Environmental and Heritable Factors in the Causation of Cancer Analyses of Cohorts of Twins from Sweden, Denmark, and Finland
Paul Lichtenstein, Ph.D., Niels V. Holm, M.D., Ph.D., Pia K. Verkasalo, M.D., Ph.D., Anastasia Iliadou, M.Sc., Jaakko Kaprio, M.D., Ph.D., Markku Koskenvuo, M.D., Ph.D., Eero Pukkala, Ph.D., Axel Skytthe, M.Sc., and Kari Hemminki, M.D., Ph.D.
Background The contribution of hereditary factors to the causationof sporadic cancer is unclear. Studies of twins make it possibleto estimate the overall contribution of inherited genes to thedevelopment of malignant diseases.
Methods We combined data on 44,788 pairs of twins listed inthe Swedish, Danish, and Finnish twin registries in order toassess the risks of cancer at 28 anatomical sites for the twinsof persons with cancer. Statistical modeling was used to estimatethe relative importance of heritable and environmental factorsin causing cancer at 11 of those sites.
Results At least one cancer occurred in 10,803 persons among9512 pairs of twins. An increased risk was found among the twinsof affected persons for stomach, colorectal, lung, breast, andprostate cancer. Statistically significant effects of heritablefactors were observed for prostate cancer (42 percent of therisk may be explained by heritable factors; 95 percent confidenceinterval, 29 to 50 percent), colorectal cancer (35 percent;95 percent confidence interval, 10 to 48 percent), and breastcancer (27 percent; 95 percent confidence interval, 4 to 41percent).
Conclusions Inherited genetic factors make a minor contributionto susceptibility to most types of neoplasms. This finding indicatesthat the environment has the principal role in causing sporadiccancer. The relatively large effect of heritability in cancerat a few sites (such as prostate and colorectal cancer) suggestsmajor gaps in our knowledge of the genetics of cancer.
Except for certain types of familial cancer, such as adenomatouspolyposis coli, the contribution of hereditary factors to thedevelopment of cancer is thought to be relatively minor.1,2,3This premise, however, applies mainly to dominant genes, whichhave been assessed in family studies that cover two or moregenerations. By contrast, the contributions of recessive traitsand combinations of genes to the causation of sporadic cancerare difficult to determine from family studies.4 Consequently,the risks associated with single-gene mutations with low penetrance,recessive genes, and oncogenic mechanisms that involve multiplegenes are poorly understood.
Family studies of breast, prostate, ovarian, and uterine cancercan estimate risks for siblings and parentoffspring pairs5,6,7,8,9,10,11,12but cannot distinguish between genetic and nongenetic (environmentalor infectious) causes of familial aggregations of cancer. Bycontrast, comparisons of the concordance of cancer between monozygoticand dizygotic pairs of twins provide information on whetherthe familial pattern is due to hereditary or environmental influences.13
If studies of groups of twins show that concordance for canceris higher among monozygotic twins (who share all genes) thanamong dizygotic twins (who, on average, share 50 percent oftheir segregating genes), genetic effects are likely to be important.If, however, the concordance is similar for both types of twins,then shared environmental effects are probably important. Furthermore,the use of statistical models to analyze data from large samplesof twins makes it possible to estimate the magnitude of thegenetic and environmental effects on susceptibility to sporadiccancer.
For these reasons, studies of twins can not only point to hereditaryeffects, but also estimate heritability, a term denoting themagnitude of the genetic effect. However, the rarity of twinslimits this approach, even for the common forms of cancer.14,15,16,17,18,19
In the present study, we used data from the Swedish, Danish,and Finnish twin registries to estimate the effects of geneticand environmental factors on the most common cancers. We alsoassessed how age at the time of diagnosis modified these estimates.
Methods
Swedish Twins
The Swedish Twin Registry consists of two birth cohorts.20 Thefirst is made up of 10,503 pairs of twins of the same sex whowere alive in 1961 and who were born during the period from1886 through 1925. Information from questionnaires completedby both twins was available for 81 percent of the eligible pairs.A second cohort consists of 12,883 pairs of twins of the samesex born from 1926 through 1958. In this cohort, both twinswere living in Sweden in 1972 and had responded to a questionnairein that year. The rate of response to this questionnaire was83 percent.
We determined vital status and any diagnoses of cancer fromthe records of the Swedish Mortality Registry and the SwedishCancer Registry, using the unique national registration numberassigned to each Swedish citizen. According to these records,cancer was diagnosed in 4490 persons in the first cohort from1961 through 1995 and in 1157 persons in the second cohort from1973 through 1995.
Danish Twins
The Danish Twin Registry holds data on 8461 pairs of twins ofthe same sex with known zygosity who were born between 1870and 1930. This registry, established in 1954, includes all twinsborn in Denmark from 1870 through 1910,21 and it was later expandedto include twins of the same sex born from 1911 through 1930.21,22,23Included in the registry are all pairs of twins who both survivedto the age of six years. A questionnaire was mailed to the twins,or to their closest relatives if one or both twins had emigratedor were dead at the time of identification.
We checked vital status annually through 1979 by obtaining copiesof death certificates from the Central Register of Deaths. After1979 vital status was regularly updated by linkage to the CivilRegistration System, which includes all persons living in Denmarksince April 1, 1968.
The Danish Cancer Registry contains information on all malignantdiseases diagnosed in Denmark since 1943.24,25,26 All pairsof twins of the same sex who were born from 1870 through 1930and were both alive on January 1, 1943, have been linked tothe Cancer Registry for the period from 1943 through 1993. Atotal of 3572 persons in this cohort received a diagnosis ofcancer (excluding nonmelanoma skin cancer).
Finnish Twins
The Finnish twin cohort includes 12,941 pairs of twins who wereborn from 1880 through 1958 and who were both living in Finlandon December 31, 1975.27 The cohort was compiled from the CentralPopulation Register in 1974. The following year, a questionnairewas mailed to all twins who were 18 years of age or older andfor whom an adequate address was available. The overall responserate was 89 percent.
Malignant neoplasms that were diagnosed among the Finnish twinsfrom 1976 through 1996 were identified by linkage of recordsto national cancer registry data with the use of the personalidentification number assigned to every resident of Finland.The Finnish Cancer Registry has information on all cancers diagnosedin Finland since 1953.28 In addition, the study cohort was linkedto the Central Population Register to obtain data on death andemigration. Cancer was diagnosed in 1584 persons in the cohort.
Determination of Zygosity
For all three studies, zygosity was determined by a questionnairethat has been shown in validation studies to classify more than95 percent of pairs of twins correctly.22,29,30
Statistical Analysis
The relative risk of cancer for persons whose twins had a particulartype of cancer, as compared with those whose twins did not,was calculated according to sex and zygosity for cancer at eachanatomical site. The risk was estimated as an odds ratio. Ninety-fivepercent confidence intervals were estimated according to theMantelHaenszel method.31
The absolute risk of cancer for the twin of a person with cancerwithin the period of the study was calculated as the proportionof all persons with cancer whose twins had cancer at the samesite (i.e., the concordance).32 For clinical guidance, we alsocalculated the risk for twins up to the age of 75 years forthe sites for which significant effects of heritable factorswere found.
Quantitative genetic analyses were used to estimate the relativeimportance of hereditary and environmental factors in determiningvariations in susceptibility to cancer,13,33,34 on the usualassumptions of a classic twin study (that there was random mating,no interaction between genes and environment, and equivalentenvironments for monozygotic and dizygotic twins).35 Phenotypicvariance was divided into a component due to inherited geneticfactors (heritability), a component due to environmental factorscommon to both members of the pair of twins (the shared environmentalcomponent), and a component due to environmental factors uniqueto each twin (the nonshared environmental component) (Table 1).Structural-equation modeling,36 which incorporates dataon all types of twins (male and female monozygotic and dizygotictwins from the three countries) simultaneously, provided estimatesof the unobserved variables that is, additive genetic,shared environmental, and nonshared environmental factors.
Table 1. Effects Estimated in the Quantitative Genetic Analyses.
The correlations between the genetic and environmental factorsfor the twins were set to their theoretical values (1.0 and0.5 for additive genetic effects for monozygotic and dizygotictwins, respectively, and 1.0 for shared environmental effectsfor both types of twins). These values, 1.0 and 0.5, reflectthe facts that monozygotic twins share their entire genomes(theoretical value, 1.0) and dizygotic twins share 50 percentof their segregating genes (theoretical value, 0.5). This method,which uses two-by-two contingency tables of disease status inpairs of twins, also tests for the sex specificity of the geneticand environmental effects. Because of considerations relatedto statistical power, analyses were performed only for cancersfor which there were at least four pairs of twins in which bothtwins had the cancer. We assumed an underlying normal distributionof susceptibility to the disease.
We defined susceptibility as the sum of the effects of manygenetic and environmental factors. When a person receives adiagnosis of cancer, a value (the threshold) in the distributionof susceptibility is assumed to have been exceeded. The thresholdvalue was estimated in the model from the prevalence of thedisease.13,37 The relative importance of hereditary and environmentaleffects for individual differences in this underlying susceptibilitywas then estimated. When sex-specific models did not fit significantlybetter than a model in which estimates were defined as beingthe same in men and women, the latter model is presented. Becausethe birth dates and follow-up periods of the twin cohorts differedamong countries, the threshold values were also allowed to differamong countries. However, the estimates for genetic and environmentalcomponents were set to be equal in all countries, because noevidence of heterogeneity according to country was found forcancer at any site.
For colorectal, breast, and prostate cancers, there were enoughaffected persons (i.e., more than 50 pairs of twins who wereconcordant for the cancer) to enable structural model-fittinganalysis to be performed in two age groups. Because of powerconsiderations, the groups were defined so that the youngergroup included about 35 percent of the affected twins. For colorectalcancer, the younger group was followed up to 63 years of age;for breast cancer, it was followed up to 56 years of age; andfor prostate cancer, it was followed up to 70 years of age.Persons in the younger group were followed until they reachedthe maximal age for that group, until they died, or until thestudy ended. For the older group, follow-up started when theyreached the maximal age for the younger group and ended at deathor at the end of the study period. At the end of follow-up inthe younger and older groups, each pair of twins was recordedas concordant for cancer (if both twins had had cancer at thesame anatomical site) or discordant for cancer (if only onetwin had had cancer at a particular site). For colorectal, breast,and prostate cancer, we examined the differences in the agesat which cancer was diagnosed in pairs of twins who were concordantfor cancer.
Results
Among the 44,788 pairs of twins included in this analysis, weidentified 10,803 persons (among 9512 pairs) in whom at leastone cancer had been diagnosed.
Overall, the twin of a person with cancer had an increased riskof having the same cancer. This was especially evident for cancerof the stomach, colorectum, lung, breast, and prostate (Table 2).The twin of a male monozygotic twin who had stomach cancerhad a risk of stomach cancer that was 9.9 times that of themonozygotic twin of a person without stomach cancer. The concordancefor stomach cancer in male monozygotic twins was 0.08, whichmeans that there is an 8 percent probability that the identicaltwin of a man with stomach cancer will have the same cancer.The concordance was usually less than 0.10, and no concordantpairs were observed for cancers at nine sites (non-Hodgkin'slymphoma, Hodgkin's disease, and cancer of the lip, oral cavity,pharynx, kidney, thyroid, bone, and soft tissue). For cancersat most of the remaining sites, the concordance between monozygotictwins, whether male or female, was greater than the concordancebetween dizygotic twins.
Table 2. Types of Cancers Included in the Study and Concordance According to Sex and Zygosity in 44,788 Pairs of Twins from Sweden, Denmark, and Finland.
Table 3 presents the results of model fitting, which we usedto obtain estimates of the contributions of heritability andenvironmental effects. For stomach cancer, for example, heritabilitywas estimated to account for 28 percent of the variation insusceptibility to that neoplasm, shared environmental effectsfor 10 percent, and nonshared environmental effects for theremaining 62 percent. Stated another way, these estimates indicatethat of the various factors that together constitute the totalrisk of developing stomach cancer, inherited genes contribute28 percent to the risk, shared environmental effects contribute10 percent, and nonshared environmental factors make up theremaining 62 percent of the risk. For stomach cancer, therefore,our model predicts the involvement of major environmental factorsplus minor genetic components, which may or may not interactwith these environmental factors.
Table 3. Effects of Heritable and Environmental Factors in Cancers at Various Sites, According to Data from the Swedish, Danish, and Finnish Twin Registries.
The statistical model we used provided an excellent fit to theobserved data (2=8.9, with 38 df; P=1.0). Estimated effectsof heritability the proportion of susceptibility tocancer that was accounted for by genetic defects thatwere statistically significant (i.e., for which the 95 percentconfidence interval did not include zero) were obtained forcancers of the colorectum (35 percent), breast (27 percent),and prostate (42 percent). The estimates for the shared environmentaleffects ranged from 0 to 20 percent, but none were statisticallysignificant. There were no significant differences between thesexes in the heritability of cancer at any of the sites thatwe studied.
Table 4 presents the risks of having the same cancer beforethe age of 75 years among twins of persons with cancer at sitesinvolving statistically significant genetic factors. For colorectal,breast, and prostate cancer, the estimated hereditary componentswere slightly greater in the younger than in the older groups(data not shown).
Table 4. Absolute Risks of Colorectal, Breast, and Prostate Cancer (Concordance Rates) in Twins of an Affected Person up to the Age of 75 Years.
The time interval between the diagnoses of prostate cancer wassignificantly shorter for concordant pairs of monozygotic twinsthan that for concordant pairs of dizygotic twins (5.7 vs. 8.8years) (Table 5). There were no significant differences betweendizygotic and monozygotic twins in the time between diagnosesof colorectal and breast cancer.
Table 5. Difference in Age at the Diagnosis of Cancer in Concordant Pairs of Monozygotic and Dizygotic Twins.
Discussion
Assessments of the contributions of inherited and environmentalfactors to the causation of cancer in studies of twins havehad a relatively small effect on research and clinical practice,because twins are rare, and only a few twin registries go backfar enough in time to provide enough cases of cancer for reliableconclusions to be drawn. The fact that we combined data fromthree Nordic countries with population-based twin registriesand well-established cancer registries adds strength to thepresent study. Moreover, with statistical methods, it was possibleto go beyond a simple comparison of concordance rates. Withthe knowledge that monozygotic twins are genetically identicaland dizygotic twins share, on average, 50 percent of their segregatinggenes, we could estimate the magnitude of the contributionsof genetic factors and environmental factors (both shared andnonshared) to the development of cancer.
There is general agreement that environmental factors and somaticevents are the predominant contributors to the causation ofsporadic cancer,38 and our results support this notion. Eventhough we found familial (hereditary or nonhereditary) effectsfor cancer at many sites, the rates of concordance in twinswere generally below 0.10. This result indicates that, for nearlyall sites, the twin of a person with cancer has only a moderateabsolute risk of having cancer at the same site. Using a statisticalmodel, we also estimated the contribution of nonshared environmentalfactors, which include any unique environmental cause of cancerthat is not inherited and not shared between twins. For differentcancers, this contribution ranged from 58 to 82 percent.
In our model, shared environment, the sum of the common familyexperiences and habits of the twins, accounted for 0 to 20 percentof causation, but none of these values were statistically significant,partly because studies of twins have limited power to detectshared environmental effects in dichotomous phenotypes (e.g.,the presence or absence of cancer).39 Risk factors in the environmentshared by a family could include human papillomavirus infectionfor cervical cancer, smoking (passive or active) for lung cancer,and diet and Helicobacter pylori infection for stomach cancer.
The total contribution of hereditary factors to the causationof sporadic cancer is unclear; previous assessments have estimatedonly the proportion of cancers caused by genetic syndromes.It has been argued that "unmistakable hereditary cancer syndromes"account for about 1 percent of cancers and "upward of 10 to15 percent of all cancers have a major inherited component,albeit one that may be enigmatic"3; that "highly penetrant single-genemutation" accounts for 5 percent1; and that "primary geneticfactors" account for 5 to 10 percent of all cancers.40 The resultsof our study summarize the total effects of heritable factors,but it should be noted that our estimates are population-specific.Thus, if environmental effects are very different in Scandinaviaand in other regions, the proportion of susceptibility to cancerthat is due to hereditary effects will also differ. And forpopulations consisting entirely of smokers or of nonsmokers,the contribution of smoking to the variation in risk would bemuch lower than in a mixed population. Previous studies of cancerin twins have found higher rates of concordance among monozygotictwins than among dizygotic twins for cancer at some sites,14,15,16,17,18,19,41,42,43,44but generally with very wide confidence intervals.
We found statistically significant effects of heritable factors,ranging from 27 percent to 42 percent, for colorectal, breast,and prostate cancer. These results are in agreement with thoseof most previous studies.14,15,16,43 Our model also revealedsuggestive evidence of limited heritability of leukemia andof cancer of the stomach, lung, pancreas, ovary, and bladder,but the estimates did not reach statistical significance. Population-basedstudies in Utah and Sweden have found a familial effect forcancers at all of these sites.45,46,47
If we consider that the contribution of inherited genetic factorsto the causation of these types of cancer is indeed 27 to 42percent, and that single-gene mutations in familial cancer syndromesaccount for 1 to 15 percent of all cancers,1,3,40 then theremust be major gaps in our understanding of the genetic basisof colorectal, breast, and prostate cancer. The frequency ofmutations in the known high-risk susceptibility genes BRCA1 and BRCA2 in breast cancer, DNA mismatch-repair genesin hereditary nonpolyposis colorectal cancer, and the candidategene HPC1 in prostate cancer is too low to explain morethan a fraction of the genetic effects we found. For example,in a recent study of 12 pairs of Swedish monozygotic twins whowere concordant for breast cancer (and who were also includedin the present study), 2 pairs had a BRCA2 mutation and nonehad a BRCA1 mutation (unpublished data). Our findings suggestthat other genes are yet to be identified, but because theyare likely to be relatively common and carry only a moderaterisk, proving that they are involved in causing cancer willbe difficult.2
Although model fitting can be used to estimate the magnitudeof the heritable component of susceptibility to cancer, it cannotreveal how this component acts or how it interacts with otherfactors. For example, a cancer gene could be expressed withoutany environmental influence or only when activated by environmentalfactors. For this reason, we cannot exclude a modifying effectof environment on the genetic component found in our analysesof twins. However, without specific environmental measurements,interactions cannot be assessed. For colorectal, breast, andprostate cancer, the estimated hereditary components were slightlyhigher in the younger than in the older groups; this findingis in accordance with observations that hereditary effects arestrongest in early-onset cancers.5,7,45,46,48
The absolute risk of the same cancer before the age of 75 yearsfor the monozygotic twin of a person with colorectal, breast,or prostate cancer was between 11 percent and 18 percent. Fordizygotic twins, who have the same degree of genetic similarityas full siblings, the risk of these cancers was 3 to 9 percent.These figures could be valuable in providing clinical guidancenot only to the twins of persons with cancer but also to otherfirst-degree relatives.
One limitation of our study is that, despite its size, it didnot have enough power to distinguish heritable genetic effectsfrom environmental factors as causes of the familial aggregationof the less common types of cancer. The main reason for thislimitation is that birth-cohort and calendar-period restrictionsof twin registries set limits for analyses. Because errors indetermining zygosity or diagnoses of cancer lead to an overestimationof nonshared environmental effects, the familial effects are,if anything, underestimated. The incidence of cancer among twinsin the Finnish study did not differ from that in the generalpopulation,15 and in the Danish study, twins who responded tothe questionnaire had the same distribution of zygosity andincidence of cancer as those who did not respond.49 Thus, biasdue to selective response rates is improbable.
We conclude that the overwhelming contributor to the causationof cancer in the populations of twins that we studied was theenvironment. For some forms of cancer, in which a shared environmentis important, it may be possible to find clues in studies ofchildhood environment or long-lasting family habits. The relativelylarge heritability proportions for cancers at some sites, despitethe wide confidence intervals, suggest major gaps in our understandingof heritable cancer. Even for cancers for which there is statisticallysignificant evidence of a heritable component, most pairs oftwins were discordant for the cancer indicating that,on the population level, the increase in the risk of cancereven among close relatives of affected persons is generallymoderate.
Supported by the Nordic Cancer Union. The Swedish Twin Registryis supported by grants from the John D. and Catherine T. MacArthurFoundation and the Swedish Council for Planning and Coordinationof Research. The Danish twin study was supported by researchgrants from the Danish Cancer Society (36/79), the NationalCancer Institute (R35 CA 42581), and the National Instituteon Aging (PO1-AG08761). The Finnish part of the study was supportedby grants from the Finnish Cancer Organizations and the Academyof Finland.
We are indebted to all the participants and staff of the Nordictwin studies, without whom this study would not have been possible.
Source Information
From the Department of Medical Epidemiology, Karolinska Institute, Stockholm, Sweden (P.L., A.I.); the Institute of Public Health (Epidemiology) and the Danish Twin Registry, University of Southern Denmark, Odense (N.V.H., A.S.); the Department of Public Health, University of Helsinki, Helsinki, Finland (P.K.V., J.K., M.K.); the Department of Public Health and General Practice, University of Oulu, Oulu, Finland (J.K.); the Department of Public Health, University of Turku, Turku, Finland (M.K.); the Finnish Cancer Registry, Helsinki, Finland (E.P.); and the Department of Biosciences at Novum, Karolinska Institute, Stockholm, Sweden (K.H.).
Address reprint requests to Dr. Lichtenstein at the Department of Medical Epidemiology, Karolinska Institute, Box 281, SE-171 77 Stockholm, Sweden, or at paul.lichtenstein{at}mep.ki.se.
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