 234 ± 99 and 240 ± 104 ng/ml in the patients with lung cancer and controls, respectively, p = 0.78). Plasma homocysteine, vitamin B12 and folate levels did not show significant difference with respect to histologic type of carcinoma. No significant correlation was found between plasma homocysteine, vitamin B12, folate levels and number of cigarettes smoked per day, duration of smoking, age of the patient, and clinical stage of carcinoma. There was also no correlation between number of cigarettes smoked per day, duration of smoking, age of the patient and clinical stage of carcinoma. A possible inverse correlation between plasma homocysteine, vitamin B12 and folate levels was not observed.

Conclusion: In conclusion, high plasma homocysteine and low folate levels could be associated with lung cancer. However, further studies performed on large patient population are needed.

https://pubmed.ncbi.nlm.nih.gov/37627515/

Targeting Homocysteine and Hydrogen Sulfide Balance as Future Therapeutics in Cancer Treatment

https://pubmed.ncbi.nlm.nih.gov/38698172/

Elevated serum homocysteine levels associated with poor recurrence-free and overall survival in patients with colorectal cancer

https://pubmed.ncbi.nlm.nih.gov/30939165/

Folate/homocysteine metabolism and lung cancer risk among smokers

https://pubmed.ncbi.nlm.nih.gov/28685147/

Genotyping the High Altitude Mestizo Ecuadorian Population Affected with Prostate Cancer

https://pubmed.ncbi.nlm.nih.gov/25296737/

The changing of serum vitamin B12 and homocysteine levels after gastrectomy in patients with gastric cancer: do they associate with clinicopathological factors?

https://pubmed.ncbi.nlm.nih.gov/39203895/

Serum Homocysteine Levels and All-Cause and Cause-Specific Mortality in Korean Adult Men: A Cohort Study

Hyperprolactinemia can be caused by several conditions and its effects on the hypothalamic-pituitary-gonadal axis are understood in more detail. Nevertheless, in recent decades, other metabolic effects have been studied and data pointed to a potential increased cardiovascular disease (CVD) risk. A recent study showed a decrease in total and LDL- cholesterol only in men with prolactinoma treated with dopamine agonists (DA) supporting the previous results of a population study with increased CVD risk in men harboring prolactinoma. However, other population studies did not find a correlation between prolactin (PRL) levels and CVD risk or mortality. There is also data pointing to an increase in high-density lipoprotein levels, and decreases in triglycerides, carotid-intima-media thickness, C-reactive protein, and homocysteine levels in patients with prolactinoma on DA treatment. PRL was also implicated in endothelial dysfunction in pre and postmenopausal women. Withdrawal of DA resulted in negative changes in vascular parameters and an increase in plasma fibrinogen. It has been shown that PRL levels were positively correlated with blood pressure and inversely correlated with dilatation of the brachial artery and insulin sensitivity, increased homocysteine levels, and elevated D-dimer levels. Regarding possible mechanisms for the association between hyperprolactinemia and CVD risk, they include a possible direct effect of PRL, hypogonadism, and even effects of DA treatment, independently of changes in PRL levels. In conclusion, hyperprolactinemia seems to be associated with impaired endothelial function and DA treatment could improve CVD risk. More studies evaluating CVD risk in hyperprolactinemic patients are important to define a potential indication of treatment beyond hypogonadism.

Objectives: To explore the relationship between serum homocysteine, a sensitive biomarker for folate inadequacy and problems in one-carbon metabolism, and invasive cervical cancer.

Methods: A large case-control study was conducted in five US areas with up to two community controls, obtained by random-digit dialing, individually matched to each case. Cervical cancer risk factors were assessed through at-home interview. Blood was drawn at least 6 months after completion of cancer treatment from 51% and 68% of interviewed cases and controls. Serum homocysteine was measured by high-performance liquid chromatography, and exposure to human papillomavirus (HPV) type 16, the most prevalent oncogenic type, was assessed using an enzyme-linked immunosorbent assay. Cases with advanced cancer and/or receiving chemotherapy were excluded, leaving 183 cases and 540 controls.

Results: Invasive cervical cancer risk was substantially elevated for women in the upper three homocysteine quartiles (> 6.31 micromol/L); multivariate-adjusted odds ratios ranged from 2.4 to 3.2 (all 95% CIs excluded 1.0). A trend was apparent and significant (p = 0.01). When cases were compared with HPV-16 seropositive controls only, odds ratios were comparable.

Conclusions: Serum homocysteine was strongly and significantly predictive of invasive cervical cancer risk. This association could reflect folate, B12 and/or B6 inadequacy, or genetic polymorphisms affecting one-carbon metabolism.

Background: Apart from being a risk factor for atherosclerotic cardiovascular diseases, the latest research suggests homocysteine as a marker for cancer. We aimed to explore the clinical utility of plasma homocysteine levels as a marker in lung cancer.

Patients and methods: Changes in serum total thiols and folate levels were investigated in newly diagnosed untreated lung cancer patients (n = 37) and compared with healthy controls (n = 26). Fluorometric HPLC methods were used for the determination of thiols. Other parameters were determined with commercial diagnostic kits.

Results: Increased total homocysteine (t-Hcy), decreased total glutathione (t-GSH) and folate levels were observed in lung cancer patients compared with healthy controls. Total levels of thiols and folate did not show any significant difference between SCLC and NSCLC patients. However, there were significantly higher t-Hcy, lower t-GSH and folate levels in the advanced-stage group compared with controls. Prevalence of hyperhomocysteinemia was 65% in lung cancer patients when 12 micromol/l were taken as a cut-off value for t-Hcy levels.

Conclusion: Homocysteine is suggested as a marker for several types of cancer, but our result did not support this hypothesis for lung cancer. Although higher homocysteine levels were observed in the present study, further investigation in the larger cancer population would clarify the importance of homocysteine as a cancer marker.

Methionine is the initiator amino acid for protein synthesis, the methyl source for most nucleotide, chromatin, and protein methylation, and the carbon backbone for various aspects of the cellular antioxidant response and nucleotide biosynthesis. Methionine is provided in the diet and serum methionine levels fluctuate based on dietary methionine content. Within the cell, methionine is recycled from homocysteine via the methionine cycle, which is linked to nutrient status via one-carbon metabolism. Unlike normal cells, many cancer cells, both in vitro and in vivo, show high methionine cycle activity and are dependent on exogenous methionine for continued growth. However, the molecular mechanisms underlying the methionine dependence of diverse malignancies are poorly understood. Methionine deprivation initiates widespread metabolic alterations in cancer cells that enable them to survive despite limited methionine availability, and these adaptive alterations can be specifically targeted to enhance the activity of methionine deprivation, a strategy we have termed "metabolic priming". Chemotherapy-resistant cell populations such as cancer stem cells, which drive treatment-resistance, are also sensitive to methionine deprivation, suggesting dietary methionine restriction may inhibit metastasis and recurrence. Several clinical trials in cancer are investigating methionine restriction in combination with other agents. This review will explore new insights into the mechanisms of methionine dependence in cancer and therapeutic efforts to translate these insights into enhanced clinical activity of methionine restriction in cancer.

Background: Venous thromboembolism is a common complication in patients with colorectal cancer who exhibit high homocysteine and low folate levels. However, whether venous thrombosis is the result of a direct effect of folic acid or the presence of a homocysteine-mediated mediating effect cannot be determined. This study aimed to explore the association and mediating effects of serum folate and homocysteine on venous thromboembolism in patients with colorectal cancer.

Methods: This study included patients with colorectal cancer who were admitted to the First Hospital of Shanxi Medical University from May 2020 to May 2022. The patients' medical records were reviewed to collect information on general demographic characteristics, the prevalence of venous thromboembolism on admission, laboratory blood indices, serum folate, and serum homocysteine. SPSS 26.0 software was used for data collation and statistical analysis; the χ² test was utilized for univariate analysis and unconditional logistic regression was applied for multivariate analysis. R 4.1.2 was used to perform the mediating effect test.

Results: A total of 236 colorectal cancer patients were investigated. The prevalence of colorectal cancer combined with venous thromboembolism was 15.3%; serum folate was <10.75 nmol/L in 25.4% of patients; and serum homocysteine was ≥22 µmol/L in 30.5% of patients. After controlling for confounding factors, the risk of venous thromboembolism was 2.48 times greater [95% confidence interval (CI): 1.04 to 5.94] in patients with low serum folate (<10.75 nmol/L) than in those with high serum folate (≥10.75 nmol/L). Also, the risk of venous thromboembolism was greater in those with high serum homocysteine (≥22 µmol/L) [odds ratio (OR) =2.99. 95% CI: 1.11 to 8.08]. The mediating effect test showed no direct effect of serum folate on venous thromboembolism combined with colorectal cancer, and a full mediating effect of serum homocysteine between serum folate and venous thromboembolism combined with colorectal cancer, with a mediating effect value of 0.002 and a total effect value of 0.0054.

Conclusions: Serum folate influences the formation of venous thromboembolism through serum homocysteine. It is recommended that the nutritional supplementation of patients be enhanced to control serum folate and serum homocysteine levels.

Neurodegenerative diseases are the diseases of the central nervous system with various aetiology and symptoms. Dementia, Alzheimer's disease (AD), Parkinson's disease (PD) and autism are some examples of neurodegenerative diseases. Hyperhomocysteinemia (Hhcy) is considered to be an independent risk factor for numerous pathological conditions under neurodegenerative diseases. Along with genetic factors that are the prime cause of homocysteine (Hcy) imbalance, the nutritional and hormonal factors are also contributing to high Hcy levels in the body. Numerous clinical and epidemiological data confirm the direct correlation of Hcy levels in the body and generation of different types of central nervous system disorders, cardiovascular diseases, cancer and others. Till now, it is difficult to say whether homocysteine is the cause of the disease or whether it is one of the impacts of the diseases. However, Hhcy is a surrogate marker of vitamin B deficiency and is a neurotoxic agent. This Mini Review will give an overview of how far research has gone into understanding the homocysteine imbalance with prognostic, causative and preventive measures in treating neurodegenerative diseases.