Novel MicroRNAs – A Biomarker For Early Detection Of Pancreatic Cancer: Research Review
Pancreatic cancer is one of the lethal types of cancer with high mortality rate, due to the late development of clinical symptoms in early stages. An early method which is non-invasive for detecting pancreatic cancer to improve survival rate has been a challenge. Circulating microRNAs (miRNAs) a non-coding small single strand RNAs is an emerging biomarker for early detection of pancreatic cancer has shown to be a non-invasive screening method however, recent advancements on miRNAs remain inconclusive. Aiming to identify plasma miRNAs specific diagnostic markers of pancreatic cancer (PCa) and to evaluate their additional role with serum carbohydrate antigen (CA19-9), in an article ‘’Plasma miRNAs Effectively Distinguish Patients with Pancreatic Cancer from the Control’’ published in the Annals of Surgery ‘’ by Xu and his colleagues. In a multiphase and multicentre study, Xu and his colleagues identified diverse miRNAs that show the ability to differentiate patients with pancreatic cancer, chronic pancreatitis from the normal volunteers.
Introduction
Pancreatic cancer (PCa) is the 10th most commonly diagnosed and the 4th leading cause of cancer related death in the United States (Buchsbaum et al., (2014), Siegal et al., (2018)) and forecast by Siegal and his colleagues claiming it will be the 2 nd most fatal cancer in in the United State by 2020. In comparison with other malignancies and the rate which their trend decline there has been little improvement in the survival rate of patient with pancreatic cancer Zhang et al., (2018) and its rate of incidence increases leading to 227,000 deaths yearly Herreros-Villanueva et al., (2016). The main reason for the lethality of pancreatic cancer is the difficulties in making an accurate prognosis due to no symptom at an early stage. Pancreatic ductal adenocarcinoma (PDAC) which arises from the ductal epithelium is the top-tier histologic type of pancreatic cancer. Majority of patients with PCa advances to either locally advanced or metastatic disease in the asymptomatic phase Herreros-Villanueva et al., (2016) about 80% accounts for patients with late metastasis at diagnosis characterised by an aggressive local invasion.
According to Liu et al., (2012), the overall 5- year survival after resection of large PCa (median size of 30mm) is 10-20% and after resection of the small tumours (≤ 20mm) it is about 30-60% while it exceeds 75% when minute tumours (≤ 10mm) are resected. Imaging techniques have poor sensitivity and specificity for PCa diagnosis and surgical resection is the only curative modality for PDAC Buchsbaum et al., (2014). Thus, Liu et al., (2012) also stated that the best strategy to increase the rate of surgical resection and prolong survival of PCa is the improvement in diagnosis at an early stage. Currently, there are no available tumor markers available and specific for early pancreatic cancer diagnosis, hence the detection of PCa associated biomarkers in plasma, serum and or blood at an early stage offers a novel diagnostic and favorable opportunity to reduce PCa death rate.
Carbohydrate antigen (CA19-9) a sialylated form of Lewis antigen and carcinoembryonic antigen (CEA) are the conventional important tumor markers for PDAC; however, CA19-19 and CEA have limited specificity and sensitivity for the detection of early PCa. Furthermore, similarities between PCa and chronic pancreatitis histologically and clinically makes the early diagnosis of pancreatic cancer difficult. Novel non-invasive and low cost biomarkers that are sensitive and specific are highly required because of the poor prognosis and the need to improve survival rates of patients with PCa. Recently, microRNAs (miRNAs) has paved way as biomarkers for PCa. MicroRNAs are tiny, endogenously expressed non-coding ribonucleic acids (RNAs) consisting of about 18-24 nucleotides that are important for post-transcriptional regulators of gene expression Liu et al., (2012). Dysregulation of miRNAs have been shown in human diseases and has been reported that aberrant expression of miRNAs in tumor tissue has suggested their possible potential as a diagnostic biomarker. The selected miRNAs quantification in plasma and or in serum of high risk pancreatic cancer patients has been put forward as an effective biomarker for the early diagnosis of pancreatic cancer. Sadly, different published signatures of miRNAs identified remain inconsistent. In addition, the precision in quantification of miRNAs in either plasma or serum is said to be affected by procedures of sample preparation, methodological variables, cDNA preparation method, and the measurement of miRNAs applied. These factors may likely be the factors behind the miRNAs profiles inconsistency published by different authors. Here, I aimed to review the author’s article to identify the circulating miRNAs proven to be an emerging diagnostic tool for early pancreatic cancer.
Results and Data presentation
Xu and his colleagues conducted the first multicenter study which seeks to determine miRNAs as a pancreatic cancer biomarker by juxtaposing the differences in miRNAs in the peripheral venous blood samples of pancreatic neuroendocrine tumor (PNET), chronic pancreatitis (CP), other pancreatic tumor (OPT) to healthy individuals. The authors used 3 pool sample from 7patients with pancreatic cancer, 6 with chronic pancreatitis, and 5 healthy volunteers in the discovery phase. Two preliminary validation phases were used to select 13 microRNAs for and additional evaluation in a larger sample size. In the first preliminary validation phase plasma sample was collected from 29 patients with pancreatic cancer, 16 patients with chronic pancreatitis, and 31 healthy volunteers. The second preliminary validation phase which is the large sample phase has 156 PCA patients, 57 CP patients, 27 PNET patients and 65 healthy volunteers using a Taqman low density arrays for the early detection of PCa. The blood samples used were pretreatment samples collected before surgery.
The Results from the discovery phase exhibit that 29 miRNAs has the potential to distinguish PCa from the healthy volunteers. MiRNAs selected from discovery phase were all validated using the quantitative real time polymerase chain reaction (qRT-PCR) in a second preliminary phase in which Xu and his colleagues selected 13 miRNAs for a further validation in a final and large sample study. Out of the 13 selected miRNAs, 5 miRNAs were markedly upregulated in PCa samples versus healthy volunteers, 3 show diagnostic potential. 8 miRNAs in PCa versus CP were markedly up-regulated, 5 were determined to show a diagnostic potential. 4 miRNAs were markedly up-regulated. PCa versus PNETs and 4 also were found to be markedly up-regulated in PCa versus OPT and one miRNAs shown to have a diagnostic value. The diagnostic values of some of the identified miRNAs profiles were selected by the authors and were compared to the carbohydrate antigen CA19-9 levels. MiR-486-5p diagnostic value did not show any significant difference with CA19-9 in PCa patients compared to the control (liken the AUC values of miR-486-5p and CA19-. P=0.602). Xu and his colleagues found that plasma 486-5p and miR- 938 to be equivalent to CA19-9 in differentiating patients with PCa from chronic pancreatitis patients while Liu et al., (2012) has shown miR-16 and MiR-196a are effective early markers for PCa which effectively supplement serum CA19-9 for PCa and differential diagnosis of CP patients. Xu and his colleagues further indicated the diagnostic value of miR-486-5p in gastric cancer and is supported by Zhu et al., (2014) to be elevated in the plasma of gastric cancer patients compared with controls.
Several studies have reported significant overexpression of miR-21 in pancreatic tumors Park et al., (2011), the study by the author’s, appraised miRNAs in the plasma broadly for the sole purpose of identifying the early stage of PDAC, OPT, PNET patients from the healthy controls. This was the first of its kind by a multiple independent center in an almost large sized well carried out design that authenticated the diagnostic potential of plasma miRNAs as a biomarker for the early detection of pancreatic cancer. Thus, the nature of this study requires to the explored deeply. Notwithstanding the prudent advancement in this study the data presented in the area under the curve (AUC) Xu and his colleagues did not determine that the miRNA signature contribute to an enhanced clinical performance over serum CA19-9 in PDAC patients from the controls. Again, the study did not evaluate the diagnostic value of CA19-9 combination with miRNAs. It is logical that the admittance of the plasma samples for miRNAs and CA19-9 could be a challenge. Another complication is the quantification circulating miRNAs as a biomarker from a small study size which affects the total RNA. Thus, it is difficult to quantify isolated RNA due to low amounts in the blood. It is utmost importance that detected miRNAs signature values are accurately and precisely normalized. U6 a conflicting normalizing agent and miR-16 has been used by the authors as an internal control to reduce false positive results. Strengths and limitation of the study Circulating miRNAs are non-invasive and so are easy to obtain with minimal damage. A high number of miRNA biomarkers are stable in healthy people and its expression levels may not be affected by age, gender, body mass index, smoking status when determining the pathogenic potential.
Finally, miRNAs altered expression pattern may be part of the routine examination for monitoring and early diagnosis of cancers. Limitation of the study is in its failure to specify the sampling methods in different patients from the control even because their expression levels differ quite little and also miRNA biomarkers exist in both healthy individuals and cancer patients.
Personal opinion
The article was a great one the author’s successfully analyzed new diagnostic approach for the early diagnosis of pancreatic cancer. Despite the fact that efforts has been made miRNAs biomarkers have limited role and more efforts are required to enhance its diagnostic mechanism. New hope based on the methylation in stools Herreros-Villanueva et al., (2012), that suggest that early diagnosis of PDAC may be possible in improving survival rate needs to be looked into and properly studied.
Conclusion
Early detection of pancreatic cancer is the best way of improving treatment and increasing survival rate in patients diagnosed with pancreatic cancer. MicroRNAs is an important diagnostic biomarker and treatment target for pancreatic cancer and host of other cancers. Finally, an efficient technical and clinical exploration in regards to the combination of microRNAs and CA19-9 requires an extended study.
