Heritability and familial risk of cancer: an update from the Nordic Twin Registry of Cancer (NorTwinCan). L. A. Mucci1, J. Kaprio2, J. Harris3, K. Czene4, P. Kraft1, T. Scheike5, R. Graff1, I. Brandt3, N. Holmes5, D. Havelick1, M. Hartman4, K. Penney1, E. Pukkala6, G. Parmigiani7, A. Skytthe5, H. O. Adami1, J. Hjelmborg5, Nordic Twin Study of Cancer (NorTwinCan) 1) Epidemiology, Harvard School of Public Health, Boston, MA; 2) Finnish Twin Cohort Study, Department of Public Health, University of Helsinki, Helsinki, Finland; 3) Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway; 4) Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; 5) Department of Biostatistics, University of Southern Denmark, Odense, Denmark; 6) Finish Cancer Registry, Helsinki, Finland; 7) Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston MA.
Background. The landmark study by Lichtenstein et al in 2000 estimated cancer heritability using unique twin cohorts from the Nordic countries. We updated analyses within the Nordic Twin Registry of Cancer (NorTwinCan), expanding the original cohort, adding 10 years of follow-up and increasing number of cancer cases 3-fold to provide precise estimates of heritability and familial cancer risk. Methods. NorTwinCan includes 133,689 monozygotic (MZ) and dizygotic (DZ) twin pairs (N=267,378 total) from nationwide registries in Denmark, Finland, Norway and Sweden. We incorporate novel time-to-event analyses to estimate the concordance risk and heritability (95%; Confidence Intervals, CI) for 23 unique malignancies, with follow-up from cancer registration and accounting for censoring and competing risks of death through 2009. Results. During a median 40 year follow-up, 29,599 cancer cases were diagnosed. The heritability (95% CI) for prostate cancer was 58% (52-63%), the highest of any malignancy. The risk of prostate cancer in a twin given his cotwin also had prostate cancer (concordance risk) was 32%; in MZ and 16%; in DZ twins. For breast cancer among women, the difference in concordance between MZ (29%) and DZ (21%) twins was smaller, and heritability was 28%; (12-52%). There were notable differences in findings for colon and rectal cancer: the data supported a significant genetic component to colon cancer (16%, 2-63%) but not for rectal cancer. For testicular cancer, with a cumulative incidence of 0.4% in the population, the concordance risk was substantial amongst MZ (23%) and DZ (11%) twins, with heritability of 36% (2-95%). Estimates of heritability (95% CI) were also significant for kidney (23%, 11-42%), lung (25%, 12-44%), melanoma (39%, 8-81%), ovarian cancer (28%, 15-47%), stomach (24%, 5-65%), and uterine cancer (24%, 14-87%). Discussion. This expanded analysis in NorTwinCan provides more precise estimates of familial risk and heritability in cancer. Estimates of heritability for prostate cancer are even greater than previously estimated. For rare cancers such as testicular, the concordance risk was substantial and provides an accurate estimate for familial risk prediction. Twin studies can also provide context for genome wide association studies.
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