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

Cost-effectiveness of human papilloma virus vaccination in Iceland

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldOBJECTIVE: To evaluate the likely cost-effectiveness of introducing routine HPV vaccination in Iceland. DESIGN: Prospective cost-effectiveness analysis of human papilloma virus (HPV) vaccination. SETTING AND SAMPLE: Population of 12-year-old girls in the Icelandic population. METHODS: A model was developed, comparing a cohort of all 12-year-old girls alive in year 2006, with or without vaccination. The model was based on the epidemiology of cervical cancer in Iceland and its premalignant stages as well as the costs involved in the treatment of each stage, assuming that the vaccines only prevent infections caused by HPV 16/18 at an efficacy of 95% and participation rate of 90%, no catch-up vaccination, no vaccination of boys and no booster dose needed. All costs were calculated on the basis of the price level of mid-year 2006 with a 3% discount rate. Incremental cost-effectiveness ratio calculations were performed and sensitivity analysis was carried out on factors most relevant for cost-effectiveness. RESULTS: Vaccination costs in excess of savings would be about euro313.000/year. Vaccination would reduce the number of women diagnosed with cervical cancer by almost 9, prevent the death of 1.7 women and result in 16.9 quality-adjusted life years gained annually. The incremental cost-effectiveness ratio was calculated to be about euro18.500/quality-adjusted life year saved. CONCLUSION: HPV vaccination seems to be cost-effective in Iceland, but this was sensitive to various parameters in the model, mainly the discount rate, the price of the vaccines and the need for a booster dose

Phase II study of palliative low-dose local radiotherapy in disseminated indolent non-Hodgkin's lymphoma and chronic lymphocytic leukemia

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldPURPOSE: Indolent non-Hodgkin's lymphoma (INHL) and chronic lymphocytic leukemia (CLL) are highly sensitive to radiotherapy (RT). Previous retrospective studies have shown high response rates after local palliative RT of 4 Gy in 2 fractions, which prompted this prospective Phase II trial of the palliative effect of this regimen in patients with disseminated INHL or CLL. METHODS AND MATERIALS: Twenty-two patients (11 men, 11 women, median age 62 years, range 30-89) with disseminated INHL (n = 15) or CLL (n = 7) were treated with local low-dose RT, 2 Gy x 2 within 3 days, with the aim of achieving palliation from localized lymphoma masses. The patients were treated to a total of 31 different sites. Seventeen patients had previously been treated with chemotherapy. The median observation time after the start of RT was 8 months (range 3-26). RESULTS: All patients and all irradiated sites were assessable for response. Of the 22 patients, 18 responded to the treatment, corresponding to an overall response rate (RR) of 82%; 12 patients (55%) achieved a complete response (CR), 5 patients (22%) a partial response (PR), and 1 patient had a CR at three sites and a PR at one site. Of the 31 irradiated sites, 27 responded to treatment, corresponding to an overall RR of 87%; in 20 sites (65%) a CR was achieved and in 7 sites (22%) a PR. Patients with disseminated INHL had an overall RR of 87% (74% CR, 13% PR); patients with CLL had an overall RR of 71% (29% CR, 42% PR). The median duration of response was estimated at 22 months. None of the patients had significant side effects from the treatment. CONCLUSION: Low-dose RT (4 Gy in 2 fractions) is a highly effective palliative treatment of localized lymphoma masses in patients with disseminated INHL and CLL. The treatment has minimal side effects

Head and neck cancer management in the Nordic countries : an effort to harmonize treatment

Non peer reviewe

Proportions of BARD1 Cys557Ser Patients, BRCA2 999del5 Patients, and Reference Groups of Patients Showing Family Histories of Breast Tumors

<p>For each member of the group of Cys557Ser carrier patients ( <i>n =</i> 55), the genealogical database and ICR records of diagnoses were searched to identify all relatives with breast tumors within a distance of three meioses. The proportion of Cys557Ser carriers who had one or more affected relatives, two or more affected relatives, and so on is indicated. For comparison, the analysis was repeated for BRCA2 999del5 patients ( <i>n =</i> 84), non-carriers of both BARD1 and BRCA2 variants ( <i>n =</i> 1,091), all patients who were tested for both variants ( <i>n =</i> 1,209), and all patients in the ICR records ( <i>n =</i> 4,306). Controls were 703 individuals chosen randomly from the genealogical database. </p