Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction

Association of ataxin-7 with the proteasome subunit S4 of the 19S regulatory complex

Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder characterized by ataxia and selective neuronal cell loss caused by the expansion of a translated CAG repeat encoding a polyglutamine tract in ataxin-7, the SCA7 gene product. To gain insight into ataxin-7 function and to decipher the molecular mechanisms of neurodegeneration in SCA7, a two-hybrid assay was performed to identify ataxin-7 interacting proteins. Herein, we show that ataxin-7 interacts with the ATPase subunit S4 of the proteasomal 19S regulatory complex. The ataxin-7/S4 association is modulated by the length of the polyglutamine tract whereby S4 shows a stronger association with the wild-type allele of ataxin-7. We demonstrate that endogenous ataxin-7 localizes to discrete nuclear foci that also contain additional components of the proteasomal complex. Immunohistochemical analyses suggest alterations either of the distribution or the levels of S4 immunoreactivity in neurons that degenerate in SCA7 brains. Immunoblot analyses demonstrate reduced levels of S4 in SCA7 cerebella without evident alterations in the levels of other proteasome subunits. These results suggest a role for S4 and ubiquitin-mediated proteasomal proteolysis in the molecular pathogenesis of SCA7

Double-Blind Phase III Randomized Trial of the Antiprogestin Agent Mifepristone in the Treatment of Unresectable Meningioma: SWOG S9005

PURPOSE: Progesterone receptors are expressed in approximately 70% of meningiomas. Mifepristone is an oral antiprogestational agent reported to have modest activity in a phase II study. This multicenter, prospective, randomized, placebo-controlled phase III trial conducted by SWOG was planned to define the role of mifepristone in the treatment of unresectable meningioma. PATIENTS AND METHODS: Eligible patients were randomly assigned to receive either mifepristone or placebo for 2 years unless disease progressed. Patients who were stable or responding to protocol therapy after 2 years had the option to continue with the same blinded therapy. Serial follow-up allowed assessment of efficacy and toxicity. Time to treatment failure and overall survival were ascertained for all randomly assigned patients. On progression, patients receiving placebo could cross over and receive active drug. RESULTS: Among 164 eligible patients, 80 were randomly assigned to mifepristone and 84 to placebo. Twenty-four patients (30%) were able to complete 2 years of mifepristone without disease progression, adverse effects, or other reasons for discontinuation. Twenty-eight patients (33%) in the placebo arm completed the 2-year study. There was no statistical difference between the arms in terms of failure-free or overall survival. CONCLUSION: Long-term administration of mifepristone was well tolerated but had no impact on patients with unresectable meningioma

Comparison of clinical and neuropathologic diagnoses of Alzheimer’s disease in 3 epidemiologic samples

Background: Studies of dementia in populations avoid many of the selection biases in clinical samples but require special evaluation and diagnostic methods to obtain high participation rates. To address this issue, we developed a unique in-home dementia assessment. We assessed validity of these assessments using neuropathologic confirmation of the clinical diagnosis in 3 epidemiologic samples. Methods: Subjects were 175 participants in 3 ongoing studies of dementia. Two were population based and identified dementia by cognitive screening. The third study sought volunteers via advertisements. Dementia evaluations were then conducted at the participants’ residences by specially trained nurses and psychometricians. Evaluation results were interpreted, and preliminary diagnoses were assigned by a geropsychiatrist or neurologist and a psychologist. Final diagnoses were assigned by a consensus panel of neurologists, geropsychiatrists, and psychologists. We compared the clinical diagnoses with the gold-standard neuropathologic diagnoses for those participants who subsequently underwent autopsy. Results: Among the demented, the sensitivity of a clinical diagnosis of probable or possible Alzheimer’s disease (AD) was 93% across the 3 studies. The rate of overall diagnostic agreement was 81%. Measures of agreement did not differ meaningfully across varying levels of dementia severity. Conclusions: Rates of neuropathologic confirmation for clinical AD diagnoses in these studies were similar to those reported from clinic-based samples. These results support the validity of clinical diagnoses of AD from a structured in-home assessment of community dwelling and institutionalized individuals using relatively economical methods of dementia screening and assessment