Genetic and environmental determinants of O6-methylguanine DNA-methyltransferase (MGMT) gene methylation: a 10-year longitudinal study of Danish twins

Background: Epigenetic inactivation of O6-methylguanine DNA-methyltransferase (MGMT) is associated with increased sensitivity to alkylating chemotherapeutic agents in glioblastoma patients. The genetic background underlying MGMT gene methylation may explain individual differences in treatment response and provide a clue to a personalized treatment strategy. Making use of the longitudinal twin design, we aimed, for the first time, to estimate the genetic contributions to MGMT methylation in a Danish twin cohort. Methods: DNA-methylation from whole blood (18 monozygotic (MZ) and 25 dizygotic (DZ) twin pairs) repeated 10 years apart from the Longitudinal Study of Aging Danish Twins (LSADT) were used to search for genetic and environmental contributions to DNA-methylation at 170 CpG sites of across the MGMT gene. Both univariate and bivariate twin models were applied. The intraclass correlations, performed on cross-sectional data (246 MZ twin pairs) from an independent study population, the Middle-Aged Danish Twins (MADT), were used to assess the genetic influence at each CpG site of MGMT for replication. Results: Univariate twin model revealed twelve CpG sites showing significantly high heritability at intake (wave 1, h2 > 0.43), and seven CpG sites with significant heritability estimates at end of follow-up (wave 2, h2 > 0.5). There were six significant CpG sites, located at the gene body region, that overlapped among the two waves (h2 > 0.5), of which five remained significant in the bivariate twin model, which was applied to both waves. Within MZ pair correlation in these six CpGs from MADT demarks top level of genetic influence. There were 11 CpGs constantly have substantial common environmental component over the 10 years. Conclusions: We have identified 6 CpG sites linked to the MGMT gene with strong and persistent genetic control based on their DNA methylation levels. The genetic basis of MGMT gene methylation could help to explain individual differences in glioblastoma treatment response and most importantly, provide references for mapping the methylation Quantitative Trait Loci (meQTL) underlying the genetic regulation.Peer reviewe

Familial Risk and Heritability of Hematologic Malignancies in the Nordic Twin Study of Cancer

Simple Summary Hematologic malignancies account for 8-9% of all incident cancers. Both genetic and environmental risk factors contribute to cancer development, but it is unclear if there is shared heritability between hematologic malignancies. This study aimed to investigate familial predisposition to hematologic malignancies using the largest twin study of cancer in the world. We compared individual risk in the general population and the risk of cancer in one twin before some age given that the other twin had (another) cancer before that age. Furthermore, by analyzing information about whether the twins were identical or fraternal, we could estimate the relative importance of genetic and environmental influences on the risk for developing hematologic cancers. This study confirmed previous findings of familial predisposition to hematologic malignancies and provides novel evidence that familial predisposition decreases with increasing age. The latter points to the importance of taking age into account in the surveillance of hematological cancers. We aimed to explore the genetic and environmental contributions to variation in the risk of hematologic malignancies and characterize familial dependence within and across hematologic malignancies. The study base included 316,397 individual twins from the Nordic Twin Study of Cancer with a median of 41 years of follow-up: 88,618 (28%) of the twins were monozygotic, and 3459 hematologic malignancies were reported. We estimated the cumulative incidence by age, familial risk, and genetic and environmental variance components of hematologic malignancies accounting for competing risk of death. The lifetime risk of any hematologic malignancy was 2.5% (95% CI 2.4-2.6%), as in the background population. This risk was elevated to 4.5% (95% CI 3.1-6.5%) conditional on hematologic malignancy in a dizygotic co-twin and was even greater at 7.6% (95% CI 4.8-11.8%) if a monozygotic co-twin had a hematologic malignancy. Heritability of the liability to develop any hematologic malignancy was 24% (95% CI 14-33%). This estimate decreased across age, from approximately 55% at age 40 to about 20-25% after age 55, when it seems to stabilize. In this largest ever studied twin cohort with the longest follow-up, we found evidence for familial risk of hematologic malignancies. The discovery of decreasing familial predisposition with increasing age underscores the importance of cancer surveillance in families with hematological malignancies.Peer reviewe