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. ABSTRACT: 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.