Jón Hrafnkelsson

Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer.

Familial clustering studies indicate that breast cancer risk has a substantial genetic component. To identify new breast cancer risk variants, we genotyped approximately 300,000 SNPs in 1,600 Icelandic individuals with breast cancer and 11,563 controls using the Illumina Hap300 platform. We then tested selected SNPs in five replication sample sets. Overall, we studied 4,554 affected individuals and 17,577 controls. Two SNPs consistently associated with breast cancer: ∼25% of individuals of European descent are homozygous for allele A of rs13387042 on chromosome 2q35 and have an estimated 1.44-fold greater risk than noncarriers, and for allele T of rs3803662 on 16q12, about 7% are homozygous and have a 1.64-fold greater risk. Risk from both alleles was confined to estrogen receptor–positive tumors. At present, no genes have been identified in the linkage disequilibrium block containing rs13387042. rs3803662 is near the 5′ end of TNRC9 , a high mobility group chromatin–associated protein whose expression is implicated in breast cancer metastasis to bone.

Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer.

We carried out a genome-wide association study of breast cancer predisposition with replication and refinement studies involving 6,145 cases and 33,016 controls and identified two SNPs (rs4415084 and rs10941679) on 5p12 that confer risk, preferentially for estrogen receptor (ER)-positive tumors (OR = 1.27, P = 2.5 × 10−12 for rs10941679). The nearest gene, MRPS30, was previously implicated in apoptosis, ER-positive tumors and favorable prognosis. A recently reported signal in FGFR2 was also found to associate specifically with ER-positive breast cancer.

Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations

In order to search for sequence variants conferring risk of thyroid cancer we conducted a genome-wide association study in 192 and 37,196 Icelandic cases and controls, respectively, followed by a replication study in individuals of European descent. Here we show that two common variants, located on 9q22.33 and 14q13.3, are associated with the disease. Overall, the strongest association signals were observed for rs965513 on 9q22.33 (OR = 1.75; P = 1.7 × 10−27) and rs944289 on 14q13.3 (OR = 1.37; P = 2.0 × 10−9). The gene nearest to the 9q22.33 locus is FOXE1 (TTF2) and NKX2-1 (TTF1) is among the genes located at the 14q13.3 locus. Both variants contribute to an increased risk of both papillary and follicular thyroid cancer. Approximately 3.7% of individuals are homozygous for both variants, and their estimated risk of thyroid cancer is 5.7-fold greater than that of noncarriers. In a study on a large sample set from the general population, both risk alleles are associated with low concentrations of thyroid stimulating hormone (TSH), and the 9q22.33 allele is associated with low concentration of thyroxin (T4) and high concentration of triiodothyronine (T3).

Discovery of common variants associated with low TSH levels and thyroid cancer risk

To search for sequence variants conferring risk of nonmedullary thyroid cancer, we focused our analysis on 22 SNPs with a P < 5 × 10−8 in a genome-wide association study on levels of thyroid stimulating hormone (TSH) in 27,758 Icelanders. Of those, rs965513 has previously been shown to associate with thyroid cancer. The remaining 21 SNPs were genotyped in 561 Icelandic individuals with thyroid cancer (cases) and up to 40,013 controls. Variants suggestively associated with thyroid cancer (P < 0.05) were genotyped in an additional 595 non-Icelandic cases and 2,604 controls. After combining the results, three variants were shown to associate with thyroid cancer: rs966423 on 2q35 (OR = 1.34; Pcombined = 1.3 × 10−9), rs2439302 on 8p12 (OR = 1.36; Pcombined = 2.0 × 10−9) and rs116909374 on 14q13.3 (OR = 2.09; Pcombined = 4.6 × 10−11), a region previously reported to contain an uncorrelated variant conferring risk of thyroid cancer. A strong association (P = 9.1 × 10−91) was observed between rs2439302 on 8p12 and expression of NRG1, which encodes the signaling protein neuregulin 1, in blood.

Incidence of cancer among Nordic airline pilots over five decades: occupational cohort study

Abstract Objective: To assess the incidence of cancer among male airline pilots in the Nordic countries, with special reference to risk related to cosmic radiation. Design: Retrospective cohort study, with follow up of cancer incidence through the national cancer registries. Setting: Denmark, Finland, Iceland, Norway, and Sweden. Participants: 10 032 male airline pilots, with an average follow up of 17 years. Main outcome measures: Standardised incidence ratios, with expected numbers based on national cancer incidence rates; dose-response analysis using Poisson regression. Results: 466 cases of cancer were diagnosed compared with 456 expected. The only significantly increased standardised incidence ratios were for skin cancer: melanoma 2.3 (95% confidence interval 1.7 to 3.0), non-melanoma 2.1 (1.7 to 2.8), basal cell carcinoma 2.5 (1.9 to 3.2). The relative risk of skin cancers increased with the estimated radiation dose. The relative risk of prostate cancer increased with increasing number of flight hours in long distance aircraft. Conclusions: This study does not indicate a marked increase in cancer risk attributable to cosmic radiation, although some influence of cosmic radiation on skin cancer cannot be entirely excluded. The suggestion of an association between number of long distance flights (possibly related to circadian hormonal disturbances) and prostate cancer needs to be confirmed.

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.

Papillary Thyroid Carcinoma in Iceland: A study of the Occurrence in families and the coexistence of other primary tumours

This paper presents evidence from Iceland which indicates that papillary thyroid carcinoma occurs in certain families more often than expected. Thyroid carcinoma was also seen to coexist with some other cancer types more often than expected. We studied all families (n = 373) with papillary thyroid carcinoma diagnosed between 1955 and 1984 in Iceland. Familial papillary carcinoma occurred in 3.8% of these families. This frequency was higher than expected but not significantly increased. Second primaries in women, and especially the incidence of kidney and breast cancer, were significantly increased. Cancer of the kidney and CNS tumours were significantly increased in propositi when both sexes were taken together. No increase in the incidence of other malignancies was observed in first degree relatives of patients with papillary thyroid carcinoma.

The BARD1 Cys557Ser Variant and Breast Cancer Risk in Iceland

Background Most, if not all, of the cellular functions of the BRCA1 protein are mediated through heterodimeric complexes composed of BRCA1 and a related protein, BARD1. Some breast-cancer-associated BRCA1 missense mutations disrupt the function of the BRCA1/BARD1 complex. It is therefore pertinent to determine whether variants of BARD1 confer susceptibility to breast cancer. Recently, a missense BARD1 variant, Cys557Ser, was reported to be at increased frequencies in breast cancer families. We investigated the role of the BARD1 Cys557Ser variant in a population-based cohort of 1,090 Icelandic patients with invasive breast cancer and 703 controls. We then used a computerized genealogy of the Icelandic population to study the relationships between the Cys557Ser variant and familial clustering of breast cancer. Methods and Findings The Cys557Ser allele was present at a frequency of 0.028 in patients with invasive breast cancer and 0.016 in controls (odds ratio [OR] = 1.82, 95% confidence interval [CI] 1.11–3.01, p = 0.014). The alleleic frequency was 0.037 in a high-predisposition group of cases defined by having a family history of breast cancer, early onset of breast cancer, or multiple primary breast cancers (OR = 2.41, 95% CI 1.22–4.75, p = 0.015). Carriers of the common Icelandic BRCA2 999del5 mutation were found to have their risk of breast cancer further increased if they also carried the BARD1 variant: the frequency of the BARD1 variant allele was 0.047 (OR = 3.11, 95% CI 1.16–8.40, p = 0.046) in 999del5 carriers with breast cancer. This suggests that the lifetime probability of a BARD1 Cys557Ser/BRCA2 999del5 double carrier developing breast cancer could approach certainty. Cys557Ser carriers, with or without the BRCA2 mutation, had an increased risk of subsequent primary breast tumors after the first breast cancer diagnosis compared to non-carriers. Lobular and medullary breast carcinomas were overrepresented amongst Cys557Ser carriers. We found that an excess of ancestors of contemporary carriers lived in a single county in the southeast of Iceland and that all carriers shared a SNP haplotype, which is suggestive of a founder event. Cys557Ser was found on the same SNP haplotype background in the HapMap Project CEPH sample of Utah residents. Conclusions Our findings suggest that BARD1 Cys557Ser is an ancient variant that confers risk of single and multiple primary breast cancers, and this risk extends to carriers of the BRCA2 999del5 mutation.

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.