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Epigenetically silenced miR-34b/c as a novel faecal-based screening marker for colorectal cancer.

Kalimutho M, Di Cecilia S, Del Vecchio Blanco G, Roviello F, Sileri P, Cretella M, Formosa A, Corso G, Marrelli D, Pallone F, Federici G, Bernardini S - Br. J. Cancer (2011)

Bottom Line: The miR-34b/c hypermethylation was found in 97.5% (79 out of 82) of primary colorectal tumours, P=0.0110.In addition, miR-148a was found to be hypermethylated in 65% (51 out of 78) of colorectal tumour tissues with no significant correlation to clinicopathological features.However, a trend with female gender and advanced age was found, P=0.083.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy. m.kalimutho@qub.ac.uk

ABSTRACT

Background: MicroRNAs are tiny non-coding small endogenous RNAs that regulate gene expression by translational repression, mRNA cleavage and mRNA inhibition. The aim of this study was to investigate the hypermethylation of miR-34b/c and miR-148a in colorectal cancer, and correlate this data to clinicopathological features. We also aimed to evaluate the hypermethylation of miR-34b/c in faeces specimens as a novel non-invasive faecal-DNA-based screening marker.

Methods: The 5-aza-2'-deoxycytidine treatment and methylation-specific PCR were carried out to detect the hypermethylation of miR-34b/c and miR-148a.

Results: The miR-34b/c hypermethylation was found in 97.5% (79 out of 82) of primary colorectal tumours, P=0.0110. In 75% (21 out of 28) of faecal specimens we found a hypermethylation of miR-34b/c while only in 16% (2 out of 12) of high-grade dysplasia. In addition, miR-148a was found to be hypermethylated in 65% (51 out of 78) of colorectal tumour tissues with no significant correlation to clinicopathological features. However, a trend with female gender and advanced age was found, P=0.083. We also observed a trend to lower survival rate in patients with miR-148a hypermethylation with 10-year survival probability: 48 vs 65%, P=0.561.

Conclusions: These findings show that aberrant hypermethylation of miR-34b/c could be an ideal class of early screening marker, whereas miR-148a could serve as a disease progression follow-up marker.

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Related in: MedlinePlus

Box and Whisker plot and Kaplan–Meier disease-free survival analysis for CRC patients according to miR-148a hypermethylation pattern. (A) The 10-year survival rate (60%) of CRC patients was calculated using the Kaplan–Meier method. (B) Survival rate of CRC patients according to depth of invasion. The difference is statistically significant (log-rank test: P<0.05). (C) The prognostic value of miR-148a methylation status was with a trend towards lower survival rate in patients with methylated alleles (10-year survival probability: 48%) compared with unmethylated cases (10-year survival probability: 65%), log-rank test: P=0.561.
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fig3: Box and Whisker plot and Kaplan–Meier disease-free survival analysis for CRC patients according to miR-148a hypermethylation pattern. (A) The 10-year survival rate (60%) of CRC patients was calculated using the Kaplan–Meier method. (B) Survival rate of CRC patients according to depth of invasion. The difference is statistically significant (log-rank test: P<0.05). (C) The prognostic value of miR-148a methylation status was with a trend towards lower survival rate in patients with methylated alleles (10-year survival probability: 48%) compared with unmethylated cases (10-year survival probability: 65%), log-rank test: P=0.561.

Mentions: We also wanted to determine the prognostic value of miR-148a methylation status in this patient cohort. Surgical approach in patients with colon cancer consisted of standard hemicolectomy (via laparotomic or laparoscopic approach) with negative macroscopic resection margin and regional lymphadenectomy in all cases. The median number (range) of removed lymph nodes was 17 (3–56). In rectal cancer, laparotomic/laparoscopic low anterior resection or abdominoperineal resections with total mesorectal excision were performed; the median number of removed lymph nodes was 13 (range: 4–37). Overall survival was calculated according to the Kaplan–Meier method in 60 patients available for survival analysis, considering cancer related death as the end point. The median follow-up period was 46 months (range: 1–266 months). Comparison between survival curves was performed with the log-rank test. The 10-year survival rate of the entire series was 60% (Figure 3A). Survival was significantly related to the stage of the tumour, and depth of invasion was one of the most important prognostic factors (log-rank test: P<0.05; Figure 3B). Interestingly, we found a trend towards lower overall survival in the patients with methylated miR-148a alleles (10-year survival probability: 48%) compared with patients with unmethylated miR-148a alleles (10-year survival probability: 65% Figure 3C); however, the difference was not statistically significant (log-rank test: P=0.561) because of the small number of patients available for survival analysis.


Epigenetically silenced miR-34b/c as a novel faecal-based screening marker for colorectal cancer.

Kalimutho M, Di Cecilia S, Del Vecchio Blanco G, Roviello F, Sileri P, Cretella M, Formosa A, Corso G, Marrelli D, Pallone F, Federici G, Bernardini S - Br. J. Cancer (2011)

Box and Whisker plot and Kaplan–Meier disease-free survival analysis for CRC patients according to miR-148a hypermethylation pattern. (A) The 10-year survival rate (60%) of CRC patients was calculated using the Kaplan–Meier method. (B) Survival rate of CRC patients according to depth of invasion. The difference is statistically significant (log-rank test: P<0.05). (C) The prognostic value of miR-148a methylation status was with a trend towards lower survival rate in patients with methylated alleles (10-year survival probability: 48%) compared with unmethylated cases (10-year survival probability: 65%), log-rank test: P=0.561.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3111174&req=5

fig3: Box and Whisker plot and Kaplan–Meier disease-free survival analysis for CRC patients according to miR-148a hypermethylation pattern. (A) The 10-year survival rate (60%) of CRC patients was calculated using the Kaplan–Meier method. (B) Survival rate of CRC patients according to depth of invasion. The difference is statistically significant (log-rank test: P<0.05). (C) The prognostic value of miR-148a methylation status was with a trend towards lower survival rate in patients with methylated alleles (10-year survival probability: 48%) compared with unmethylated cases (10-year survival probability: 65%), log-rank test: P=0.561.
Mentions: We also wanted to determine the prognostic value of miR-148a methylation status in this patient cohort. Surgical approach in patients with colon cancer consisted of standard hemicolectomy (via laparotomic or laparoscopic approach) with negative macroscopic resection margin and regional lymphadenectomy in all cases. The median number (range) of removed lymph nodes was 17 (3–56). In rectal cancer, laparotomic/laparoscopic low anterior resection or abdominoperineal resections with total mesorectal excision were performed; the median number of removed lymph nodes was 13 (range: 4–37). Overall survival was calculated according to the Kaplan–Meier method in 60 patients available for survival analysis, considering cancer related death as the end point. The median follow-up period was 46 months (range: 1–266 months). Comparison between survival curves was performed with the log-rank test. The 10-year survival rate of the entire series was 60% (Figure 3A). Survival was significantly related to the stage of the tumour, and depth of invasion was one of the most important prognostic factors (log-rank test: P<0.05; Figure 3B). Interestingly, we found a trend towards lower overall survival in the patients with methylated miR-148a alleles (10-year survival probability: 48%) compared with patients with unmethylated miR-148a alleles (10-year survival probability: 65% Figure 3C); however, the difference was not statistically significant (log-rank test: P=0.561) because of the small number of patients available for survival analysis.

Bottom Line: The miR-34b/c hypermethylation was found in 97.5% (79 out of 82) of primary colorectal tumours, P=0.0110.In addition, miR-148a was found to be hypermethylated in 65% (51 out of 78) of colorectal tumour tissues with no significant correlation to clinicopathological features.However, a trend with female gender and advanced age was found, P=0.083.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy. m.kalimutho@qub.ac.uk

ABSTRACT

Background: MicroRNAs are tiny non-coding small endogenous RNAs that regulate gene expression by translational repression, mRNA cleavage and mRNA inhibition. The aim of this study was to investigate the hypermethylation of miR-34b/c and miR-148a in colorectal cancer, and correlate this data to clinicopathological features. We also aimed to evaluate the hypermethylation of miR-34b/c in faeces specimens as a novel non-invasive faecal-DNA-based screening marker.

Methods: The 5-aza-2'-deoxycytidine treatment and methylation-specific PCR were carried out to detect the hypermethylation of miR-34b/c and miR-148a.

Results: The miR-34b/c hypermethylation was found in 97.5% (79 out of 82) of primary colorectal tumours, P=0.0110. In 75% (21 out of 28) of faecal specimens we found a hypermethylation of miR-34b/c while only in 16% (2 out of 12) of high-grade dysplasia. In addition, miR-148a was found to be hypermethylated in 65% (51 out of 78) of colorectal tumour tissues with no significant correlation to clinicopathological features. However, a trend with female gender and advanced age was found, P=0.083. We also observed a trend to lower survival rate in patients with miR-148a hypermethylation with 10-year survival probability: 48 vs 65%, P=0.561.

Conclusions: These findings show that aberrant hypermethylation of miR-34b/c could be an ideal class of early screening marker, whereas miR-148a could serve as a disease progression follow-up marker.

Show MeSH
Related in: MedlinePlus