Cancer Incidence and Mortality in 260,000 Nordic Twins With 30,000 Prospective Cancers.

The Nordic countries have comprehensive, population-based health and medical registries linkable on individually unique personal identity codes, enabling complete long-term follow-up. The aims of this study were to describe the NorTwinCan cohort established in 2010 and assess whether the cancer mortality and incidence rates among Nordic twins are similar to those in the general population. We analyzed approximately 260,000 same-sexed twins in the nationwide twin registers in Denmark, Finland, Norway and Sweden. Cancer incidence was determined using follow-up through the national cancer registries. We estimated standardized incidence (SIR) and mortality (SMR) ratios with 95% confidence intervals (CI) across country, age, period, follow-up time, sex and zygosity. More than 30,000 malignant neoplasms have occurred among the twins through 2010. Mortality rates among twins were slightly lower than in the general population (SMR 0.96; CI 95% [0.95, 0.97]), but this depends on information about zygosity. Twins have slightly lower cancer incidence rates than the general population, with SIRs of 0.97 (95% CI [0.96, 0.99]) in men and 0.96 (95% CI [0.94, 0.97]) in women. Testicular cancer occurs more often among male twins than singletons (SIR 1.15; 95% CI [1.02, 1.30]), while cancers of the kidney (SIR 0.82; 95% CI [0.76, 0.89]), lung (SIR 0.89; 95% CI [0.85, 0.92]) and colon (SIR 0.90; 95% CI [0.87, 0.94]) occur less often in twins than in the background population. Our findings indicate that the risk of cancer among twins is so similar to the general population that cancer risk factors and estimates of heritability derived from the Nordic twin registers are generalizable to the background populations.

The Danish Twin Registry: An Updated Overview.

The Danish Twin Registry (DTR) was established in the 1950s, when twins born from 1870 to 1910 were ascertained, and has since been extended to include twins from birth cohorts until 2009. The DTR currently comprises of more than 175,000 twins from the 140 birth cohorts. This makes the DTR the oldest nationwide twin register and among the largest in the world. The combination of data from several surveys, including biological samples and repeated measurements on the same individuals, and data from Danish national registers provides a unique resource for a wide range of twin studies. This article provides an updated overview of the data in the DTR: First, we provide a summary of the establishment of the register, the different ascertainment methods and the twins included; then follows an overview of major surveys conducted in the DTR since 1994 and a description of the DTR biobank, including a description of the molecular data created so far; finally, a short description is given of the linkage to Danish national registers at Statistics Denmark and some recent examples of studies using the various data resources in the DTR are highlighted.

Sexual Function in a Nationwide Cohort of 2,260 Survivors of Testicular Cancer after 17 Years of Followup.

PURPOSE: Evidence on the long-term impact of testicular cancer treatment on sexual function is not clear. Our aim was to estimate the effect of testicular cancer treatment on the risk of sexual dysfunction in long-term survivors of testicular cancer. MATERIALS AND METHODS: We performed a cross-sectional study of 2,260 long-term survivors of testicular cancer with a median followup of 17 years (IQR 12-24), including 1,098 who underwent orchiectomy alone (surveillance), 788 treated with bleomycin, etoposide and cisplatin alone or post-chemotherapy retroperitoneal surgery, 300 treated with abdominal radiotherapy and 74 who received more than 1 line of treatment. Sexual function was evaluated by the IIEF-15 (International Index of Erectile Function-15) questionnaire. Results were compared between treatment groups using logistic regression analysis with the results on each of the 5 IIEF-15 dimensions as the outcome and treatment as exposure using surveillance as the referent. RESULTS: The risk of erectile dysfunction was increased in all treatment groups compared to surveillance, including bleomycin, etoposide and cisplatin alone (OR 1.5, 95% CI 1.0-2.1, p <0.05), bleomycin, etoposide and cisplatin with post-chemotherapy surgery (OR 2.1, 95% CI 1.4-3.4, p <0.005), radiotherapy (OR 1.7, 95% CI 1.1-2.5, p <0.05) and more than 1 line of treatment (OR 3.2, 95% CI 1.6-6.3, p <0.005). Orgasmic dysfunction was associated with radiotherapy, bleomycin, etoposide and cisplatin with post-chemotherapy surgery and more than 1 line of treatment. CONCLUSIONS: Treatment with bleomycin, etoposide and cisplatin, radiotherapy and more than 1 treatment line increased the risk of erectile dysfunction in long-term survivors of testicular cancer compared to surveillance. Patients should be informed about this as part of the information on treatment related late effects.

Surveillance versus adjuvant radiotherapy for patients with high-risk stage I seminoma.

BACKGROUND: The optimal treatment strategy for patients with clinical stage I (CS-1) seminoma is controversial. The objective of the current study was to evaluate the outcomes for patients considered to be at high risk of disease recurrence with a tumor size ≥6 cm. Patients were treated with either adjuvant radiotherapy (RT) or followed with surveillance. METHODS: From the Danish Testicular Cancer database, the authors identified 473 patients with CS-1 seminoma with a tumor size ≥6 cm. Of these, 254 patients underwent adjuvant RT and 219 were followed with surveillance. Cumulative incidence function was applied to estimate the risk of disease recurrence, risk of second malignant neoplasm, and risk of receiving >1 line of treatment. Survival of the 2 groups was compared with the log-rank test and Cox model including age at diagnosis. RESULTS: No significant differences were found with regard to overall survival or risk of a second malignant neoplasm. Patients undergoing adjuvant RT received more treatments per patient than patients followed with surveillance, but there was no significant difference noted with regard to the risk of receiving >1 line of treatment. The 10-year cumulative incidence of disease recurrence was 32% versus 2.8%, respectively, for patients followed with surveillance and adjuvant RT. In patients followed with surveillance who developed disease recurrence, there was a high incidence of second recurrences after RT. CONCLUSIONS: The 10-year overall survival was found to be similar irrespective of primary treatment. Adjuvant RT was found to effectively reduce the rate of disease recurrence but resulted in the overtreatment of approximately two-thirds of the patients. The high incidence of second disease recurrences after RT in the patients followed with surveillance needs be addressed in future studies. Cancer 2017;123:1212-1218. © 2016 American Cancer Society.

Trends in tumors in the central nervous system in elderly in Denmark, 2008-2012.

BACKGROUND: Tumors in the central nervous system (CNS) comprise a heterogeneous group of tumors with different treatment strategies and prognoses. Current treatment regimens are based on studies on patients mainly younger than 70 years. The aim of the present study was to analyze and describe trends in incidence, mortality, prevalence, and relative survival in Denmark from 1980 to 2012 focusing on patients older than 70 years. MATERIAL AND METHODS: Tumors in the CNS were defined as ICD-10 codes C70-72, D32-33 and D42-43. Data with comparable data on cancer incidence, mortality, prevalence and relative survival derived from the NORDCAN database were delivered from the Danish Cancer Registry and the Danish Cause of Death Registry with follow-up for death or emigration until the end of 2013. RESULTS: During the period 1980-2012 the number of patients with CNS tumors increased from 603 to 1378 patients. The increase is seen mainly in the elderly patients, and especially in women aged 84-89 and 90 + at the time of diagnosis. During the same time period, the mortality rates increased within all age groups, most significantly in patients aged 70 years or older. This may reflect an increased focus on and identification of these patients. Noteworthy; the number of patients living with a CNS tumor increased from 2952 in 1980 to 12 147 patients in 2010. CONCLUSION: This study suggests that the current treatment strategies in general may have improved survival in patients with CNS tumors, but in order to improve survival further in the increasing group of elderly patients more knowledge about treatment of these patients is needed.

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

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.

The Danish Twin Registry: linking surveys, national registers, and biological information.

Over the last 60 years, the resources and the research in the Danish Twin Registry (DTR) have periodically been summarized. Here, we give a short overview of the DTR and a more comprehensive description of new developments in the twenty-first century. First, we outline our experience over the last decade of combining questionnaire and survey data with national demographic, social, and health registers in Statistics Denmark. Second, we describe our most recent data collection effort, which was conducted during the period 2008-2011 and included both in-person assessments of 14,000+ twins born 1931-1969 and sampling of biological material, hereby expanding and consolidating the DTR biobank. Third, two examples of intensively studied twin cohorts are given. The new developments in the DTR in the last decade have facilitated the ongoing research and laid the groundwork for new research directions.

Register-based research on twins.

INTRODUCTION: The Danish Twin Registry (DTR) has for more than 50 years been based on surveys and clinical investigations and over the two last decades also on register linkage. Currently these two approaches are merged within Statistics Denmark. RESEARCH TOPICS: Here we report on three major groups of register-based research in the DTR that used the uniqueness of twinning. First, we focus on the ''long-term prognosis'' of being a twin compared with being a singleton and show that Danish twins have health trajectories in adulthood similar to singletons, which is a result of interest for twins and their families as well as a test of the fetal origins hypothesis that states that fetal growth restriction has long-term health consequences. Secondly, we summarise some of the most important register-based ''classical twin studies'', e.g. heritability studies on lifespan and exceptional longevity. Finally, we illustrate how the co-twin control method in a register setting can be used to control for the effect of rearing environment and genetic factors in studies of the association between exposures and health. CONCLUSION: The spectrum of register-based twin studies is very wide and have changed in accordance with methodological and data resource developments.

Sexual Function and Quality of Life in a National Cohort of Survivors of Bilateral Testicular Cancer.

BACKGROUND: Sexual function and quality of life remain unexplored among long-term survivors of bilateral testicular cancer (TC). OBJECTIVE: To investigate sexual function, fatigue, anxiety, and depression among long-term survivors of bilateral TC (unilateral TC with contralateral germ cell neoplasia in situ [TC+GCNIS] or bilateral TC [BTC]). DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional study of 2479 long-term TC survivors, of whom 126 were treated with contralateral radiotherapy for GCNIS, 93 were treated with bilateral orchiectomy for BTC, and 2260 had unilateral TC (reference group). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes were assessed using validated questionnaires at a median time since diagnosis of 17 yr (interquartile range 12-23). Results for survivors of TC+GCNIS and of BTC were compared with those for the reference group. Adjustment was made for age and treatment for disseminated disease. RESULTS AND LIMITATIONS: The age-adjusted risk of anxiety was significantly higher among BTC survivors (odds ratio 1.7, 95% confidence interval [CI] 1.1-2.8; p=0.002) than in the reference group. Apart from a higher risk of reduced motivation among survivors of TC+GCNIS (ß=0.067, 95% CI 0.0013-0.13; p=0.046) there were no significant differences between the groups. Limitations include the low number of cases with symptoms of depression. CONCLUSIONS: Survivors of BTC had a higher risk of anxiety but did not experience impairment of other aspects of quality of life when compared to survivors of unilateral TC. These results are of importance for evidence-based information on late effects for bilateral TC patients. PATIENT SUMMARY: We evaluated quality of life and sexual function among long-term survivors of bilateral testicular cancer. Reassuringly, we did not find impaired quality of life apart from a higher risk of anxiety when comparing survivors of bilateral testicular cancer with survivors of unilateral testicular cancer.

Psychological stress in long-term testicular cancer survivors: a Danish nationwide cohort study.

PURPOSE: Long-term cancer survivors may develop psychological late effects. The aim of the present study was to determine prevalence of high level of stress in testicular cancer survivors (TCS) compared with the general population and prevalence of high level of stress among TCS stratified by type of treatment (surveillance, bleomycin, etoposide and cisplatin (BEP), or abdominal radiotherapy (RT)). METHODS: In this large, nationwide and population-based, cross-sectional study, a total of 2252 TCS filled in a questionnaire between 2014-2016 covering psychological stress (Perceived Stress Scale (PSS)), sociodemographic factors, and physical health variables. Results were compared with a reference population. The reference population consisted of 61,927 men without prior or present cancer and sampled at random from the central population. High level of stress was defined as a PSS score ≥ 16, equivalent to the highest scoring quintile in the reference population. Logistic regression models adjusted for relevant covariates were used to estimate prevalence ratios of high level of stress. RESULTS: Distribution of TCS was: surveillance, n = 1134; BEP, n = 807; and RT, n = 311 (median time since diagnosis was 19 years). TCS were more likely to have high level of stress compared to the reference population with a prevalence ratio of 1.56 (95% CI, 1.40-1.73). Individually, surveillance, BEP and RT groups had higher level of stress compared to the reference population. CONCLUSIONS: TCS are more likely to have high level of stress. Screening programs for psychological stress should be considered as part of the follow-up program. IMPLICATIONS FOR CANCER SURVIVORS: A higher level of stress is observed in TCS irrespective of treatment.

Prognostic Factors and Treatment Results After Bleomycin, Etoposide, and Cisplatin in Germ Cell Cancer: A Population-based Study.

BACKGROUND: First-line treatment for patients with disseminated germ cell cancer (GCC) is bleomycin, etoposide, and cisplatin (BEP). A prognostic classification of patients receiving chemotherapy was published by the International Germ Cell Cancer Collaborative Group (IGCCCG) in 1997, but only a small proportion of the patients received BEP. OBJECTIVE: To estimate survival probabilities after BEP, evaluate the IGCCCG prognostic classification, and propose new prognostic factors for outcome. DESIGN, SETTING, AND PARTICIPANTS: Of a Danish population-based cohort of GCC patients (1984-2007), 1889 received first-line BEP, with median follow-up of 15 yr. Covariates evaluated as prognostic factors were age, year of treatment, primary site, non-pulmonary visceral metastases, pulmonary metastases, and tumor markers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes measured were 5-yr progression-free survival (PFS), 5-yr disease-specific survival (DSS), and 5-yr overall survival (OS) as calculated using the Kaplan-Meier method and the Cox proportional hazards model. RESULTS AND LIMITATIONS: The 5-yr PFS, DSS, and OS were 87%, 95%, and 93%, respectively, for patients with seminomatous GCC (SGCC) and good prognosis. For nonseminomatous GCC (NSGCC) with good, intermediate, and poor prognosis, the 5-yr probabilities were 90%, 76%, and 55% for PFS; 97%, 87%, and 66% for DSS; and 95%, 85%, and 64% for OS, respectively. For SGCC patients, new adverse prognostic factors not included in the IGCCCG classification were higher age and lactate dehydrogenase ≥1.5 times the upper limit of normal. For NSGCC patients, higher age and pulmonary metastases were additional adverse prognostic factors. Treatment in earlier years was associated with higher mortality. Limitations include the small number of patients in the prognostic groups, and the inability to adjust for performance status and comorbidity. CONCLUSIONS: Our study reveals improved survival for disseminated GCC throughout the study period. We propose new prognostic factors for outcome for validation in larger cohorts of patients. PATIENT SUMMARY: In this study of testicular cancer patients, we evaluated prognostic factors for outcome and calculated survival after standard chemotherapy. We find that survival has improved over the years and we propose new prognostic factors for outcome for validation in larger patient cohorts.

Risk factors for breast cancer at young ages in twins: an international population-based study.

BACKGROUND: Breast cancer etiology in women may relate to exposures early in life as well as in adulthood, but it has been difficult to gain information on childhood variables, and evidence on their effects is very limited. Comparison of risk factor levels between affected probands and unaffected twins in twin pairs can provide a unique method to investigate risk factors that act in early life. METHODS: We conducted four population-based case-control studies of breast cancer risk in twins in Denmark, England and Wales, Finland, and Sweden and pooled the data from these studies. The case patients were 400 women with incident breast cancer before the age of 50 years, and the control subjects were their twin sisters who had not had breast cancer by that time. Data on risk factors (e.g., demographic and anthropomorphic variables, reproductive history, and family history) were collected by interview and by a mailed questionnaire and were analyzed by calculating matched odds ratios [ORs]. All statistical tests were two-sided. RESULTS: The risk of breast cancer was increased for women who were less obese (OR = 1.44, 95% confidence interval [CI] = 1.08 to 1.91) or taller (OR = 1.27, 95% CI = 0.95 to 1.70) than their co-twin at age 10 years, for women who developed breasts earlier than their co-twin (OR = 1.53, 95% CI = 1.14 to 2.06), and for women who had a smaller waist-to-hip ratio at age 20 years than their co-twin (OR = 1.79, 95% CI = 1.00 to 3.21). Analysis according to family history of breast cancer showed that the associations of childhood height and weight with risk of breast cancer were only apparent in women without a family history of breast cancer. CONCLUSIONS: Childhood growth before puberty may affect the risk of premenopausal breast cancer, at least in women without a family history of breast cancer. The distribution of body fat in young adulthood may also be related to breast cancer risk.

The Heritability of Breast Cancer among Women in the Nordic Twin Study of Cancer.

BACKGROUND: Family history is an established risk factor for breast cancer. Although some important genetic factors have been identified, the extent to which familial risk can be attributed to genetic factors versus common environment remains unclear. METHODS: We estimated the familial concordance and heritability of breast cancer among 21,054 monozygotic and 30,939 dizygotic female twin pairs from the Nordic Twin Study of Cancer, the largest twin study of cancer in the world. We accounted for left-censoring, right-censoring, as well as the competing risk of death. RESULTS: From 1943 through 2010, 3,933 twins were diagnosed with breast cancer. The cumulative lifetime incidence of breast cancer taking competing risk of death into account was 8.1% for both zygosities, although the cumulative risk for twins whose co-twins had breast cancer was 28% among monozygotic and 20% among dizygotic twins. The heritability of liability to breast cancer was 31% [95% confidence interval (CI), 10%-51%] and the common environmental component was 16% (95% CI, 10%-32%). For premenopausal breast cancer these estimates were 27% and 12%, respectively, and for postmenopausal breast cancer 22% and 16%, respectively. The relative contributions of genetic and environmental factors were constant between ages 50 and 96. Our results are compatible with the Peto-Mack hypothesis. CONCLUSION: Our findings indicate that familial factors explain almost half of the variation in liability to develop breast cancer, and results were similar for pre- and postmenopausal breast cancer IMPACT: We estimate heritability of breast cancer, taking until now ignored sources of bias into account.

Second Malignant Neoplasms and Cause of Death in Patients With Germ Cell Cancer: A Danish Nationwide Cohort Study.

IMPORTANCE: Patients given systemic treatment for testicular germ cell cancer (GCC) are at increased risk for a second malignant neoplasm (SMN). Previous studies on SMN and causes of death lacked information on the exact treatment applied or were based on patients receiving former treatment options. OBJECTIVE: To evaluate the treatment-specific risks for SMN and death in a nationwide population-based cohort of patients with GCC treated with current standard regimens. DESIGN, SETTING, AND PARTICIPANTS: This study examined a Danish nationwide cohort of 5190 men with GCC who entered the Danish Testicular Cancer database between January 1, 1984, and December 31, 2007. Treatment results were compared with a randomly sampled, age-stratified, population-based control group. Cases of gonadal and extragonadal primary were included in the nationwide cohort. The treatments were surveillance only; retroperitoneal radiotherapy (RT); bleomycin, etoposide, and cisplatin (BEP); or more than 1 line of treatment (MTOL). MAIN OUTCOMES AND MEASURES: Cumulative incidence and hazard ratios (HRs) for SMN and death calculated by the Cox proportional hazards model were compared with those of age-matched controls. RESULTS: The study population comprised 2804 patients with seminoma and 2386 with nonseminoma. The median follow-up was 14.4 years (interquartile range, 8.6-20.5 years). The 20-year cumulative incidence of SMN with death as a competing risk was 7.8% (surveillance), 7.6% (BEP), 13.5% (RT), 9.2% (MTOL), and 7.0% (controls). We found no increased risk for SMN after surveillance, while the HRs were 1.7 (95% CI, 1.4-2.0), 1.8 (95% CI, 1.5-2.3), and 3.7 (95% CI, 2.5-5.5), respectively, after BEP, RT, and MTOL. Mortality owing to non-GCC causes was decreased after surveillance, but increased by 1.3 times after BEP and RT and by 2.6 times after MTOL. Excess mortality due to SMN was found after BEP (HR, 1.6; 95% CI, 1.2-2.2), RT (HR, 2.1; 95% CI, 1.5-2.9), and MTOL (HR, 5.8; 95% CI, 3.6-9.6). CONCLUSIONS AND RELEVANCE: We found no increased risk for SMN or death among patients undergoing surveillance only. The risks for SMN and death due to SMN were increased after BEP alone, RT alone, and MTOL. Approaches to define patients who might benefit from less intensive treatment are needed.

Germ Cell Cancer and Multiple Relapses: Toxicity and Survival.

PURPOSE: A small number of patients with germ cell cancer (GCC) receive more than one line of treatment for disseminated disease. The purpose of this study was to evaluate late toxicity and survival in an unselected cohort of patients who experienced relapse after receiving first-line treatment for disseminated disease. METHODS: From the Danish Testicular Cancer database, we identified all patients who received more than one line of treatment for disseminated disease. Information about late toxicity and mortality was obtained by means of linkage to national registers. Prognostic factors for relapse and death were identified and compared with the International Prognostic Factors Study Group (IPFSG) classification. RESULTS: In total, 268 patients received more than one line of treatment for disseminated GCC. Approximately half of patients (n=136) died as a result of GCC. The 132 remaining patients, compared with patients treated with only orchiectomy, had an increased risk for a second cancer (hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.5), major cardiovascular disease (HR, 1.9; 95% CI, 1.0 to 3.3), pulmonary disease (HR, 2.0; 95% CI, 1.0 to 3.8), GI disease (HR, 7.3; 95% CI, 3.6 to 14.8), renal impairment (HR, 8.3; 95% CI, 3.0 to 23.2), neurologic disorders (HR, 6.3; 95% CI, 3.1 to 12.6), and death as a result of other causes (HR, 2.6; 95% CI, 1.6 to 4.2). In large part, the IPFSG classification was confirmed in our population; however, we could not confirm the primary site and the level of human chorionic gonadotropin as independent factors. We identified increasing age as a possible new prognostic factor for treatment failure after second-line treatment (HR, 1.2 per 10 years; 95% CI, 1.2 to 15). CONCLUSION: Patients with GCC who survive after more than one line of treatment for disseminated disease have a highly increased risk of late toxicity and death as a result of causes other than GCC. Therefore, they should be candidates for life-long follow-up. The IPFSG classification was confirmed in this unselected population.

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

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.

Cancer and longevity--is there a trade-off? A study of cooccurrence in Danish twin pairs born 1900-1918.

BACKGROUND: Animal models and a few human studies have suggested a complex interaction between cancer risk and longevity indicating a trade-off where low cancer risk is associated with accelerating aging phenotypes and, vice versa, that longevity potential comes with the cost of increased cancer risk. This hypothesis predicts that longevity in one twin is associated with increased cancer risk in the cotwin. METHODS: A total of 4,354 twin pairs born 1900-1918 in Denmark were followed for mortality in the Danish Civil Registration System through 2008 and for cancer incidence in the period 1943-2008 through the Danish Cancer Registry. RESULTS: The 8,139 twins who provided risk time for cancer occurrence entered the study between ages 24 and 43 (mean 33 years), and each participant was followed up to death, emigration, or at least 90 years of age. The total follow-up time was 353,410 person-years and, 2,524 cancers were diagnosed. A negative association between age at death of a twin and cancer incidence in the cotwin was found in the overall analyses as well as in the subanalysis stratified on sex, zygosity, and random selection of one twin from each twin pair. CONCLUSIONS: This study did not find evidence of a cancer-longevity trade-off in humans. On the contrary, it suggested that longevity in one twin is associated with lower cancer incidence in the cotwin, indicating familial factors associated with both low cancer occurrence and longevity.

The danish twin registry: past and present.

The Danish Twin Registry was established formally in 1954 and thus celebrates its 50th anniversary in 2004. Here we give an account of its founding and the early years, and a brief summary of more recent progress.

Relative importance of genetic effects in rheumatoid arthritis: historical cohort study of Danish nationwide twin population.

OBJECTIVE: To determine the relative importance of environmental and genetic effects in the development of rheumatoid arthritis. DESIGN: Historical cohort study with record linkage between a twin registry and the Danish discharge registry as well as the Danish national registry of deaths used to estimate completeness. SETTING: Two population based nationwide twin birth cohorts. PARTICIPANTS: 37 338 twins were sent a questionnaire about rheumatic diseases. Self reported rheumatoid arthritis was verified by clinical examination and from medical records. MAIN OUTCOME MEASURES: The probandwise concordance rate of rheumatoid arthritis in monozygotic and dizygotic twins. RESULTS: The response rate was 84.7%. Rheumatoid arthritis was verified in 13 monozygotic and 36 dizygotic twins. There were no concordant monozygotic twin pairs and two concordant dizygotic twin pairs. Based on capture-recapture methods the probability of ascertainment was 78.3%. The probandwise concordance rate was 0 (95% confidence interval 0 to 24.7) in monozygotic twins and 8.8 (1.9 to 23.7) in dizygotic twins. CONCLUSION: Genes are of minor importance in the development of rheumatoid arthritis.

The Danish Twin Registry: 127 birth cohorts of twins.

The Danish Twin Registry is the oldest national twin register in the world, initiated in 1954 by ascertainment of twins born from 1870 to 1910. During a number of studies birth cohorts have been added to the register, and by the recent addition of birth cohorts from 1931 to 1952 the Registry now comprizes 127 birth cohorts of twins from 1870 to 1996, with a total of more than 65,000 twin pairs included. In all cohorts the ascertainment has been population-based and independent of the traits studied, although different procedures of ascertainment have been employed. In the oldest cohorts only twin pairs with both twins surviving to age 6 have been included while from 1931 all ascertained twins are included. The completeness of the ascertainment after adjustment for infant mortality is high, with approximately 90% ascertained up to 1968, and complete ascertainment of all liveborn twin pairs since 1968. The Danish Twin Registry is used as a source for large studies on genetic influence on aging and age-related health problems, normal variation in clinical parameters associated with the metabolic syndrome and cardiovascular diseases, and clinical studies of specific diseases. The combination of survey data with data obtained by linkage to national health related registers enables follow-up studies both of the general twin population and of twins from clinical studies.