A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes.

The BRCA2 gene on chromosome 13 has been shown to be associated with familial male and female breast cancer. Here we describe a study on BRCA2 in 21 Icelandic families, including 9 with male breast cancer. We have previously reported linkage to the BRCA2 region in an Icelandic male breast cancer family and subsequently found a strong indication of linkage to BRCA2 and the same BRCA2 haplotype in breast cancer cases from 15 additional families, indicating a common origin. We describe a five base-pair deletion in exon 9 of BRCA2 in an affected male from the male breast cancer family. The same mutation occurs in all the families with the shared BRCA2 haplotype indicating a founder effect. Among mutation carriers there are 12 males with breast cancer, which accounts for 40% of all males diagnosed with breast cancer in Iceland over the past 40 years. Three of them have no family history of breast cancer indicating that this mutation may have variable penetrance. The same BRCA2 mutation appears to be associated with different cancer phenotypes in this population including male and female breast cancer, prostate cancer, pancreas cancer and ovarian cancer.

Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies.

A recent report estimated the breast cancer risks in carriers of the three Ashkenazi founder mutations to be higher than previously published estimates derived from population based studies. In an attempt to confirm this, the breast and ovarian cancer risks associated with the three Ashkenazi founder mutations were estimated using families included in a previous meta-analysis of populatrion based studies. The estimated breast cancer risks for each of the founder BRCA1 and BRCA2 mutations were similar to the corresponding estimates based on all BRCA1 or BRCA2 mutations in the meta-analysis. These estimates appear to be consistent with the observed prevalence of the mutations in the Ashkenazi Jewish population.

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 Hodgkin's 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 Hodgkin's 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-Hodgkin's lymphoma (SIR, 15; 95% CI, 4.9 to 35). The relative risk increased from 3.3 (95% CI, 1.2 to 7.1) for Hodgkin's 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 Hodgkin's disease in the 1980s. CONCLUSION: Patients who survive Hodgkin's 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 Hodgkin's disease in the teenage years calls for enhanced activity for early diagnosis.

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.

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.

Risk factors for malignant diseases: a cohort study on a population of 22,946 Icelanders.

The records of a cohort of 11,580 females and 11,366 males participating in an Icelandic cardiovascular risk factor study were linked with the Icelandic Cancer Registry, identifying 1,785 males and 1,490 females who had been registered with neoplastic diseases from 1968 to 1995. The interval between the time of measurement of the variables and the diagnosis of the malignancy ranged from 4 to 27 years. The variables consisted of answers from a questionnaire on smoking and the use of hypertensive drugs and anthropometric and biochemical measurements. Cox's regression was applied to analyze the predictive power of the variables on the risk of cancer after the first examination at the Heart Preventive Clinic, Reykjavík. Univariate analyses, adjusted for age, were performed for each variable and each major site. Within each major site, multivariate regression analysis was applied for variables that were found significantly (10% level in univariate analysis) positive or negative as risk factors. The results show that smoking is the most important risk factor, negative only for endometrium. For lung cancer, the risk is twice as strong for females as it is for males, whereas for pancreas, males have a relative risk ratio of 4.5, compared with 2.4 for females. Height is a risk factor for all sites for each sex, for breast in females, and for kidney in males. Several anthropometric risk factors were studied. Some of these can describe positive or negative relative risk ratios for cancer, and their use may shed light on cancer pathogenesis. Serum cholesterol is a negative risk factor for breast cancer in females, but triglycerides are a positive risk factor for cervix cancer in females and for colon or rectum and thyroid cancer in males. Serum glucose is a positive risk factor for prostate cancer and a negative risk factor for lymphomas and leukemias.

Tumours in Iceland. 10. Malignant tumours of the female breast. A histological classification, laterality, survival and epidemiological considerations.

The Icelandic Cancer Registry has records of 1,720 cases of malignant tumours of the female breast diagnosed in 1,659 patients in the 30-year period 1955-1984. Of these, 1,658 tumours were invasive. Sufficient histological material existed for 1,666 malignant tumours to make it possible to classify them according to the criteria published by the WHO. The most frequent histological type was Ductal carcinoma: 1,064 neoplasms, or 64%. Second in frequency was Lobular carcinoma: 175 neoplasms, or 10%; third was Mucinous carcinoma: 115 neoplasms, or 7%; and fourth in frequency was Medullary carcinoma: 69 neoplasms, or 4%. The incidence of carcinoma of the breast increased by 74% from 37.0 per 100,000 per annum in 1955-59 to 64.4 per 100,000 in 1980-84. This increase in incidence affected all morphological types, but Lobular and Mucinous more than Ductal and Medullary. The survival times have improved with time. Unilateral tumours were 710 in the right and 837 in the left breast. Both breasts were involved 167 times (106 patients), and in 6 patients the side was not recorded. A second primary was more likely to develop when the first one was in the right breast. This study of malignant tumours of the breast is the tenth in a series of investigations into histological classification of tumours occurring in Iceland.

Tumours in Iceland. 16. Malignant tumours of the stomach. Histological classification and description of epidemiological changes in a high-risk population during 30 years.

Iceland is one of the high-risk countries for stomach cancer. During the period 1955-84 the incidence declined from 76 to 28 per 10(5) p.a. for males and from 30 to 12 for females. Tissue material from the primary site in 978 males and 448 females was available for histological typing. By the WHO classification tubular carcinoma was most frequent in both sexes, 66% in males and 63% in females, and signet-ring carcinoma second, 13% in males and 16% in females. By the Laurén classification in males 78.1% were intestinal and 16.5% diffuse carcinomas, and in females 73.1% were intestinal and 20.7% diffuse carcinomas. The decline in stomach cancer in Icelanders has mostly affected the intestinal type of tumour (Laurén) and the tubular type of tumour (WHO). Diffuse type tumours (Laurén) have declined slightly. This supports the theory that intestinal carcinomas are more influenced by environmental and especially dietary factors, and that diffuse carcinomas are more influenced by other as yet unknown factors. For epidemiological studies both histological classifications have their value, the WHO especially in that it is based on standard histopathological criteria and the Laurén especially in that it only includes two tumour types. The WHO classification can roughly be transcribed to the Laurén classification as tubular, mucinous and papillary carcinomas fall into the group of intestinal tumours, and signet-ring and more than half of undifferentiated carcinomas into the group of diffuse tumours.

Helicobacter pylori antibodies and gastric cancer in Iceland - The decline in IgG antibody level is a risk factor.

H. pylori infection is considered a causal agent of duodenal ulcer and a significant risk factor for gastric cancer. Retrospective cohort studies have demonstrated a significant association between presence of antibody to H. pylori and gastric cancer when using samples obtained years before the diagnosis but not at the time of diagnosis. The present study investigates, in a population-based cohort, whether a decline occurs in H. pylori antibody levels before the diagnosis of stomach cancer. Repeat samples (2 to 5) were available from 23 persons with gastric cancer taken up to 20 years before the diagnosis and 128 control subjects matched for gender, age, time and number of repeat samples. The odds ratio of developing stomach cancer was 1.16 (95% CI 1.05-1.28) for those showing decline in antibody levels of 1 relative antibody activity unit per year versus those with constant or rising levels. We conclude that this decline in antibody levels in cases, and not in controls, supports an active role of H. pylori in the pathogenesis of gastric cancer by causing atrophic gastritis, and provides a better risk assessment for gastric cancer compared to single measurements.

Whooping cough and Parkinson's disease. The Europarkinson Preparatory Activity Research Group.

BACKGROUND: We reported high levodopa use and prevalences of Parkinson's Disease (PD) in periodically, time-clustered, icelandic cohorts born after major whooping cough epidemics (MWCE). METHODS: In order to quantify a possible relationship between age at first post-birth MWCE and risk of PD we: 1) calculated cumulative incidences of PD during the period 1954-1963 in one-year Icelandic cohorts born between 1869 and 1927, using raw material from a reported survey; 2) identified MWCE from 1869 onwards in Iceland; 3) estimated cohort ages at onset of incidence period and at first MWCE; and 4) combined the above-mentioned information using log-linear models. In addition, we studied the prevalence of levodopa users in Icelandic birth cohorts during a recent period. RESULTS: The curves of the above-mentioned incidences and prevalences in one-year birth-cohorts showed: 1) a similar, age-related, inverted V profile; and 2) a systematic notchy pattern, with peak values for one or both measurements for cohorts born during or after each of nine MWCE identified during the period 1869-1927. When 13 cohorts born in years with MWCE were excluded from the analysis, the risk of PD rose with age at first defined MWCE, with the linear increase being 8.4% per year (95% CI: -0.1-18.3%). CONCLUSIONS: These results are consistent with reported effects of age at exposure in animal models of toxic parkinsonism, age-related changes in the dopamine receptor-GPT-binding protein-adenylatecyclase system observed in rats treated with pertussis toxin, and some PD epidemiological features. They suggest that pertussis neurotoxicity could be casually treated to PD worldwide.

Breast cancer risk in airline cabin attendants: a nested case-control study in Iceland.

AIMS: To investigate whether length of employment as a cabin attendant was related to breast cancer risk, when adjusted for reproductive factors. METHODS: Age matched case-control study nested in a cohort of cabin attendants. The cases were found from a nationwide cancer registry (followed up to end of year 2000) and the reproductive factors (age at first childbirth and number of children) from a registry of childbirth, in both instances by record linkage with the cabin attendants' identification numbers. The employment time of the cabin attendants at the airline companies and the reproductive factors had been systematically recorded prior to the diagnosis of breast cancer in the cohort. A total of 35 breast cancer cases and 140 age matched controls selected from a cohort of 1532 female cabin attendants were included in the study. RESULTS: The matched odds ratio from conditional logistic regression of breast cancer risk among cases and controls of cabin attendants was 5.24 (95% CI 1.58 to 17.38) for those who had five or more years of employment before 1971 compared with those with less than five years of employment before 1971, adjusted for age at first childbirth and length of employment from 1971 or later. CONCLUSIONS: The association between length of employment and risk of breast cancer, adjusted for reproductive factors, indicates that occupational factors may be an important cause of breast cancer among cabin attendants; the association is compatible with a long induction period.

Risk factors for cutaneous malignant melanoma among aircrews and a random sample of the population.

AIMS: To evaluate whether a difference in the prevalence of risk factors for malignant melanoma in a random sample of the population and among pilots and cabin attendants could explain the increased incidence of malignant melanoma which had been found in previous studies of aircrews. METHODS: A questionnaire was used to collect information on hair colour, eye colour, freckles, number of naevi, family history of skin cancer and naevi, skin type, history of sunburn, sunbed, all sunscreen use, and number of sunny vacations. RESULTS: The 239 pilots were all males and there were 856 female cabin attendants, which were compared with 454 males and 1464 females of the same age drawn randomly from the general population. The difference in constitutional and behavioural risk factors for malignant melanoma between the aircrews and the population sample was not substantial. The aircrews had more often used sunscreen and had taken more sunny vacations than the other men and women. The predictive values for use of sunscreen were 0.88 for pilots and 0.85 for cabin attendants and the predictive values for sunny vacation were 1.36 and 1.34 respectively. CONCLUSION: There was no substantial difference between the aircrew and the random sample of the population with respect to prevalence of risk factors for malignant melanoma. Thus it is unlikely that the increased incidence of malignant melanoma found in previous studies of pilots and cabin attendants can be solely explained by excessive sun exposure.

Late determinants of cancer.

The paper reviews some findings on the frequency of latent carcinoma. Latent carcinomas are found much more frequently in the prostate, than would be expected from mortality or incidence data. The same applies to neuroblastomas in the adrenal cortex in infants. The problem has not been studied in detail in other organs. A satisfactory explanation of spontaneous regression of human cancers or the variable disease-free survival time of cancer patients has not been found. It is concluded that defence mechanisms of paramount importance exist, and need to be studied. Recent reports on serum retinol and serum cholesterol are reviewed since these are both lower in people who later develop cancer. Much more knowledge is needed but these phenomena could be linked.

Left and right sided breast cancer.

Many studies have shown that unilateral breast cancer is more frequent in the left breast than in the right. This has been investigated in the Icelandic Cancer Registry. Information on all but 18 female breast cancer cases diagnosed in the forty-year-period from 1948 to 1987, a total of 2139 cases, was used. Of these 2011 were unilateral, 1069 were in the left breast, an excess of 13%. Primary breast cancer in both breasts was diagnosed in 81 women, 35 in the left breast first, and 46 in the right breast first. The excess risk of developing cancer remains for the left breast also for women who have already lost one breast because of cancer. Information on whether their relatives had developed breast cancer existed for 1197 of these women. Patients with an affected first degree relative were of 2.54 fold risk of developing contralateral primary breast cancer, but women with no affected relative were at a reduced risk (not significant). Patients with right sided breast cancer are more likely to have a relative with breast cancer. The breast cancer status of the relatives did not influence the risk of death, so a better survival of familial cases could not be shown.

Latent thyroid carcinoma in Iceland at autopsy.

The annual incidence rate of thyroid carcinoma in Iceland is high, 4.4 pr. 100,000 men, and 11.7 pr. 100,000 women, as published by the Icelandic Cancer Registry for the period 1955-1984. This rate is more than twice that in the other Nordic countries and one of the highest incidence rates reported anywhere. This led us to investigate the prevalence rate of latent thyroid carcinoma in Iceland. We serially sectioned and examined thyroid glands from 201 consecutive forensic autopsies. Altogether, sixteen carcinomas were identified in fourteen glands: fourteen papillary, one follicular and one medullary carcinoma. We conclude that the prevalence rate of latent thyroid carcinoma in each sex does not follow the frequency distribution of clinical disease, being 7.5% in males and 5.1% in females. Comparisons between populations show the same lack of consistency. Further, most, but not all, latent carcinomas of the thyroid gland are of the papillary type. These findings suggest that promoting factors might be of particular importance where incidence and mortality rates are high, but further research is needed into the role of host resistance.

Mortality and cancer incidence among marine engineers and machinists in Iceland.

A retrospective cohort study of mortality and cancer morbidity was carried out among 295 marine engineers and 182 machinists with special regard to cancer of the lung. The cohort was defined as all graduates from engineering and machinists school in Iceland during 1936-1955. During vocational training, as well as in their professional lives, marine engineers and machinists are exposed to asbestos, different kinds of mineral oils, and exhaust gases with marked individual variation as regards mode and magnitude of exposure. For deaths occurring between 1951 and 1982 information was obtained from the Statistical Bureau of Iceland. Significantly increased standardized mortality ratios were determined for cancer of the trachea, bronchus, and lung for the entire cohort. Record linkage with the Cancer Register revealed 36 cancers in the period 1955-1982. No statistically significant excess was found for the overall cancer incidence or for the incidence of cancer at any particular site. A special survey of smoking status showed that cigarette smoking was not as common among the subjects of the cohort as among the general male population in Reykjavik. These results support the suggestion that the increased mortality of lung cancer in the study group had a causal relationship to occupational exposure, particularly to asbestos exposure.

Risk of prostate, ovarian, and endometrial cancer among relatives of women with breast cancer.

OBJECTIVE: To investigate the risk of prostate, ovarian, and endometrial cancer among relatives of patients with breast cancer. DESIGN: Cohort study of 947 pedigrees in which the proband had breast cancer, linked with the Icelandic cancer registry. SETTING: Iceland. SUBJECTS: The 947 pedigrees included 29,725 people, of whom 1539 had breast cancer, 467 had prostate cancer, 135 ovarian cancer, and 105 endometrial cancer. MAIN OUTCOME MEASURES: Risk of prostate, ovarian, and endometrial cancer among blood relatives of women with breast cancer compared with risk in spouses. RESULTS: The risk of prostate cancer was significantly raised for all relatives (1.5), first degree relatives (1.4), and second degree relatives (1.3) of women with breast cancer. Risk of ovarian cancer was raised for all relatives (1.9) and first degree relatives (1.9) and risk of endometrial cancer was raised for all relatives only (1.9). The risk of prostate cancer was raised if the proband with breast cancer had a first degree relative with prostate cancer. CONCLUSIONS: Coaggregation exists between breast cancer and cancers of the prostate, ovaries, and endometrium. This risk relation is probably based on genes which act by increasing the risk for cancer at these sites. Environmental factors that are common among relatives may also play a part. Continued research is required into pathophysiological mechanisms that could explain these observations.

Trends in childhood leukaemia in the Nordic countries in relation to fallout from atmospheric nuclear weapons testing.

OBJECTIVE: To obtain further information about the risks of childhood leukaemia after exposure to ionising radiation at low doses and low dose rates before or after birth or to the father's testes shortly before conception. DESIGN: Observational study of trends in incidence of childhood leukaemia in relation to estimated radiation exposures due to fallout from atmospheric nuclear weapons testing during the 1950s and 1960s. SETTING: Nordic countries. SUBJECTS: Children aged under 15 years. MAIN OUTCOME MEASURES: Incidence rates of leukaemia by age at diagnosis, sex, country, and calendar year of diagnosis or year of birth; exposure category; relation between leukaemia and exposure for children aged 0-14 and 0-4 separately. RESULTS: During the high fallout period the average estimated dose equivalent to the fetal red bone marrow was around 140 mu Sv and the average annual testicular dose 140 mu Sv. There was little evidence of increased incidence of leukaemia among children born in these years. Doses to the red bone marrow of a child after birth were higher, and during the high exposure period children would have been subjected to an additional dose equivalent of around 1500 mu Sv, similar to doses received by children in several parts of central and eastern Europe owing to the Chernobyl accident and about 50% greater than the annual dose equivalent to the red bone marrow of a child from natural radiation. leukaemia incidence and red marrow dose was not related overall, but rates of leukaemia in the high exposure period were slightly higher than in the surrounding medium exposure period (relative risk for ages 0-14: 1.07, 95% confidence interval 1.00 to 1.14; for ages 0-4: 1.11, 1.00 to 1.24). CONCLUSIONS: Current predicted risks of childhood leukaemia after exposure to radiation are not greatly underestimated for low dose rate exposures.