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: approximately 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.

Prostate cancer is the most prevalent noncutaneous cancer in males in developed regions, with African American men having among the highest worldwide incidence and mortality rates. Here we report a second genetic variant in the 8q24 region that, in conjunction with another variant we recently discovered, accounts for about 11%-13% of prostate cancer cases in individuals of European descent and 31% of cases in African Americans. We made the current discovery through a genome-wide association scan of 1,453 affected Icelandic individuals and 3,064 controls using the Illumina HumanHap300 BeadChip followed by four replication studies. A key step in the discovery was the construction of a 14-SNP haplotype that efficiently tags a relatively uncommon (2%-4%) susceptibility variant in individuals of European descent that happens to be very common (approximately 42%) in African Americans. The newly identified variant shows a stronger association with affected individuals who have an earlier age at diagnosis.

To cite this article: Jaspers Focks J, van Vugt SPG, Albers-Akkers MTH, Lamfers EJP, Bloem-de Vries LM, Verheugt FWA, Brouwer MA.Low performance of bleeding risk models in the very elderly with atrial fibrillation using vitamin K antagonists. J Thromb Haemost 2016; 14: 1715-24.See also Lip GYH, Lane DA. Bleeding risk assessment in atrial fibrillation: observations on the use and misuse of bleeding risk scores. This issue, pp 1711-4. Essentials• Under-treatment of oral anticoagulation in the elderly with atrial fibrillation is common.• As bleeding prediction is challenging, we compared HAS-BLED, ATRIA and HEMORR 2 HAGES.• All three were associated with major bleeding in the elderly, but with poor predictive abilities.• Future studies with focus on elderly-specific risk factors for bleeding are warranted.Summary. Background: Anticipated bleeding complications contribute to underuse of oral anticoagulants, especially in elderly patients with atrial fibrillation (AF). Bleeding risk models could provide guidance; however, these were developed in the general AF population. Objective: To study and compare the performance of the HAS-BLED, ATRIA and HEMORR 2 HAGES for major bleeding in very elderly AF patients. Methods: Subjects were a random sample (N = 1157) of AF patients ≥ 80 years using a vitamin-K antagonist with prospective clinical follow-up from 2011 to 2014. The primary outcome was major bleeding (International Society on Thrombosis and Haemostasis criteria). Results: Patients aged 84 years (median; 25th-75th 82-87) were classified as low risk by HAS-BLED (25.2%), ATRIA (59.6%) and HEMORR 2 HAGES (23.3%). Three-year rates of major, clinically relevant and any bleeding were 6.7%, 28.3% and 42.3%, respectively. We observed a statistically significant association for all models with major bleeding, but discriminatory abilities were rather poor (Cstatistics < 0.60) without clear superiority for any of the three. Only two (anemia and antiplatelet therapy) of the various classical risk factors were associated with bleeding. An estimated risk-benefit profile indicated a favorable trade-off for oral anticoagulation in this specific cohort (number needed to treat, 22; number needed to harm, 91). Conclusions: In this large prospective cohort of very elderly AF patients, the currently used bleeding risk scores were all associated with major bleeding, but with poor predictive abilities. Use of the ATRIA model may inadvertently result in less attention being paid to modifiable risk factors in this particular population. In light of the issues of under-treatment and the suggested favorable risk-benefit profile, future models with incorporation of elderly-specific risk factors may provide more guidance in this growing population of AF patients.

We conclude that in elderly AF patients treated with OAC, intensive cholesterol-lowering therapy (atorvastatin 40 mg/day and ezetimibe 10 mg/day) is well tolerated. No increased risk in bleeding was found.