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. 2019 Feb 13:11:1337-1348.
doi: 10.2147/CMAR.S188192. eCollection 2019.

Claudin gene expression profiles and clinical value in colorectal tumors classified according to their molecular subtype

Sara Cherradi  1 , Pierre Martineau  1 , Céline Gongora  1 , Maguy Del Rio  1
Affiliations

Claudin gene expression profiles and clinical value in colorectal tumors classified according to their molecular subtype

Sara Cherradi et al. Cancer Manag Res. .

Abstract

Purpose: Colorectal cancer (CRC) is a heterogeneous disease that can be classified into distinct molecular subtypes. The aims of this study were 1) to compare claudin (CLDN) gene expression in CRC samples and normal colon mucosa, and then in the different CRC molecular subtypes, and 2) to assess their prognostic value.

Patients and methods: CLDN expression in CRC samples was analyzed using gene expression data for a cohort of 143 primary CRC samples, and compared in the same CRC samples classified into different molecular subtypes (C1 to C6 according to the Marisa's classification, and CMS1 to CMS4 of the consensus classification). Comparison of CLDN expression in normal and tumor colon samples was also made on a smaller number of samples. Then, the relationship between CLDN expression profiles and overall survival (OS) and progression-free survival was examined.

Results: Compared with normal mucosa, CLDN1 and CLDN2 were upregulated, whereas CLDN5, 7, 8, and 23 were downregulated in CRC samples. Variations in CLDN expression profiles were observed mainly in the CMS2/C1 and CMS4/C4 subtypes. Overall, expression of CLDN2 or CLDN4 alone had a strong prognostic value that increased when they were associated. In the CMS4/C4 subtypes, lower expressions of CLDN11, CLDN12, and CLDN23 were associated with longer OS. Conversely, in the CMS2 and C1 subtypes, low CLDN23 expression was associated with shorter OS and progression-free survival, suggesting a dual role for CLDN23 as a tumor suppressor/promoter in CRC. CLDN6 and CLDN11 had a prognostic value in the CMS2 and C4 subtypes, respectively.

Conclusion: This analysis of CLDN gene expression profiles and prognostic value in CRC samples classified according to their molecular subtype shows that CRC heterogeneity must be taken into account when assessing CLDN potential value as prognostic markers or therapeutic targets.

Keywords: cancer; classification; claudin; colon; heterogeneity; prognosis; target; tight junction.

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Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Expression of CLDN genes. Notes: (A) Mean expression of 18 CLDN genes in NM (n=17), PT (n=20), and HM (n=19). The Affymetrix RNA expression data were log2 transformed. (B) Detailed analysis of the RNA expression levels of six CLDN genes in the NM, PT, and HM samples described in (A). Horizontal bars indicate the mean value. ***P<0.001= (Kruskal–Wallis test). Abbreviations: CRC, colorectal cancer; HM, hepatic metastases; NM, normal mucosa; PT, primary CRC tumors.
Figure 2
Figure 2
Interrelationships between the consensus classification (four subtypes: CMS1 to 4) and the Marisa’s classification (six molecular subtypes: C1 to C6) of the 143 CRC samples included in this study. Notes: (A) Chord diagram to visualize the relationships among subtypes (in different colors) of the two CRC classifications arranged radially. Data are connected to each other using arcs; each connection is proportional to the arc size. (B) Percentage of CRC samples classified as C1 to C6 included in each CMS subtype. Abbreviation: CRC, colorectal cancer.
Figure 3
Figure 3
Differential CLDN expression in CRC samples classified using the CMS classification. Notes: (A) CLDN genes upregulated in tumor samples compared with normal mucosa. (B) CLDN genes downregulated in tumors compared with normal mucosa. (C) CLDN genes with similar expression in normal mucosa and tumor samples. The red horizontal line indicates CLDN expression in normal mucosa within the CRC samples. The arrow highlights the subtype where CLDN expression is the most significantly different compared with the other subtypes (Kruskal–Wallis/Dunn’s test). *P<0.05; **P<0.01; ***P<0.001. Abbreviation: CRC, colorectal cancer.
Figure 4
Figure 4
Clinical value of CLDN gene expression in the 143 CRC samples. Notes: Association between CLDN2 and CLDN4 gene expression levels and (A) OS and (B) PFS (log-rank test). High and low: higher or lower expressions relative to the median expression for that CLDN gene. (C) Association of combined CLDN2 and CLDN4 gene expressions with OS. Abbreviations: CRC, colorectal cancer; OS, overall survival; PFS, progression-free survival.
Figure 5
Figure 5
Association of CLDN gene expression with OS in the different CRC subtypes. Notes: Log-rank test. High/low: expression higher/lower than the median value for that CLDN gene. Abbreviation: CRC, colorectal cancer; OS, overall survival.
Figure 6
Figure 6
Summary of CLDN gene expression and prognostic value in CRC. Notes: (1) Expression in CRC samples (n=20) compared with normal mucosa samples (n=17); red = upregulated; green = downregulated; white, no expression difference with normal mucosa. (2) Comparison of CLDN expression in the different CRC subtypes; red = subtype where CLDN expression is strongest; green = subtype where the expression of that CLDN gene is lowest compared with the other subtypes; white = no expression difference among subtypes. YES indicates that the expression level of that CLDN gene shows prognostic value, with the correlation between CLDN expression level (high/low relative to the median expression of that gene) and improved prognosis. Abbreviation: CRC, colorectal cancer.
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