Psychosocial effects of whole-body MRI screening in adult high-risk pathogenic <i>TP53</i> mutation carriers: a case-controlled study (SIGNIFY).

Background Germline TP53 gene pathogenic variants (pv) cause a very high lifetime risk of developing cancer, almost 100% for women and 75% for men. In the UK, annual MRI breast screening is recommended for female TP53 pv carriers. The SIGNIFY study (Magnetic Resonance Imaging screening in Li Fraumeni syndrome: An exploratory whole body MRI) study reported outcomes of whole-body MRI (WB-MRI) in a cohort of 44 TP53 pv carriers and 44 matched population controls. The results supported the use of a baseline WB-MRI screen in all adult TP53 pv carriers. Here we report the acceptability of WB-MRI screening and effects on psychosocial functioning and health-related quality of life in the short and medium terms.Methods Psychosocial and other assessments were carried out at study enrolment, immediately before MRI, before and after MRI results, and at 12, 26 and 52 weeks' follow-up.Results WB-MRI was found to be acceptable with high levels of satisfaction and low levels of psychological morbidity throughout. Although their mean levels of cancer worry were not high, carriers had significantly more cancer worry at most time-points than controls. They also reported significantly more clinically significant intrusive and avoidant thoughts about cancer than controls at all time-points. There were no clinically significant adverse psychosocial outcomes in either carriers with a history of cancer or in those requiring further investigations.Conclusion WB-MRI screening can be implemented in TP53 pv carriers without adverse psychosocial outcomes in the short and medium terms. A previous cancer diagnosis may predict a better psychosocial outcome. Some carriers seriously underestimate their risk of cancer. Carriers of pv should have access to a clinician to help them develop adaptive strategies to cope with cancer-related concerns and respond to clinically significant depression and/or anxiety

Baseline results from the UK SIGNIFY study: a whole-body MRI screening study in TP53 mutation carriers and matched controls

In the United Kingdom, current screening guidelines for TP53 germline mutation carriers solely recommends annual breast MRI, despite the wide spectrum of malignancies typically seen in this group. This study sought to investigate the role of one-off non-contrast whole-body MRI (WB MRI) in the screening of asymptomatic TP53 mutation carriers. 44 TP53 mutation carriers and 44 population controls were recruited. Scans were read by radiologists blinded to participant carrier status. The incidence of malignancies diagnosed in TP53 mutation carriers against general population controls was calculated. The incidences of non-malignant relevant disease and irrelevant disease were measured, as well as the number of investigations required to determine relevance of findings. In TP53 mutation carriers, 6 of 44 (13.6, 95% CI 5.2-27.4%) participants were diagnosed with cancer during the study, all of which would be considered life threatening if untreated. Two were found to have two primary cancers. Two participants with cancer had abnormalities on the MRI which were initially thought to be benign (a pericardial cyst and a uterine fibroid) but transpired to be sarcomas. No controls were diagnosed with cancer. Fifteen carriers (34.1, 95% CI 20.5-49.9%) and seven controls (15.9, 95% CI 6.7-30.1%) underwent further investigations following the WB MRI for abnormalities that transpired to be benign (p = 0.049). The cancer detection rate in this group justifies a minimum baseline non-contrast WB MRI in germline TP53 mutation carriers. This should be adopted into national guidelines for management of adult TP53 mutation carriers in addition to the current practice of contrast enhanced breast MRI imaging.This work was supported by The Annabel Evens Memorial Fund. The investigators at The Institute of Cancer Research and The Royal Marsden National Health Service (NHS) Foundation Trust are supported by an NIHR research grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust

Prostate-specific antigen velocity in a prospective prostate cancer screening study of men with genetic predisposition.

This corrects the article DOI: 10.1038/bjc.2017.429

Serum testosterone and prostate cancer in men with germline BRCA1/2 pathogenic variants.

OBJECTIVES: The relation of serum androgens and the development of prostate cancer (PCa) is subject of debate. Lower total testosterone (TT) levels have been associated with increased PCa detection and worse pathological features after treatment. However, data from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) and Prostate Cancer Prevention (PCPT) trial groups indicate no association. The aim of this study is to investigate the association of serum androgen levels and PCa detection in a prospective screening study of men at higher genetic risk of aggressive PCa due to BRCA1/2 pathogenic variants (PVs), the IMPACT study. METHODS: Men enrolled in the IMPACT study provided serum samples during regular visits. Hormonal levels were calculated using immunoassays. Free testosterone (FT) was calculated from TT and sex hormone binding globulin (SHBG) using the Sodergard mass equation. Age, body mass index (BMI), prostate-specific antigen (PSA) and hormonal concentrations were compared between genetic cohorts. We also explored associations between age and TT, SHBG, FT and PCa, in the whole subset and stratified by BRCA1/2 PVs status. RESULTS: A total of 777 participants in the IMPACT study had TT and SHBG measurements in serum samples at annual visits, giving 3940 prospective androgen levels, from 266 BRCA1 PVs carriers, 313 BRCA2 PVs carriers and 198 non-carriers. The median number of visits per patient was 5. There was no difference in TT, SHBG and FT between carriers and non-carriers. In a univariate analysis, androgen levels were not associated with PCa. In the analysis stratified by carrier status, no significant association was found between hormonal levels and PCa in non-carriers, BRCA1 or BRCA2 PVs carriers. CONCLUSIONS: Male BRCA1/2 PVs carriers have a similar androgen profile to non-carriers. Hormonal levels were not associated with PCa in men with and without BRCA1/2 PVs. Mechanisms related to the particularly aggressive phenotype of PCa in BRCA2 PVs carriers may therefore not be linked with circulating hormonal levels

Concesión de viático a fray Buenaventura Malaquías, fray Guillermo Siredan y fray Bernardino Cornelio, religiosos de la orden de San Francisco, para ir a la Misión de Irlanda

Fecha del documento: 1640-11-21. 3 páginasAndrés de Rozas al secretario Juan de Otalora sobre la resolución regia de conceder a fray Buenaventura Malaquías, fray Guillermo Siredan y fray Bernardino Cornelio, religiosos de la orden de San Francisco, un viático de 100 ducados a cada uno para ir a la Misión de Irlanda. Acudan de Antonio de Campo Redondo. Orden del Antonio de Campo Redondo al secretario Juan García Dávila Muñoz para que haga la cédula para que el tesorero general Pedro Baza de Herrera libre el dinero del arca de las tres llaves y pueda entregarlo a don Alonso Pérez de Guzmán, patriarca de Indias. Hecha la cédula.Proyecto Proyección Política y Social de la Comunidad Irlandesa en la Monarquía hispánica y en la América Colonial de la Edad Moderna(siglos XVI-XVIII) (HAR2009-11339 - subprograma HIST) del Ministerio de Economía y Competitividad en colaboración con el Consejo Superior de Investigaciones Científicas (CSIC), Embajada de Irlanda en Madrid, National University of Ireland (NUI) Maynooth, University College Dublin y Trinity College DublinAndrés de Rozas, secretario del Consejo de EstadoJuan de Otalora, secretario del Consejo de HaciendaOrden de San FranciscoSí300 ducados (100x3)NoN

Post-GWAS in prostate cancer: from genetic association to biological contribution

Genome-wide association studies (GWAS) have been successful in deciphering the genetic component of predisposition to many human complex diseases including prostate cancer. Germline variants identified by GWAS progressively unravelled the substantial knowledge gap concerning prostate cancer heritability. With the beginning of the post-GWAS era, more and more studies reveal that, in addition to their value as risk markers, germline variants can exert active roles in prostate oncogenesis. Consequently, current research efforts focus on exploring the biological mechanisms underlying specific susceptibility loci known as causal variants by applying novel and precise analytical methods to available GWAS data. Results obtained from these post-GWAS analyses have highlighted the potential of exploiting prostate cancer risk-associated germline variants to identify new gene networks and signalling pathways involved in prostate tumorigenesis. In this Review, we describe the molecular basis of several important prostate cancer-causal variants with an emphasis on using post-GWAS analysis to gain insight into cancer aetiology. In addition to discussing the current status of post-GWAS studies, we also summarize the main molecular mechanisms of potential causal variants at prostate cancer risk loci and explore the major challenges in moving from association to functional studies and their implication in clinical translation