Study of Promoter Methylation Patterns of HOXA2, HOXA5, and HOXA6 and Its Clinicopathological Characteristics in Colorectal Cancer

Research on DNA methylation offers great potential for the identification of biomarkers that can be applied for accurately assessing an individual's risk for cancer. In this article, we try to find the ideal epigenetic genes involved in colorectal cancer (CRC) based on a CRC database and our CRC cohort. The top 20 genes with an extremely high frequency of hypermethylation in CRC were identified in the latest database. Remarkably, 3 HOXA genes were included in this list and ranked at the top. The percentage of methylation in the HOXA5, HOXA2, and HOXA6 genes in CRC were up to 67.62, 58.36, and 31.32%, respectively, and ranked first in CRC among all human tumor tissues. Paired colorectal tumor samples and adjacent non-tumor colorectal tissue samples and four CRC cell lines were selected for MethylTarget™ assays. The results demonstrated that CRC tissues and cells had a stronger methylation status around the 3 HOXA gene promoter regions compared with adjacent non-tumor colonic tissue samples. The Receiver operator characteristic curve (ROC) curves for HOXA genes show excellent diagnostic ability in distinguishing tissue from healthy individuals and CRC patients, especially for Stage I patients (AUC = 0.9979 in HOXA2, 0.9309 in HOXA5, and 0.8025 in HOXA6). An association analysis between the methylation pattern of HOXA genes and clinical indicators was performed and found that HOXA2 methylation was significantly associated with age, N, stage, M, lymphovascular invasion, perineural invasion, lymph node number. HOXA5 methylation was associated with age, T, M, stage, and tumor status, and HOXA6 methylation was associated with age and KRAS mutation. Notably, we found that the highest methylation of HOXA5 and HOXA2 occurs in the early stages of colorectal cancer tissues such as stage I, N0, MO, and non-invasive tissues. The methylation levels declined as tumors progressed. However, methylation level at any stage of the tumor was still significantly higher than in normal tissues (p < 0.0001). The mRNA of the 3 HOXA genes was downregulated in early tumor stages due to hypermethylation of CpG islands adjacent to the promoters of the genes. In addition, hypermethylation of HOXA5 and HOXA6 mainly occurred in patients < 60 years old and with MSI-L, MSS, CIMP.L and non-CIMP tumors. Together, this suggests that epigenetic silencing of 3 adjacent HOXA genes may be an important event in the progression of colorectal cancer

Relationship between lung function impairment, hypertension, and major adverse cardiovascular events: A 10‐year follow‐up study

Abstract Lung function impairment and hypertension, especially hypertension, are risk factors of major adverse cardiovascular events (MACEs). However, the relationships among lung function impairment, hypertension, and MACEs have not been well‐reported. We aimed to investigate the association between lung function and hypertension and MACEs. We studied 6769 people who were a representative sample of the general population in Jiangsu Province using the multi‐stage stratified cluster sampling method. The average age was 51.54 years. Cox proportional hazards models were used to analyze the relationships between the blood pressure status and various types of lung function impairment related to MACEs. Over a follow‐up of 10 years, 236 MACEs occurred. After adjusting for age, sex, BMI, smoking, drinking, education, physical activity, diabetes mellitus, dyslipidemia, creatine and use of antihypertensive drugs, hypertension [hazard ratio (HR) = 2.154, 95% confidence intervals (CI): 1.565–2.966], and restrictive lung function impairment (RLFI) (HR = 1.398, 95% CI: 1.021–1.879) were independently associated with MACEs. Individuals with hypertension and RFLI had the highest risk for MACEs (HR = 2.930, 95% CI: 1.734–4.953) and stroke (HR = 3.296, 95% CI: 1.862–5.832). Moreover, when combined with hypertension, obstructive lung function impairment (OLFI) (HR = 2.376, 95% CI: 1.391–4.056) and mixed lung function impairment (MLFI) (HR = 2.423, 95% CI: 1.203–4.882) were associated with MACEs. There is a synergistic effect of lung function impairment (especially RLFI) and hypertension on MACEs. Therefore, more attention should be paid to the incidence of MACEs in individuals with impaired lung function, especially those who have hypertension