Limits...
LINE-1 hypomethylation in gastric cancer, detected by bisulfite pyrosequencing, is associated with poor prognosis.

Shigaki H, Baba Y, Watanabe M, Murata A, Iwagami S, Miyake K, Ishimoto T, Iwatsuki M, Baba H - Gastric Cancer (2012)

Bottom Line: Tumoral LINE-1 methylation range was 11.6-97.5 on a 0-100 scale (n = 203; mean 71.4, median 74.4, standard deviation 12.9).LINE-1 hypomethylation was significantly associated with shorter overall survival [log-rank p = 0.029; univariate HR 2.01, 95 % confidence interval (CI) 1.09-3.99, p = 0.023; stage-matched HR 1.88, 95 % CI 1.02-3.74, p = 0.041; multivariate HR 1.98, 95 % CI 1.04-4.04, p = 0.036].No significant effect modification was observed by any of the covariates in survival analysis (all p interaction >0.25).

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, Kumamoto, 860-8556, Japan.

ABSTRACT

Background: Genome-wide DNA hypomethylation plays an important role in genomic instability and carcinogenesis. DNA methylation in the long interspersed nucleotide element-1, L1 (LINE-1) repetitive element is a good indicator of the global DNA methylation level. In some types of human neoplasms, LINE-1 methylation level is attracting interest as a predictive marker for patient prognosis. However, the prognostic significance of LINE-1 hypomethylation in gastric cancer remains unclear.

Methods: Using 203 resected gastric cancer specimens, we quantified LINE-1 methylation using bisulfite-pyrosequencing technology. A Cox proportional hazards model was used to calculate the hazard ratio (HR), adjusted for the clinical and pathological variables.

Results: Gastric cancers showed significantly lower LINE-1 methylation levels compared to matched normal gastric mucosa (p < 0.0001; n = 74). Tumoral LINE-1 methylation range was 11.6-97.5 on a 0-100 scale (n = 203; mean 71.4, median 74.4, standard deviation 12.9). LINE-1 hypomethylation was significantly associated with shorter overall survival [log-rank p = 0.029; univariate HR 2.01, 95 % confidence interval (CI) 1.09-3.99, p = 0.023; stage-matched HR 1.88, 95 % CI 1.02-3.74, p = 0.041; multivariate HR 1.98, 95 % CI 1.04-4.04, p = 0.036]. No significant effect modification was observed by any of the covariates in survival analysis (all p interaction >0.25).

Conclusions: LINE-1 hypomethylation in gastric cancer is associated with shorter survival, suggesting that it has potential for use as a prognostic biomarker.

Show MeSH

Related in: MedlinePlus

Kaplan–Meier curves for overall survival according to tertiles (Ter1–3) of LINE-1 methylation in gastric cancer. In panels on the right, Ter2–3 represents the hypomethylated group and Ter1 represents the hypermethylated group
© Copyright Policy - OpenAccess
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3824342&req=5

Fig4: Kaplan–Meier curves for overall survival according to tertiles (Ter1–3) of LINE-1 methylation in gastric cancer. In panels on the right, Ter2–3 represents the hypomethylated group and Ter1 represents the hypermethylated group

Mentions: During the follow-up of the 203 patients, there were a total of 56 deaths. The median follow-up time for censused patients was 2.9 years. The primary statistical survival analysis was the Cox regression test with LINE-1 methylation as a continuous variable. LINE-1 hypomethylation was associated with a statistically significant increase in overall survival rate (univariate analysis p = 0.014). The univariate hazard ratio for overall survival rate associated with a 20 % decrease in LINE-1 methylation was 1.96 [95 % confidence interval (CI) = 1.33–2.87]. We also performed analyses using categorical variables (i.e., tertile). In a univariate Cox regression analysis, compared to first tertile (Ter1) cases, the third tertile (Ter3) cases experienced a significantly lower overall survival rate (p = 0.017, HR 2.24, 95 % CI 1.15–4.63). The second tertile (Ter2) cases experienced a slightly, but not significantly, lower overall survival rate compared to Ter1 cases (p = 0.12, HR 1.76, 95 %CI 0.85–3.74) (Table 2; Fig. 4). Based on these results, we made a dichotomous LINE-1 methylation variable (i.e., hypomethylation vs. hypermethylation), defining Ter1 as the “hypermethylated group” and combining Ter2 and Ter3 into the “hypomethylated group.” Thus, in this study, “LINE-1 hypomethylation” was defined as “≤77.3 %” and “LINE-1 hypermethylation” was defined as “≥77.4 %.”Table 2


LINE-1 hypomethylation in gastric cancer, detected by bisulfite pyrosequencing, is associated with poor prognosis.

Shigaki H, Baba Y, Watanabe M, Murata A, Iwagami S, Miyake K, Ishimoto T, Iwatsuki M, Baba H - Gastric Cancer (2012)

Kaplan–Meier curves for overall survival according to tertiles (Ter1–3) of LINE-1 methylation in gastric cancer. In panels on the right, Ter2–3 represents the hypomethylated group and Ter1 represents the hypermethylated group
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3824342&req=5

Fig4: Kaplan–Meier curves for overall survival according to tertiles (Ter1–3) of LINE-1 methylation in gastric cancer. In panels on the right, Ter2–3 represents the hypomethylated group and Ter1 represents the hypermethylated group
Mentions: During the follow-up of the 203 patients, there were a total of 56 deaths. The median follow-up time for censused patients was 2.9 years. The primary statistical survival analysis was the Cox regression test with LINE-1 methylation as a continuous variable. LINE-1 hypomethylation was associated with a statistically significant increase in overall survival rate (univariate analysis p = 0.014). The univariate hazard ratio for overall survival rate associated with a 20 % decrease in LINE-1 methylation was 1.96 [95 % confidence interval (CI) = 1.33–2.87]. We also performed analyses using categorical variables (i.e., tertile). In a univariate Cox regression analysis, compared to first tertile (Ter1) cases, the third tertile (Ter3) cases experienced a significantly lower overall survival rate (p = 0.017, HR 2.24, 95 % CI 1.15–4.63). The second tertile (Ter2) cases experienced a slightly, but not significantly, lower overall survival rate compared to Ter1 cases (p = 0.12, HR 1.76, 95 %CI 0.85–3.74) (Table 2; Fig. 4). Based on these results, we made a dichotomous LINE-1 methylation variable (i.e., hypomethylation vs. hypermethylation), defining Ter1 as the “hypermethylated group” and combining Ter2 and Ter3 into the “hypomethylated group.” Thus, in this study, “LINE-1 hypomethylation” was defined as “≤77.3 %” and “LINE-1 hypermethylation” was defined as “≥77.4 %.”Table 2

Bottom Line: Tumoral LINE-1 methylation range was 11.6-97.5 on a 0-100 scale (n = 203; mean 71.4, median 74.4, standard deviation 12.9).LINE-1 hypomethylation was significantly associated with shorter overall survival [log-rank p = 0.029; univariate HR 2.01, 95 % confidence interval (CI) 1.09-3.99, p = 0.023; stage-matched HR 1.88, 95 % CI 1.02-3.74, p = 0.041; multivariate HR 1.98, 95 % CI 1.04-4.04, p = 0.036].No significant effect modification was observed by any of the covariates in survival analysis (all p interaction >0.25).

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, Kumamoto, 860-8556, Japan.

ABSTRACT

Background: Genome-wide DNA hypomethylation plays an important role in genomic instability and carcinogenesis. DNA methylation in the long interspersed nucleotide element-1, L1 (LINE-1) repetitive element is a good indicator of the global DNA methylation level. In some types of human neoplasms, LINE-1 methylation level is attracting interest as a predictive marker for patient prognosis. However, the prognostic significance of LINE-1 hypomethylation in gastric cancer remains unclear.

Methods: Using 203 resected gastric cancer specimens, we quantified LINE-1 methylation using bisulfite-pyrosequencing technology. A Cox proportional hazards model was used to calculate the hazard ratio (HR), adjusted for the clinical and pathological variables.

Results: Gastric cancers showed significantly lower LINE-1 methylation levels compared to matched normal gastric mucosa (p < 0.0001; n = 74). Tumoral LINE-1 methylation range was 11.6-97.5 on a 0-100 scale (n = 203; mean 71.4, median 74.4, standard deviation 12.9). LINE-1 hypomethylation was significantly associated with shorter overall survival [log-rank p = 0.029; univariate HR 2.01, 95 % confidence interval (CI) 1.09-3.99, p = 0.023; stage-matched HR 1.88, 95 % CI 1.02-3.74, p = 0.041; multivariate HR 1.98, 95 % CI 1.04-4.04, p = 0.036]. No significant effect modification was observed by any of the covariates in survival analysis (all p interaction >0.25).

Conclusions: LINE-1 hypomethylation in gastric cancer is associated with shorter survival, suggesting that it has potential for use as a prognostic biomarker.

Show MeSH
Related in: MedlinePlus