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Original Investigation |

Familial Risk and Heritability of Cancer Among Twins in Nordic Countries

Lorelei A. Mucci, ScD, MPH1,2,3; Jacob B. Hjelmborg, PhD4,5; Jennifer R. Harris, PhD6; Kamila Czene, PhD7; David J. Havelick, ALM1; Thomas Scheike, PhD8; Rebecca E. Graff, ScD1,9; Klaus Holst, PhD8; Sören Möller, PhD4,5; Robert H. Unger, BS1; Christina McIntosh, SM10; Elizabeth Nuttall, BA1; Ingunn Brandt, MSc6; Kathryn L. Penney, ScD3; Mikael Hartman, MD, PhD7,11; Peter Kraft, PhD1,10; Giovanni Parmigiani, PhD10,12; Kaare Christensen, MD, PhD4,5; Markku Koskenvuo, MD, PhD13; Niels V. Holm, MD, PhD5,14; Kauko Heikkilä, PhLic13; Eero Pukkala, PhD15,16; Axel Skytthe, PhD4,5; Hans-Olov Adami, MD, PhD1,7; Jaakko Kaprio, MD13,17,18 ; for the Nordic Twin Study of Cancer (NorTwinCan) Collaboration
[+] Author Affiliations
1Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
2Division of Public Health Sciences, University of Iceland, Reykjavik
3Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
4Department of Biostatistics and Epidemiology, University of Southern Denmark, Odense
5Danish Twin Registry, University of Southern Denmark, Odense
6Division of Epidemiology, Norwegian Institute of Public Health, Oslo, Norway
7Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
8Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark
9Department of Epidemiology and Biostatistics, University of California, San Francisco
10Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
11Department of Surgery, National University Hospital and NUHS, Singapore
12Department of Computational Biology and Biostatistics, Dana Farber Cancer Institute, Boston, Massachusetts
13University of Helsinki, Hjelt Institute, Department of Public Health, Helsinki, Finland
14Department of Oncology, Odense University Hospital, Odense, Denmark
15Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland
16School of Health Sciences, University of Tampere, Tampere, Finland
17National Institute for Health and Welfare, Department of Health, Helsinki, Finland
18University of Helsinki, Institute for Molecular Medicine, Helsinki, Finland
JAMA. 2016;315(1):68-76. doi:10.1001/jama.2015.17703.
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Importance  Estimates of familial cancer risk from population-based studies are essential components of cancer risk prediction.

Objective  To estimate familial risk and heritability of cancer types in a large twin cohort.

Design, Setting, and Participants  Prospective study of 80 309 monozygotic and 123 382 same-sex dizygotic twin individuals (N = 203 691) within the population-based registers of Denmark, Finland, Norway, and Sweden. Twins were followed up a median of 32 years between 1943 and 2010. There were 50 990 individuals who died of any cause, and 3804 who emigrated and were lost to follow-up.

Exposures  Shared environmental and heritable risk factors among pairs of twins.

Main Outcomes and Measures  The main outcome was incident cancer. Time-to-event analyses were used to estimate familial risk (risk of cancer in an individual given a twin’s development of cancer) and heritability (proportion of variance in cancer risk due to interindividual genetic differences) with follow-up via cancer registries. Statistical models adjusted for age and follow-up time, and accounted for censoring and competing risk of death.

Results  A total of 27 156 incident cancers were diagnosed in 23 980 individuals, translating to a cumulative incidence of 32%. Cancer was diagnosed in both twins among 1383 monozygotic (2766 individuals) and 1933 dizygotic (2866 individuals) pairs. Of these, 38% of monozygotic and 26% of dizygotic pairs were diagnosed with the same cancer type. There was an excess cancer risk in twins whose co-twin was diagnosed with cancer, with estimated cumulative risks that were an absolute 5% (95% CI, 4%-6%) higher in dizygotic (37%; 95% CI, 36%-38%) and an absolute 14% (95% CI, 12%-16%) higher in monozygotic twins (46%; 95% CI, 44%-48%) whose twin also developed cancer compared with the cumulative risk in the overall cohort (32%). For most cancer types, there were significant familial risks and the cumulative risks were higher in monozygotic than dizygotic twins. Heritability of cancer overall was 33% (95% CI, 30%-37%). Significant heritability was observed for the cancer types of skin melanoma (58%; 95% CI, 43%-73%), prostate (57%; 95% CI, 51%-63%), nonmelanoma skin (43%; 95% CI, 26%-59%), ovary (39%; 95% CI, 23%-55%), kidney (38%; 95% CI, 21%-55%), breast (31%; 95% CI, 11%-51%), and corpus uteri (27%; 95% CI, 11%-43%).

Conclusions and Relevance  In this long-term follow-up study among Nordic twins, there was significant excess familial risk for cancer overall and for specific types of cancer, including prostate, melanoma, breast, ovary, and uterus. This information about hereditary risks of cancers may be helpful in patient education and cancer risk counseling.

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Figure.
Cumulative Incidence and Familial Risk of Developing Any Cancer Over Time in the NorTwinCan Cohort

The cumulative incidence is the risk of developing a first cancer over time within the full twin cohort, and the estimate is adjusted for censoring and competing risks of death. Familial risk is defined as the risk of developing any cancer given the twin’s co-twin also developed cancer. At the start of follow-up, there were 79 980 individual monozygotic twins and 122 888 individual dizygotic twins in the risk set. The extent to which the estimate of familial risk is higher than the cumulative incidence gives a sense of the magnitude of excess risk that may be associated with familial factors. Shaded areas indicate 95% confidence intervals; NorTwinCan, Nordic Twin Study of Cancer.

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