Abstract
A part of colorectal cancer which is characterized by simultaneous numerous hypermethylation CpG islands sites is defined as CpG island methylator phenotype (CIMP) status. Stage II and III CIMP−positive (CIMP+) right-sided colon cancer (RCC) patients have a better prognosis than CIMP−negative (CIMP−) RCC treated with surgery alone. However, there is no gold standard available in defining CIMP status. In this work, we selected the gene pairs whose relative expression orderings (REOs) were associated with the CIMP status, to develop a qualitative transcriptional signature to individually predict CIMP status for stage II and III RCC. Based on the REOs of gene pairs, a signature composed of 19 gene pairs was developed to predict the CIMP status of RCC through a feature selection process. A sample is predicted as CIMP+ when the gene expression orderings of at least 12 gene pairs vote for CIMP+; otherwise the CIMP−. The difference of prognosis between the predicted CIMP+ and CIMP− groups was more significantly different than the original CIMP status groups. There were more differential methylation and expression characteristics between the two predicted groups. The hierarchical clustering analysis showed that the signature could perform better for predicting CIMP status of RCC than current methods. In conclusion, the qualitative transcriptional signature for classifying CIMP status at the individualized level can predict outcome and guide therapy for RCC patients.
Highlights
Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of mortality in the world (Bray et al, 2018)
Several studies indicated that the stage II and III CRC patients with CpG island methylator phenotype (CIMP)+ status are associated with a better prognosis than CIMP−negative (CIMP−) CRC patients, and CIMP+ CRC patients cannot benefit from 5-Fluorouracil (5-FU)-based adjuvant chemotherapy (ACT; Ogino et al, 2009; Jover et al, 2011)
After a redundancy removal process for each panel of gene pairs, we calculated the largest harmonic mean value (F-score) with the optimal vote rule (Figure 2A, see section “Materials and Methods”)
Summary
Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of mortality in the world (Bray et al, 2018). Several studies indicated that the stage II and III CRC patients with CIMP+ status are associated with a better prognosis than CIMP−negative (CIMP−) CRC patients, and CIMP+ CRC patients cannot benefit from 5-Fluorouracil (5-FU)-based adjuvant chemotherapy (ACT; Ogino et al, 2009; Jover et al, 2011). The CIMP status is commonly detected by methylation-specific polymerase chain reaction (PCR) and methylight techniques. It is worth noting that the technologies commonly used could cause false-positive and false-negative results. The false-negative results are caused by the insufficient amount of input DNA, DNA degradation during bisulfite treatment, low stability of single-strand DNA, and strand-specific PCR amplification (Liu et al, 2016; Advani et al, 2018). It is worthwhile to develop a credible signature for predicting CIMP status
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