m6A As An Effective Biomarker for Gastric Cancer

N6-Methyladenosine (m6A) is the most abundant RNA modification found in eukaryotes and is largely responsible for RNA methylation. It’s formed when a methyl group is added to the nitrogen-6 position of adenosine. This dynamic process is also regulated by two epigenetic mechanisms known as demethylases and methyltransferases.

Levels of m6A in Peripheral Blood of GC Patients

(A) The m6A levels of peripheral blood RNA in 100 GC patients, 30 BGD patients, and 75 HCs; (B) the m6A levels of peripheral blood RNA in different pathologic stages of GC patients (C) comparison of m6A levels of peripheral blood RNA between GC patients with and without metastasis; (D) the m6A levels of peripheral blood RNA in GC patients before and after operation (7 days).

Gastric cancer (GC) is a common and deadly type of cancer found all over the world. Unfortunately, there are not many known biomarkers that effectively detect the early stages of GC, so it is often already in an advanced stage when found. m6A is linked with various human cancers like leukemia, breast cancer, and prostate cancer, making it an important modification to explore.

In a study published in Clinical Chemistry, scientists from the Medical School of Nanjing University investigated the effect that m6A had on the development of gastric cancer. The team investigated m6A levels in peripheral blood samples from 100 patients with GC; 30 patients with benign gastric disease (BGD) and 75 healthy controls (HC).

To quantify m6A in the blood, the team used the EpiQuik™ m6A RNA Methylation Quantification Kit (Colorimetric). The m6A levels in GC patients were then mapped against the BGD and healthy patients. According to figure 1, m6A amounts were significantly higher in patients with GC when compared to the BGD and HC groups. Interestingly, they also sought to determine whether m6A levels could diagnose different stages of GC. They found that patients with stage IV GC exhibited significantly higher levels of m6A than those with stage I or II GC.

The results suggest that the high levels of m6A may be due to the extreme downregulation of ALKBH5 and FTO -- two proteins that normally operate as m6A demethylases to help regulate RNA methylation.

Diagnostic Value of m6A Levels in Peripheral Blood RNA

Clinical utility of peripheral blood RNA m6A level, CEA, and CA199 in the diagnosis of GC. (A) ROC curve (left) and cutoff value (right) for m6A including GC patients and HCs; (B) ROC curves (left) for m6A, CEA, and CA199 alone or together and cutoff value (right) for m6A, CEA, and CA199 in combination including GC patients and HCs.

Additionally, m6A levels in GC patients were found to have increased as cancer progressed and metastasized, but they significantly decreased after surgery. This occurrence could potentially be due to the compensatory upregulation of ALKBH5.

The researchers looked to confirm their findings in mouse models using a xenograft. They found that the high m6a levels in peripheral blood and the decreased expression of both ALKBH5 and FTO were consistent with the human samples in vitro and in vivo.

One of the purposes of this study was to determine if m6A could be a valid biomarker in detecting GC. In figure 2, the team mapped out the levels of cancer biomarkers m6A, carcinoembryonic antigen (CEA), carbohydrate antigen (CA) found in the blood of patients with GC versus healthy patients. They found that m6a was a more specific indicator for GC when compared to CEA and CA. However, a combination of all three markers offered the greatest diagnostic capability for patients with GC.

These findings illustrate the importance of having additional biomarkers to identify GC before it has an opportunity to advance. In the future, testing m6A levels in peripheral blood samples may offer a hopeful, non-invasive solution for detecting GC and other cancers.

Source
Wang J. et al. (2020) Level of N⁶-Methyladenosine in Peripheral Blood RNA: A Novel Predictive Biomarker for Gastric Cancer, Clinical Chemistry, 66 (2), Feb. 2020, Pg 342–351

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