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A 19-Gene expression signature as a predictor of survival in colorectal cancer

View Article: PubMed Central - PubMed

ABSTRACT

Background: Histopathological assessment has a low potential to predict clinical outcome in patients with the same stage of colorectal cancer. More specific and sensitive biomarkers to determine patients’ survival are needed. We aimed to determine gene expression signatures as reliable prognostic marker that could predict survival of colorectal cancer patients with Dukes’ B and C.

Methods: We examined microarray gene expression profiles of 78 archived tissues of patients with Dukes’ B and C using the Illumina DASL assay. The gene expression data were analyzed using the GeneSpring software and R programming.

Results: The outliers were detected and replaced with randomly chosen genes from the 90 % confidence interval of the robust mean for each group. We performed three statistical methods (SAM, LIMMA and t-test) to identify significant genes. There were 19 significant common genes identified from microarray data that have been permutated 100 times namely NOTCH2, ITPRIP, FRMD6, GFRA4, OSBPL9, CPXCR1, SORCS2, PDC, C12orf66, SLC38A9, OR10H5, TRIP13, MRPL52, DUSP21, BRCA1, ELTD1, SPG7, LASS6 and DUOX2. This 19-gene signature was able to significantly predict the survival of patients with colorectal cancer compared to the conventional Dukes’ classification in both training and test sets (p < 0.05). The performance of this signature was further validated as a significant independent predictor of survival using patient cohorts from Australia (n = 185), USA (n = 114), Denmark (n = 37) and Norway (n = 95) (p < 0.05). Validation using quantitative PCR confirmed similar expression pattern for the six selected genes.

Conclusion: Profiling of these 19 genes may provide a more accurate method to predict survival of patients with colorectal cancer and assist in identifying patients who require more intensive treatment.

Electronic supplementary material: The online version of this article (doi:10.1186/s12920-016-0218-1) contains supplementary material, which is available to authorized users.

No MeSH data available.


Validation of detected genes using qPCR. The normalized gene expression ratio for six genes including FRMD6, ELTD1, ITPRIP, MRPL52, TRIP13 and SLC38A9 which was determined using qPCR (p < 0.05). (*) represents the significant genes
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Fig4: Validation of detected genes using qPCR. The normalized gene expression ratio for six genes including FRMD6, ELTD1, ITPRIP, MRPL52, TRIP13 and SLC38A9 which was determined using qPCR (p < 0.05). (*) represents the significant genes

Mentions: Validation using qPCR demonstrated similar trends between poor and good survival groups when compared with the microarray data. All up-regulated genes (FRMD6, ELTD1 and ITPRIP) and down-regulated genes (MRPL52, TRIP13 and SLC38A9) were confirmed by qPCR according to 2-∆∆CT method as seen in Fig. 4.Fig. 4


A 19-Gene expression signature as a predictor of survival in colorectal cancer
Validation of detected genes using qPCR. The normalized gene expression ratio for six genes including FRMD6, ELTD1, ITPRIP, MRPL52, TRIP13 and SLC38A9 which was determined using qPCR (p < 0.05). (*) represents the significant genes
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5016995&req=5

Fig4: Validation of detected genes using qPCR. The normalized gene expression ratio for six genes including FRMD6, ELTD1, ITPRIP, MRPL52, TRIP13 and SLC38A9 which was determined using qPCR (p < 0.05). (*) represents the significant genes
Mentions: Validation using qPCR demonstrated similar trends between poor and good survival groups when compared with the microarray data. All up-regulated genes (FRMD6, ELTD1 and ITPRIP) and down-regulated genes (MRPL52, TRIP13 and SLC38A9) were confirmed by qPCR according to 2-∆∆CT method as seen in Fig. 4.Fig. 4

View Article: PubMed Central - PubMed

ABSTRACT

Background: Histopathological assessment has a low potential to predict clinical outcome in patients with the same stage of colorectal cancer. More specific and sensitive biomarkers to determine patients&rsquo; survival are needed. We aimed to determine gene expression signatures as reliable prognostic marker that could predict survival of colorectal cancer patients with Dukes&rsquo; B and C.

Methods: We examined microarray gene expression profiles of 78 archived tissues of patients with Dukes&rsquo; B and C using the Illumina DASL assay. The gene expression data were analyzed using the GeneSpring software and R programming.

Results: The outliers were detected and replaced with randomly chosen genes from the 90&nbsp;% confidence interval of the robust mean for each group. We performed three statistical methods (SAM, LIMMA and t-test) to identify significant genes. There were 19 significant common genes identified from microarray data that have been permutated 100 times namely NOTCH2, ITPRIP, FRMD6, GFRA4, OSBPL9, CPXCR1, SORCS2, PDC, C12orf66, SLC38A9, OR10H5, TRIP13, MRPL52, DUSP21, BRCA1, ELTD1, SPG7, LASS6 and DUOX2. This 19-gene signature was able to significantly predict the survival of patients with colorectal cancer compared to the conventional Dukes&rsquo; classification in both training and test sets (p&thinsp;&lt;&thinsp;0.05). The performance of this signature was further validated as a significant independent predictor of survival using patient cohorts from Australia (n&thinsp;=&thinsp;185), USA (n&thinsp;=&thinsp;114), Denmark (n&thinsp;=&thinsp;37) and Norway (n&thinsp;=&thinsp;95) (p&thinsp;&lt;&thinsp;0.05). Validation using quantitative PCR confirmed similar expression pattern for the six selected genes.

Conclusion: Profiling of these 19 genes may provide a more accurate method to predict survival of patients with colorectal cancer and assist in identifying patients who require more intensive treatment.

Electronic supplementary material: The online version of this article (doi:10.1186/s12920-016-0218-1) contains supplementary material, which is available to authorized users.

No MeSH data available.