The heritability of prostate cancer in the Nordic Twin Study of Cancer

Abstract

Background: Prostate cancer is thought to be the most heritable cancer, although little is known about how this genetic contribution varies across age.

Methods: To address this question, we undertook the world's largest prospective study in the Nordic Twin Study of Cancer cohort, including 18,680 monozygotic (MZ) and 30,054 dizygotic (DZ) same-sex male twin pairs. We incorporated time-to-event analyses to estimate the risk concordance and heritability while accounting for censoring and competing risks of death, essential sources of biases that have not been accounted for in previous twin studies modeling cancer risk and liability.

Results: The cumulative risk of prostate cancer was similar to that of the background population. The cumulative risk for twins whose co-twin was diagnosed with prostate cancer was greater for MZ than for DZ twins across all ages. Among concordantly affected pairs, the time between diagnoses was significantly shorter for MZ than DZ pairs (median, 3.8 versus 6.5 years, respectively). Genetic differences contributed substantially to variation in both the risk and the liability [heritability = 58% (95% confidence interval, 52%-63%)] of developing prostate cancer. The relative contribution of genetic factors was constant across age through late life with substantial genetic heterogeneity even when diagnosis and screening procedures vary.

Conclusions: Results from the population-based twin cohort indicate a greater genetic contribution to the risk of developing prostate cancer when addressing sources of bias. The role of genetic factors is consistently high across age.

Impact: Findings affect the search for genetic and epigenetic markers and frame prevention efforts.

Figure 1. The cumulative incidence of prostate cancer in Nordic twin cohorts adjusted for censoring, delayed entry due to initiation time of cancer registration in cohorts and competing risk of death

Figure 2

a: Casewise concordance of prostate cancer risk by age at diagnosis. The risk of prostate cancer given co-twin prostate cancer by age for monozygotic pairs (MZ, black) and dizygotic pairs (DZ, red). Cumulative incidence twins (thin black). Risks are adjusted for cohort effects, censoring and competing risk of death and are significantly different for MZ and DZ pairs over time (p-value<0.0001). b: Heritability of prostate cancer risk by age at diagnosis. Heritability in risk is twice the difference between MZ and DZ concordance to the total variance in risk (adjusted for cohort effects, censoring and competing risk of death).

Figure 3

The cumulative heritability in liability to prostate cancer by age at diagnosis (time) modeling additive genetic, common and unique environmental components of liability to disease. Correlation in MZ and DZ pairs. Bias-correction due to censorings by the inverse probability weighting technique. Transparent areas show 95% confidence bands.