We report a genome-wide association follow up study on prostate cancer. We identify four variants associated with the disease in European populations: rs10934853-A (OR = 1.12, P = 2.9×10−10) on 3q21.3, two moderately correlated (r2 = 0.07) variants on 8q24.21; rs16902094-G (OR = 1.21, P = 6.2×10−15) and rs445114-T (OR = 1.14, P = 4.7×10−10) and rs8102476-C (OR = 1.12, P = 1.6×10−11) on 19q13.2. We also refine a previous association signal on 11q13 with the SNP rs11228565-A (OR =1.23, P = 6.7 × 10−12). In a multi-variant analysis, using 22 prostate cancer risk variants typed in the Icelandic population, we estimate that carriers belonging to the top 1.3% of the risk distribution have a risk of developing the disease that is more than 2.5 times greater than the population average risk estimates.

We conducted a genome-wide SNP association study on prostate cancer on over 23,000 Icelanders, followed by a replication study including over 15,500 individuals from Europe and the United States. Two newly identified variants were shown to be associated with prostate cancer: rs5945572 on Xp11.22 and rs721048 on 2p15 (odds ratios (OR) = 1.23 and 1.15; P = 3.9 x 10(-13) and 7.7 x 10(-9), respectively). The 2p15 variant shows a significantly stronger association with more aggressive, rather than less aggressive, forms of the disease.

Background A recent study of familial and early onset prostate cancer reported a recurrent rare germline mutation of HOXB13 among men of European descent. The gene resides within the 17q21 hereditary prostate cancer linkage interval. Methods We evaluated the G84E germline mutation (rs138213197) of HOXB13 in a case-control study of familial prostate cancer at Vanderbilt University to independently evaluate the association of the mutation with familial prostate cancer. We genotyped 928 familial prostate cancer probands, and 930 control probands without a personal or family history of prostate cancer. Results Our study confirmed the association between the G84E mutation of HOXB13 and risk of prostate cancer among subjects of European descent. We observed the mutation in 16 familial cases and in two controls, each as heterozygotes. The odds ratio for prostate cancer was 7.9 (95% CI 1.8 – 34.5, P = 0.0062) among carriers of the mutation. The carrier rate was 1.9% among all familial case probands, and 2.7% among probands of pedigrees with ≥ 3 affected. In a separate case series of 268 probands of European descent with no additional family history of prostate cancer, the carrier rate was 1.5%. Conclusions The germline mutation G84E of HOXB13 is a rare but recurrent mutation associated with elevated risk of prostate cancer in men of European descent, with an effect size that is greater than observed for previously validated risk variants of genome wide association studies. Impact This study independently confirms the association of a germline HOXB13 mutation with familial prostate cancer.

Purpose:To undertake the first substantial clinical study of breast radiotherapy toxicity in BRCA1 and BRCA2 mutation carriers in the United Kingdom. Experimental Design: Acute and late radiation effects were evaluated in a retrospective study of 55 BRCA1 and BRCA2 mutation carriers treated with radiotherapy for breast cancer at four centers between 1983 and 2002. Individual matching with controls who had sporadic breast cancer was undertaken for age at diagnosis, time since completion of radiation, and treatment variables. Detailed assessments were undertaken by one examiner. Median follow-up was 6.75 years for carriers and 7.75 years for controls. Rates of late events (rib fractures, lung fibrosis, necrosis of soft tissue/bone, and pericarditis) as well as LENT-SOMA scores and clinical photography scores of breast size, shape, and skin telangiectasia were the primary end points. Results: No increase in clinically significant late toxicity was seen in the mutation carriers. Conclusions:These data add substantial weight to the evidence that the outcomes in the treated breast from radiotherapy in women with BRCA1 or BRCA2 mutations are comparable with those in women with sporadic breast cancer.Because BRCA1 and BRCA2 were identified as high-risk breast-ovarian cancer susceptibility genes in the last decade, much effort has gone into addressing issues of how best to treat women who develop familial breast cancer. Given that these genes are integral to the DNA repair pathways, an important issue is whether ionizing radiation therapy induces excessive normal tissue reaction and/or the formation of second cancers in BRCA mutation carriers. Thus far, epidemiologic data suggests that there is no effect, but there are limitations in the data set which have made it difficult to exclude a difference. Early studies of radiotoxicity were limited by their use of a loosely defined family history as a surrogate for mutation status (1, 2). Similarly, reports on outcomes in known mutation carriers have had limitations. Gaffney et al. (3) evaluated acute (not chronic) radiotherapy reactions in 30 BRCA1 and 20 BRCA2 carriers, but did not have a control group. The most comprehensive and recent review of the issues of radiation effect is that of Pierce et al. (4), who assessed the reactions of 71 carriers and 213 matched controls. However, this was a multicenter analysis which was undertaken by chart review only, at nine different hospitals in North America. Data on acute and chronic toxicity were collected following conservative surgery and radiotherapy. No differences in toxicity were seen in the carriers versus controls with a median follow-up of 5.3 years for carriers and 4.6 years for controls.In the absence of data from prospective studies on outcomes, the current study was based on that of Pierce et al. (4), to be able to compare data sets, but was designed in more detail to minimize interobserver variation by having a single clinician perform all studies. Furthermore, in order to detect smaller differences than migh...