Hrafn Tulinius

Population-Based Study of Risk of Breast Cancer in Carriers of BRCA2 Mutation

BACKGROUND Estimates of an 80-90% risk of breast cancer for carriers of germline mutations in the BRCA1 and BRCA2 genes are based on studies of families at high risk of breast cancer. Risk estimates for a population are possible if the mutation status of a representative sample of that population can be assessed. In Iceland, one common founder BRCA2 mutation occurs in 0.6% of the population. Iceland has a population-based cancer registry and a large collection of pedigrees, and estimation of cancer risk in mutation carriers is therefore possible. METHODS We studied 575 breast-cancer patients, 541 women and 34 men unselected for family history of breast cancer. Data on cancer in first-degree relatives were available from the cancer registry. Risk of cancer was estimated by comparing the history of cancer in first-degree relatives of carriers and non-carriers. FINDINGS 56 (10.4%) of the 541 women and 13 (38%) of the 34 men carried the 999del5 mutation. The estimated risk of breast cancer at age 50 for all female carriers of the 999del5 mutation was 17.0% (95% CI 9.1-25.9) and 37.2% (22.4-53.9) at age 70. INTERPRETATION The results of our population-based study show that the mean risk of breast cancer in carriers of mutation in BRCA2 is lower than previously suggested. Individual risk assessment will, however, have to take account of family history.

Decreasing Late Mortality Among Five-Year Survivors of Cancer in Childhood and Adolescence: A Population-Based Study in the Nordic Countries

PURPOSE To assess the risk of death in patients who survive more than 5 years after diagnosis of childhood cancer and to evaluate causes of death in fatal cases. PATIENTS AND METHODS This was a population-based study in the five Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) using data of the nationwide cancer registries and the cause-of-death registries. The study cohort included 13,711 patients who were diagnosed with cancer before the age of 20 years between 1960 and 1989 and who survived at least 5 years from diagnosis. By December 31, 1995, 1,422 patients had died, and death certificates were assessed in 1,402. Standardized mortality ratios (SMRs) for validated causes of death were calculated based on 156,046 patient-years at risk. RESULTS The overall SMR was 10.8 (95% confidence interval [CI], 10.3 to 11.5), mainly due to high excess mortality from the primary cancer. SMR for second cancer was 4.9 (95% CI, 3.9 to 5.9) and was 3.1 (95% CI, 2.8 to 3.5) for noncancer death. The pattern of causes of death varied markedly between different groups of primary cancer diagnoses and was highly dependent on time passed since diagnosis. Overall late mortality was significantly lower in patients treated during the most recent period of time, 1980 to 1989, compared with those treated from 1960 to 1979 (hazard ratio, 0.61; 95% CI, 0.54 to 0.70), and there was no increase in rates of death due to cancer treatment. CONCLUSION Long-term survivors of childhood cancer had an increased mortality rate, mainly dying from primary cancers. However, modern treatments have reduced late cancer mortality without increasing the rate of therapy-related deaths.

Risk of breast cancer in female flight attendants: a population-based study (Iceland)

AbstractObjectives: To study whether increased cancer risk, particularly of cancer types previously related to radiation, was found among cabin attendants, using employment time as a surrogate of exposure to cosmic radiation. Methods: A cohort of 1690 cabin attendants, 158 men and 1532 women from the Icelandic Cabin Crew Association and two airline companies in Iceland, was established. Cancer sites were ascertained between 1955 and 1997 by follow-up in a cancer registry. The personal identification number of each subject was used in record linkage to population-based registers containing vital and emigration status, reproductive factors and histologically verified cancer diagnosis. Standardized incidence rates (SIR) of different cancer sites in relation to employment time and year of hiring were calculated, as well as predictive values of breast cancer risk for evaluating possible confounding due to reproductive factors. Results: The total number of person-years was 27,148. Among the women, 64 cancers were observed whereas 51.63 were expected (SIR 1.2, 95% CI 1.0–1.6), and significantly increased risk for malignant melanoma (SIR 3.0, 95% CI 1.2–6.2) was found. Significantly increased risks of overall cancers (SIR 1.3, 95% CI 1.0–1.8) and breast cancer (SIR 1.6, 95% CI 1.0–2.4) were observed among the female cabin attendants when 15 years lag time was applied. Those hired in 1971 or later had the heaviest exposure to cosmic radiation at a young age and had significantly increased risk of overall cancer (SIR 2.8, 95% CI 1.4–4.9) and breast cancer (SIR 4.1, 95% CI 1.7–8.5). Predictive values calculated on the basis of reproductive factors among the cabin attendants and the population, and risk of breast cancer were 1.0 for parous vs. nulliparous, 1.0 for number of children, and 1.1 for age at birth of first child. Conclusion: The increased risk of breast cancer and malignant melanoma among cabin attendants seems to be occupationally related. The part played by occupational exposures, i.e. cosmic radiation, disturbance of the circadian rhythm, and electromagnetic fields or combination of these factors in the etiology of breast cancer among the cabin crew, is still a puzzle as confounding due to parity appears to be ruled out. The relationship between the sunbathing habits of the cabin crew and the increased risk of malignant melanoma needs to be clarified. There is also an urgent need to elucidate the importance of these findings for todays aviation.

Risk of subsequent malignant neoplasms among 1,641 Hodgkin's disease patients diagnosed in childhood and adolescence: a population-based cohort study in the five Nordic countries. Association of the Nordic Cancer Registries and the Nordic Society of Pediatric Hematology and Oncology.

PURPOSE To assess the risk of subsequent malignant neoplasms among Hodgkins disease patients diagnosed before 20 years of age in the five Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden). PATIENTS AND METHODS There were 1,641 Hodgkins disease patients identified through the national cancer registries since the 1940s or 1950s. The patients were monitored for 17,000 person-years until the end of 1991. Expected figures were derived from the age-specific incidence rates in each country and standardized incidence ratios (SIR) were calculated. RESULTS A total of 62 subsequent neoplasms were diagnosed (SIR, 7.7; 95% confidence interval [CI], 5.9 to 9.9). The overall cumulative risk of subsequent neoplasms was 1.9% at the 10-year follow-up point, 6.9% at 20 years, and 18% at 30 years. There were 26 subsequent neoplasms among males (SIR, 6.5; 95% CI, 4.3 to 9.6) and 36 among females (SIR, 8.9; 95% CI, 6.2 to 12), of which 16 were breast cancers (SIR, 17; 95% CI, 9.9 to 28). High risks were seen for thyroid cancer (SIR, 33; 95% CI, 15 to 62), for secondary leukemia (SIR, 17; 95% CI, 6.9 to 35), and for non-Hodgkins lymphoma (SIR, 15; 95% CI, 4.9 to 35). The relative risk increased from 3.3 (95% CI, 1.2 to 7.1) for Hodgkins disease patients diagnosed in the 1940s and 1950s to 15 (95% CI, 7.4 to 27) in the 1980s. The highest risk of secondary leukemia (SIR, 68; 95% CI, 18 to 174) was seen among those diagnosed with Hodgkins disease in the 1980s. CONCLUSION Patients who survive Hodgkins disease at a young age are at very high relative risk of subsequent malignant neoplasms throughout their lives. In particular, the high relative risk of breast cancer following Hodgkins disease in the teenage years calls for enhanced activity for early diagnosis.

SECOND MALIGNANT NEOPLASMS AFTER CANCER IN CHILDHOOD AND ADOLESCENCE: A POPULATION-BASED CASE-CONTROL STUDY IN THE 5 NORDIC COUNTRIES

Our purpose was to assess the risk of developing a second malignant neoplasm (SMN) after cancer in childhood and adolescence associated with different treatment modalities. Our investigation was performed as a nested case‐control study within a Nordic cohort of 25,120 patients younger than 20 years old at first malignant neoplasm (FMN) diagnosed in 1960 through 1987. SMNs were diagnosed in 1960 through 1991. For each case of SMN, 3 controls were sampled, matched by sex, age, calendar year of diagnosis and length of follow‐up. For the final analysis, there were 234 cases and 678 controls. Relative risks (RRs) of various exposures were estimated by means of conditional logistic regression, with non‐exposed as the reference. The RR of developing SMN in the radiated volume was 4.3 (95% confidence interval 3.0–6.2). The risk was highest in children diagnosed before the age of 5 years; it increased with the dose of radiation and with increasing follow‐up time after FMN. Chemotherapy alone was not associated with an increased RR, but it significantly potentiated the effect of radiotherapy. RRs were unchanged between the periods 1960–1973 and 1974–1987, and since the use of chemotherapy increased in the latter period, the number of SMNs may increase. Hereditary factors were important for the occurrence of SMN independently of therapy. We conclude that radiation was the most important treatment‐related risk factor for the development of SMN. Chemotherapy appeared to play only an accessory role during the study period, potentiating the carcinogenic effect of radiotherapy. Int. J. Cancer 88:672–678, 2000.

Risk of cancer among offspring of childhood-cancer survivors

BACKGROUND Increasing numbers of children with cancer survive and reach reproductive age. However, the risk of cancer (other than retinoblastoma) in the offspring of survivors of childhood and adolescent cancer is uncertain. METHODS Using data from national cancer and birth registries, we assessed the risk of cancer among 5847 offspring of 14,652 survivors of cancer in childhood or adolescence diagnosed since the 1940s and 1950s in Denmark, Finland, Iceland, Norway, and Sweden. The offspring were followed up for a diagnosis of cancer for 86,780 person-years, and standardized incidence ratios were calculated. RESULTS Among the 5847 offspring, 44 malignant neoplasms were diagnosed (standardized incidence ratio, 2.6; 95 percent confidence interval, 1.9 to 3.5). There were 17 retinoblastomas, yielding a standardized incidence ratio of 37. There were 27 neoplasms other than retinoblastoma (standardized incidence ratio, 1.6; 95 percent confidence interval, 1.1 to 2.4). The second most common primary site of cancer among the offspring was the brain and nervous system, in which eight tumors were observed (standardized incidence ratio, 2.0; 95 percent confidence interval, 0.9 to 3.9.) There were between zero and four apparently sporadic cases of cancer in other primary sites among the offspring. Excluding 4 likely cases of hereditary cancer and 2 subsequent cancers among the offspring with hereditary retinoblastoma, there were 22 sporadic cancers, for a standardized incidence ratio of 1.3 (95 percent confidence interval, 0.8 to 2.0). CONCLUSIONS There is no evidence of a significantly increased risk of nonhereditary cancer among the offspring of survivors of cancer in childhood.

Incidence of cancer among commercial airline pilots

OBJECTIVES To describe the cancer pattern in a cohort of commercial pilots by follow up through the Icelandic Cancer Registry. METHODS This is a retrospective cohort study of 458 pilots with emphasis on subcohort working for an airline operating on international routes. A computerised file of the cohort was record linked to the Cancer Registry by making use of personal identification numbers. Expected numbers of cancer cases were calculated on the basis of number of person-years and incidences of cancer at specific sites for men provided by the Cancer Registry. Numbers of separate analyses were made according to different exposure variables. RESULTS The standardised incidence ratio (SIR) for all cancers was 0.97 (95% confidence interval (95% CI) 0.62 to 1.46) in the total cohort and 1.16 (95% CI 0.70 to 1.81) among those operating on international routes. The SIR for malignant melanoma of the skin was 10.20, 95% CI 3.29 to 23.81 in the total cohort and 15.63, 95% CI 5.04 to 36.46 in the restricted cohort. Analyses according to number of block-hours and radiation dose showed that malignant melanomas were found in the subgroups with highest exposure estimates, the SIRs were 13.04 and 28.57 respectively. The SIR was 25.00 for malignant melanoma among those who had been flying over five time zones. CONCLUSIONS The study shows a high occurrence of malignant melanoma among pilots. It is open to discussion what role exposure of cosmic radiation, numbers of block-hours flown, or lifestyle factors—such as possible excessive sunbathing—play in the aetiology of cancer among pilots. This calls for further and more powerful studies. The excess of malignant melanoma among those flying over five time zones suggests that the importance of disturbance of the circadian rhythm should be taken into consideration in future studies.

Linkage to BRCA2 region in hereditary male breast cancer

Breast cancer is rare in men, and family history of the disease is a risk factor. The recently discovered BRCA2 gene on chromosome 13q is thought to account for some families with increased risk of breast cancer, including male breast cancer. We describe a family with multiple cases of male breast cancer but, interestingly, no increase in female breast cancer. Linkage to the BRCA2 region is demonstrated and all the affected men share the same haplotype for the BCRA2 markers and loss of the other alleles in their tumours.

The effect of a single BRCA2 mutation on cancer in Iceland.

Objective: To estimate the risk of malignant diseases in families of probands with the same mutation in the BRCA2 gene. Design: A cohort study using record linkage of a breast cancer family resource and the Icelandic Cancer Registry. Setting: Iceland. Subjects: Families of 995 breast cancer patients, from which 887 were tested for a single founder 999del5 mutation; 90 had the mutation and 797 did not. Results: Relatives of probands with the mutation had significantly increased relative risk (RR) of breast cancer. For first degree relatives, the RR was 7.55 (95% CI 6.04 to 9.03) but was 1.72 (95% CI 1.49 to 1.96) in first degree relatives of probands without the mutation. For prostate and ovarian cancer, the first and second degree relatives of probands with the mutation had a significantly increased RR, but in families of probands without the mutation no significant familial risk was found. Conclusions: The 999del5 mutation in the BRCA2 gene explains a substantial proportion of familial risk of breast cancer in Iceland, but significant familial risk remains in relatives of probands without the mutation. For prostate and ovarian cancer, the mutation accounts for most of the familiality observed in families of breast cancer patients.

Mortality from cancer and other causes among male airline cockpit crew in Europe

Airline pilots and flight engineers are exposed to ionizing radiation of cosmic origin and other occupational and life‐style factors that may influence their health status and mortality. In a cohort study in 9 European countries we studied the mortality of this occupational group. Cockpit crew cohorts were identified and followed‐up in Denmark, Finland, Germany, Great Britain, Greece, Iceland, Italy, Norway and Sweden, including a total of 28,000 persons. Observed and expected deaths for the period 1960–97 were compared based on national mortality rates. The influence of period and duration of employment was analyzed in stratified and Poisson regression analyses. The study comprised 547,564 person‐years at risk, and 2,244 deaths were recorded in male cockpit crew (standardized mortality ratio [SMR] = 0.64, 95% confidence interval [CI] = 0.61–0.67). Overall cancer mortality was decreased (SMR = 0.68; 95% CI = 0.63–0.74). We found an increased mortality from malignant melanoma (SMR = 1.78, 95% CI = 1.15–2.67) and a reduced mortality from lung cancer (SMR = 0.53, 95% CI = 0.44–0.62). No consistent association between employment period or duration and cancer mortality was observed. A low cardiovascular mortality and an increased mortality caused by aviation accidents were noted. Our study shows that cockpit crew have a low overall mortality. The results are consistent with previous reports of an increased risk of malignant melanoma in airline pilots. Occupational risk factors apart from aircraft accidents seem to be of limited influence with regard to the mortality of cockpit crew in Europe.