Original article
Alimentary tract
Familial Risk and Heritability of Colorectal Cancer in the Nordic Twin Study of Cancer

https://doi.org/10.1016/j.cgh.2016.12.041Get rights and content

Background & Aims

We analyzed data from twins to determine how much the familial risk of colorectal cancer can be attributed to genetic factors vs environment. We also examined whether heritability is distinct for colon vs rectal cancer, given evidence of distinct etiologies.

Methods

Our data set included 39,990 monozygotic and 61,443 same-sex dizygotic twins from the Nordic Twin Study of Cancer. We compared each cancer’s risk in twins of affected co-twins relative to the cohort risk (familial risk ratio [FRR]). We then estimated the proportion of variation in risk that could be attributed to genetic factors (heritability).

Results

From earliest registration in 1943 through 2010, there were 1861 individuals diagnosed with colon cancer and 1268 diagnosed with rectal cancer. Monozygotic twins of affected co-twins had an FRR for colorectal cancer of 3.1 (95% confidence interval [CI], 2.4–3.8) relative to the cohort risk. Dizygotic twins of affected co-twins had an FRR for colorectal cancer of 2.2 (95% CI, 1.7–2.7). We estimated that 40% (95% CI, 33%–48%) of the variation in colorectal cancer risk could be attributed to genetic factors; unique environment only accounted for the remaining liability. For colon cancer, the FRR was 3.3 (95% CI, 2.1–4.5) for monozygotic twins and 2.6 (95% CI, 1.7–3.5) for dizygotic twins. For rectal cancer, comparable estimates were 3.3 (95% CI, 1.5–5.1) for monozygotic twins and 2.6 (95% CI, 1.2–4.0) for dizygotic twins. Heritability estimates for colon and rectal cancer were 16% (95% CI, 0–46%) and 15% (95% CI, 0–50%), common environment estimates were 15% (95% CI, 0–38%) and 11% (95% CI, 0–38%), and unique environment estimates were 68% (95% CI, 57%–79%) and 75% (95% CI, 61%–88%), respectively.

Conclusions

Interindividual genetic differences could account for 40% of the variation in susceptibility to colorectal cancer; risk for colon and rectal cancers might have less of a genetic component than risk for colorectal cancer. Siblings, and particularly monozygotic co-twins, of individuals with colon or rectal cancer should consider personalized screening.

Section snippets

The Population-Based Twin Cohorts

The Nordic Twin Study of Cancer cohort aggregates the population-based twin registries from Denmark, Finland, Norway, and Sweden, and their respective national cancer and mortality registries. Follow-up evaluation for cancer incidence essentially is complete. For this study, we excluded twins of unknown zygosity (n = 57,057) and opposite-sex twins (n = 96,499). Analyses were based on 203,690 twins. The Supplementary Materials and Methods contain additional information about the cohort.

The

Results

Among 203,690 same-sex twins, 3094 were diagnosed with colorectal cancer during follow-up evaluation (Table 1). Roughly half of colorectal cancers occurred in males, and approximately three-fifths originated from the colon. Among 1532 colon cancers that could be classified further by subsite, just over half were proximal. There were 60 twin pairs (31 MZ and 29 DZ) concordant for colorectal cancer but discordant for colon or rectal subsite. Among 40 twin pairs (22 MZ) concordant for colon cancer

Discussion

We found that twins of affected co-twins were at a substantially increased risk of colorectal cancer relative to the general population. We also found that genetic factors explain two fifths of the variation in liability to the disease. Heritability was greater among women than men, and greatest when colorectal cancer combining all subsites together was analyzed. The concordance relative risk for colon and rectal cancer was higher for MZ than DZ twins, suggesting that colon and rectal cancer

Acknowledgments

The authors are grateful to the participants of the twin registries in Denmark, Finland, Norway, and Sweden.

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    Conflicts of interest The authors disclose the following: Jaakko Kaprio has received personal fees from Pfizer for serving as a consultant on nicotine dependence from 2012 to 2014, and Jennifer R. Harris was a consultant at the National Institute on Aging, National Institutes of Health, from 2000 to 2016. The remaining authors disclose no conflicts.

    Funding This work was supported by funding from the Ellison Foundation to the Harvard T. H. Chan School of Public Health (L.A.M., H.-O.A.) and the Nordic Union of Cancer (J.K.). The Danish Twin Cohort was supported by the Odense University Hospital AgeCare program (Academy of Geriatric Cancer Research). The Finnish Twin Cohort and Jaakko Kaprio were supported by the Academy of Finland (213506, 129680, 265240, and 263278) and US BioSHaRE-EU (HEALTH-F4-2010-261433). Research stemming from the Norwegian Twin Registry was supported in part by the European Union’s Seventh Framework Programme, BioSHaRE-EU (HEALTH-F4-2010-261433). The Swedish Twin Registry was supported by the Ministry for Higher Education. Lorelei A. Mucci is supported by a Prostate Cancer Foundation Young Investigator Award and Hans-Olov Adami has a Distinguished Professor Award at Karolinska Institutet (Dnr: 2368/10-221). Also supported by training grants from the National Cancer Institute (R25 CA098566, R25 CA112355 to R.E.G.).

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