Familial Risk and Heritability of Cancer Among Twins in Nordic Countries.

Mucci LA1, Hjelmborg JB2, Harris JR3, Czene K4, Havelick DJ5, Scheike T6, Graff RE7, Holst K6, Möller S2, Unger RH5, McIntosh C8, Nuttall E5, Brandt I3,Penney KL9, Hartman M10, Kraft P11, Parmigiani G12, Christensen K13, Koskenvuo M14, Holm NV15, Heikkilä K14, Pukkala E16, Skytthe A2, Adami HO17,Kaprio J18; Nordic Twin Study of Cancer (NorTwinCan) Collaboration.

Abstract

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.