A comparative study of Korean with Caucasian breast cancer reveals frequency of methylation in multiple genes correlates with breast cancer in young, ER, PR-negative breast cancer in Korean women

To test whether promoter hypermethylation in breast cancer provides a basis for the interethnic difference in breast cancer incidence and distribution, we compared the methylation profiles of tumors arising in native Korean women with Caucasian women in the United States. Methylation-specific PCR analysis of seven genes frequently methylated in breast cancer (HIN-1, Twist, Cyclin D2, RAR-beta, GSTP1, RASSF1A and CDH1) was performed on DNA from 67 Korean and 50 Caucasian invasive ductal breast cancers which were categorized into four subgroups by ER status and age. Methylation frequencies for individual genes were similar between the two races. However, tumors in Korean women of age (<= 50) at diagnosis had a trend of higher prevalence of promoter hypermethylation for all seven genes compared to those in women at an older age (> 50). Furthermore, methylation of multiple genes (four or more genes per case) was associated with younger age at diagnosis (OR = 3.2; 95% CI = 1.2-8.7; p = 0.03). In contrast, there was no association between promoter hypermethylation and age at diagnosis in Caucasian women. A significantly higher frequency of methylation, for all seven genes and in multiple genes, was observed in ER-/PR- breast carcinomas in Korean women of age <= 50 compared to the same subgroup of tumors in Caucasians. In contrast, compared to Korean breast cancer, the subgroup of ER+/PR+ breast carcinomas arising in Caucasian women age > 50 had a significantly higher frequency of methylation in three of seven genes. Our data suggest that promoter hypermethylation is a prevalent phenomenon in breast cancer of young Korean women. By analyzing the methylation patterns in tumors stratified by race, ER/PR status, and age, dissimilarities in promoter hypermethylation profiles, particularly in the ER-/PR- tumors arising in young women, were revealed that characterize tumors of one ethnicity from the other.