Novel epigenetic biomarkers for hematopoietic cancer found in twins.

BACKGROUND AND PURPOSE: This article aims to identify epigenetic markers and detect early development of hematopoietic malignancies through an epigenome wide association study of DNA methylation data. MATERIALS AND METHODS: This register-based study includes 1,085 Danish twins with 31 hematopoietic malignancies and methylation levels from 450,154 5'-C-phospate-G-3' (CpG) sites. Associations between methylation levels and incidence of hematopoietic malignancy is studied through time-to-event regression. The matched case-cotwin design, where one twin has a malignancy and the cotwin does not, is applied to enhance control for unmeasured shared confounding and false discoveries. Predictive performance is validated in the independent Older Finnish Twin Cohort. RESULTS AND INTERPRETATION: We identified 67 epigenetic markers for hematopoietic malignancies of which 12 are linked to genes associated with hematologic malignancies. For some markers, we discovered a 2-3-fold relative risk difference for high versus low methylation. The identification of these 67 sites enabled the formation of a predictor demonstrating a cross-validated time-varying area under the curve (AUC) of 92% 3 years after individual blood sampling and persistent performance above 70% up to 6 years after blood sampling. This predictive performance was to a large extent recovered in the validation sample showing an overall Harrell's C of 73%. In conclusion, from a large population representative twin study on hematopoietic cancers, novel epigenetic markers were identified that may prove useful for early diagnosis.

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

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.