microRNA Biomarkers as Potential Diagnostic Markers for Cancer - Genomic Biomarkers for Pharmaceutical Development - page 110

oncogenic activity by targeting a number of cancer suppressor genes [184-186] . miR-21 was
reported to be elevated in peripheral blood of gastric cancer patients compared to controls,
and it was further reported that this miRNA was associated with TNM stage [187] .
Zhou et al. spiked gastric cancer cells into blood samples from healthy volunteers and
showed a correlation between the number of gastric cancer cells and the levels miR-106a and
miR-17 [188] . These two miRNAs were significantly (p<0.05) higher in peripheral blood of pre-
and post-operative gastric patients (N = 90) relative to controls (N = 27). Studies by Tsujiura and
coworkers corroborated the miR-106a findings of Zhou et al. [188] in addition to reporting other
miRNAs like miR-106b, miR-21, and miR-17-5p as being significantly up-regulated in plasma
of gastric cancer patients (N = 69) relative to controls (N = 30) [189] . Interestingly, Tsujiura and
et al. also found that the expression levels of let-7a were lower in gastric cancer patients rela-
tive to controls (p = 0.002). The miRNA pair, miR-106a and let-7a, was able to distinguish gas-
tric cancer patients from controls with an AUC of 0.879, which was better than that of miR-106a
alone (AUC = 0.721). However, with the exception of miR-21, miR-106a, and miR-17-5p, there is
very little consensus on the potential diagnostic circulating miRNAs in gastric cancer.
5.3.2.6 Colorectal Cancer
Colorectal cancer (CRC) is one of the major cancer types that affects both men and women.
In the US, there are over 143,000 new cases of CRC every year, and in 2012 approximately
52,000 will die of the disease [190] . Although colonoscopy has significantly increased the
number of cases detected at an early and manageable stage, a number of people do not have
the necessary screening, in part due to cost and in part due to avoidance of the invasive pro-
cedure [191] . A molecular screening test, Cologuard, has been developed by Exact Science for
the detection of pre-cancerous polyps and CRC based on DNA mutation and methylation
markers combined with the immunohistochemical analysis of occult blood in stool [192-194] .
However, a need still exists to identify biomarkers for the early detection of CRC in non-inva-
sive specimens. For that reason, blood-based miRNAs are promising, and have recently been
widely explored as diagnostic analytes for CRC.
In 2009, Ng et al. evaluated the expression of 95 miRNAs in plasma and CRC tissues, and
found that miR-17-3p and miR-92 were elevated in both sample types [195] . Furthermore,
the plasma levels of both miRNAs were reduced following curative surgery, suggesting that
these markers could be used for diagnosis and monitoring of CRC. Huang and coworkers
substantiated these findings by showing that plasma levels of miR-29a and miR-92a were
able to distinguish healthy controls from patients with advanced CRC with an AUC of 0.844
and 0.838, respectively [196] . In the same study, the miRNAs were also used to distinguish
controls from advanced adenomas, making miR-92a and miR-29a good candidates for poten-
tial early diagnostic markers for CRC. On the other hand, Wang et al. showed that miR-29a
was elevated in serum of 38 CRC patients with liver metastasis when compared to CRC
patients without metastasis [197] , suggesting that miR-29a could be used as a marker for dis-
ease progression.
miR-21 has been demonstrated to be up-regulated in several cancer types relative to cor-
responding controls [198] . Levels of circulating miR-21 are also up-regulated in many cancer
types including ALL, lung cancer, gastric cancer, breast cancer, pancreatic cancer, and CRC.
In studies on circulating miRNAs in CRC, Pu et al. found that plasma levels of miR-21, in
addition to miR-221 and miR-222, were significantly higher in 103 CRC patients relative to 37