Hereditary Predisposition to LINE-1 Hypomethylated Colorectal Cancer: Potential Clinical Utility of Tumor LINE-1 Methylation Test for Familial Cancer Risk Assessment
Reiko Nishihara, Charles Fuchs, Shuji Ogino. Dana-Farber Cancer Institute, Boston, MA; Brigham and Women's Hospital, Boston, MA
Background: Beyond known familial colorectal cancer (CRC) syndromes, the mechanisms underlying the elevated CRC risk associated with CRC family history (seen in ∼20% of all newly diagnosed CRCs) remain largely unknown. Because LINE-1 hypomethylated CRCs are associated with young age of onset, we hypothesized that some LINE-1 hypomethylated CRCs may represent a new familial CRC predisposition syndrome, and that LINE-1 methylation test may help familial CRC risk assessment (beyond MSI).
Design: Using a population of 134,079 individuals with 3,184,415 person-years of follow-up, we prospectively examined the association between CRC family history and the risk of CRC (N=1,224) according to tumor LINE-1 methylation level. We excluded individuals with polyposis and those with inflammatory bowel diseases. We excluded MSI-high CRC from outcome, to eliminate the influence of Lynch syndrome (i.e., hereditary susceptibility to MSI-positive cancer).
Results: CRC family history significantly increased the risk of LINE-1 methylation-low CRC (P<0.001), and to a lesser degree, that of LINE-1 methylation-intermediate CRC (p=0.002).
|No. of first-degree relatives with CRC||0||1||>=2||P value for trend|
|Person-years of follow-up||2,787,643||370,088||26,684|
|LINE-1 M-low (<55% methylated)||Multivariate HR (95% CI)||1 (reference)||1.68 (1.19-2.38)||3.48 (1.59-7.63)||P <0.001|
|LINE-1 55-65% methylated||Multivariate HR (95% CI)||1 (reference)||1.50 (1.17-1.93)||1.42 (0.64-3.14)||P = 0.002|
|LINE-1 M-high (>=65% methylated)||Multivariate HR (95% CI)||1 (reference)||1.11 (0.83-1.48)||1.43 (0.59-3.49)||P = 0.35|