Increased and decreased methylation at specific sequences(hypermethylation and hypomethylation, respectively) is characteristic of tumor DNA compared to normal DNA and promotes carcinogenesis in multiple ways including genomic instability. Long interspersed element( LINE), an abundant class of retrotransposons, provides a surrogate marker for global hypomethylation. We developed methylationspecific multiplex ligation-dependent probe amplification assays to study LINE-1methylation in cases of colorectal, gastric, and endometrial cancer( N =276), stratified by patient category [ sporadic; Lynch syndrome( LS); familial colorectal cancer type X( FCCX) ] and microsatellite instability status. Within each patient group,LINE-1 showed lower methylation in tumor DNA relative to paired normal DNA and hypomethylation was statistically significant in most cases. Interestingly, normal colorectal mucosa samples from different patient groups displayed differences in LINE-1methylation that mirrored differences between the respective tumor tissues, with a decreasing trend for LINE-1 methylation from patients with sporadic colorectal cancer to LS to FCCX. Despite the fact that the degree of LINE-1 methylation is generally tissue specific, normal colorectal mucosa, gastric mucosa, and endometrium from LS patients showed similar levels of LINE-1methylation. Our results suggest that the degree of LINE-1 methylation may constitute a “ field defect” that may predispose normal tissues for cancer development. Increased and decreased methylation at specific sequences (hypermethylation and hypomethylation, respectively) is characteristic of tumor DNA compared to normal DNA and promotes carcinogenesis in multiple ways including genomic instability. Long interspersed element (LINE), an abundant class of retrotransposons, provide a surrogate marker for global hypomethylation. We developed methylationspecific multiplex ligation-dependent probe amplification assays to study LINE-1methylation in cases of colorectal, gastric, and endometrial cancer (N = 276), stratified by patient category [sporadic; Lynch syndrome Within each patient group, LINE-1 showed lower methylation in tumor DNA relative to paired normal DNA and hypomethylation was substantially significant most in patients. Interestingly, normal colorectal mucosa samples from different patient groups displayed differences in LINE-1methylation that mirrored di fferences between the respective tumor tissues, with a decreasing trend for LINE-1 methylation from patients with sporadic colorectal cancer to LS to FCCX. Despite the fact that the degree of LINE-1 methylation is generally tissue specific, normal colorectal mucosa, gastric mucosa, Our results suggest that the degree of LINE-1 methylation may constitute a “field defect ” that may predispose normal tissues for cancer development.