Abstract

The incidence and mortality rates of colorectal cancer (CRC) have been high in recent years. Prevention and early detection are crucial for decreasing the death rate. Therefore, this study aims to characterize the alteration patterns of mothers against decapentaplegic homolog 3 (SMAD3) in patients with CRC and its applications in early detection by using a genome-wide methylation array to identify an aberrant hypomethylation site in the intron position of the SMAD3 gene. Quantitative methylation-specific polymerase chain reaction showed that hypomethylated SMAD3 occurred in 91.4% (501/548) of Taiwanese CRC tissues and 66.6% of benign tubular adenoma polyps. In addition, SMAD3 hypomethylation was observed in 94.7% of patients with CRC from The Cancer Genome Atlas dataset. A decrease in circulating cell-free methylation SMAD3 was detected in 70% of CRC patients but in only 20% of healthy individuals. SMAD3 mRNA expression was low in 42.9% of Taiwanese CRC tumor tissues but high in 29.4% of tumors compared with paired adjacent normal tissues. Hypomethylated SMAD3 was found in cancers of the digestive system, such as liver cancer, gastric cancer, and colorectal cancer, but not in breast cancer, endometrial cancer, and lung cancer. In conclusion, SMAD3 hypomethylation is a potential diagnostic marker for CRC in Western and Asian populations.

Highlights

  • Colorectal cancer (CRC) has become an increasing global health burden in recent years

  • According to the results of the aforementioned analysis, we demonstrated the methylation levels using a heatmap. cg24032190, which is located on the gene body of SMAD3, showing that they were hypomethylated in 94.7% (36/38) of colorectal cancer (CRC) paired tissues and 92.0% (289/314) of nonpaired colorectal tumor tissues (Figure 3A,B)

  • The results revealed that SMAD3 hypomethylation can be detected in both early and late stages of CRC (Table 1 and Table S1)

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Summary

Introduction

Colorectal cancer (CRC) has become an increasing global health burden in recent years. The mortality rate of CRC is the third-highest for cancers in the United States and Taiwan [1,2]. The rate of increase in new cases and deaths is estimated to grow to 60% by 2030 [4]. The U.S Food and Drug Administration proved that Septin 9 (SEPT9) serves as a putative biomarker in the early detection of CRC, with significant sensitivity (71.1–95.6%) and specificity (81.5–99%) [11]. Methylated ccfDNA is beneficial for early diagnosis and for prognosis in metastatic CRC [13]. These novel findings motivate us to conduct an in-depth study to identify new potential biomarkers for detecting CRC early. The SMAD3 methylation level in CRC tumors, which was half that of adjacent normal colorectal tissue, was defined as hypomethylation

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