BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder

PURPOSE: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). METHODS: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. RESULTS: We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. CONCLUSION: Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals

Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder

Purpose We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Methods Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. Results We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. Conclusion Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals

The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study

Objective To evaluate the contemporary prevalence of urinary tract cancer (bladder cancer, upper tract urothelial cancer [UTUC] and renal cancer) in patients referred to secondary care with haematuria, adjusted for established patient risk markers and geographical variation. Patients and Methods This was an international multicentre prospective observational study. We included patients aged ≥16 years, referred to secondary care with suspected urinary tract cancer. Patients with a known or previous urological malignancy were excluded. We estimated the prevalence of bladder cancer, UTUC, renal cancer and prostate cancer; stratified by age, type of haematuria, sex, and smoking. We used a multivariable mixed-effects logistic regression to adjust cancer prevalence for age, type of haematuria, sex, smoking, hospitals, and countries. Results Of the 11 059 patients assessed for eligibility, 10 896 were included from 110 hospitals across 26 countries. The overall adjusted cancer prevalence (n = 2257) was 28.2% (95% confidence interval [CI] 22.3–34.1), bladder cancer (n = 1951) 24.7% (95% CI 19.1–30.2), UTUC (n = 128) 1.14% (95% CI 0.77–1.52), renal cancer (n = 107) 1.05% (95% CI 0.80–1.29), and prostate cancer (n = 124) 1.75% (95% CI 1.32–2.18). The odds ratios for patient risk markers in the model for all cancers were: age 1.04 (95% CI 1.03–1.05; P < 0.001), visible haematuria 3.47 (95% CI 2.90–4.15; P < 0.001), male sex 1.30 (95% CI 1.14–1.50; P < 0.001), and smoking 2.70 (95% CI 2.30–3.18; P < 0.001). Conclusions A better understanding of cancer prevalence across an international population is required to inform clinical guidelines. We are the first to report urinary tract cancer prevalence across an international population in patients referred to secondary care, adjusted for patient risk markers and geographical variation. Bladder cancer was the most prevalent disease. Visible haematuria was the strongest predictor for urinary tract cancer

Trauma Informed Literacy Practices for the 21st Century Classroom

This experiential workshop teaches participants trauma informed literacy practices for 21st Century learners in high risk settings. Participants will collaborate using role-playing, prompt driven scenarios and discussions to foster an understanding of the key components of trauma-informed instructional research based practices. Our session utilizes evidenced-based literacy strategies, which provide interventions using writing therapy and bibliotherapy to support the health, well-being and academic success of students

Is Your School an A.S.S.E.T.?: Focusing on School Mental Health and Equitable Instruction

This workshop provides Educators classroom resources that can be used within existing curriculum frameworks to enhance the mental health literacy of both students and teachers. The session suggests strategies to implement strategic, systemic and sustainable changes which promote academic growth, resiliency and wellness

Patient Satisfaction After Biceps Tenotomy

Background: Biceps tenotomy and tenodesis are frequently performed for proximal biceps lesions; however, there continues to be debate as to which method is superior. This study examined patient-reported outcomes after biceps tenotomy. Hypothesis: Biceps tenotomy in the setting of concomitant shoulder pathology is a reasonable option with high satisfaction rates and a low incidence of pain and cramping in middle-aged to older individuals. Study Design: Case series; Level of evidence, 4. Methods: A total of 104 patients (mean age, 63.5 years; range, 40-81 years) were evaluated at the time of surgery and at a mean follow-up of 38.4 months (range, 22-57 months). Biceps tenotomy was performed as a component of more extensive shoulder surgery in all patients. Patient satisfaction, frequency of cramping and spasms, biceps pain, weakness, and cosmetic deformity were evaluated at over 1-year follow-up. Results: Ninety-one percent of patients were satisfied or very satisfied with their surgical outcome, and 95% would have their surgery again. Three patients who reported being unsatisfied or very unsatisfied had either advanced glenohumeral arthritis or an irreparable rotator cuff tear. Cosmetic deformity occurred in 13% of patients. Twenty percent reported spasms and cramping in their biceps, and 19% reported some biceps pain; however, frequency of spasms and cramping was typically once weekly, and biceps pain was reported as severe or very severe in only 2 patients. Subjective biceps weakness was reported in 17% of patients. Age had no effect on outcome measures, and female sex was associated with less limitation and greater satisfaction after tenotomy compared with men. Conclusion: Our results indicate that patient-reported downsides to biceps tenotomy were usually mild and/or infrequent and did not affect patient satisfaction. We conclude that biceps tenotomy is a viable option that can lead to a high rate of patient satisfaction and outcomes in middle-aged to older individuals undergoing shoulder surgery with biceps pathology

Combined genetic and splicing analysis of BRCA1 c.[594-2A>C; 641A>G] highlights the relevance of naturally occurring in-frame transcripts for developing disease gene variant classification algorithms.

A recent analysis using family history weighting and co-observation classification modeling indicated that BRCA1 c.594-2A > C (IVS9-2A > C), previously described to cause exon 10 skipping (a truncating alteration), displays characteristics inconsistent with those of a high risk pathogenic BRCA1 variant. We used large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia to assess pathogenicity of c.594-2A > C. The combined odds for causality considering case-control, segregation and breast tumor pathology information was 3.23 × 10-8 Our data indicate that c.594-2A > C is always in cis with c.641A > G. The spliceogenic effect of c.[594-2A > C;641A > G] was characterized using RNA analysis of human samples and splicing minigenes. As expected, c.[594-2A > C; 641A > G] caused exon 10 skipping, albeit not due to c.594-2A > C impairing the acceptor site but rather by c.641A > G modifying exon 10 splicing regulatory element(s). Multiple blood-based RNA assays indicated that the variant allele did not produce detectable levels of full-length transcripts, with a per allele BRCA1 expression profile composed of ≈70-80% truncating transcripts, and ≈20-30% of in-frame Δ9,10 transcripts predicted to encode a BRCA1 protein with tumor suppression function.We confirm that BRCA1c.[594-2A > C;641A > G] should not be considered a high-risk pathogenic variant. Importantly, results from our detailed mRNA analysis suggest that BRCA-associated cancer risk is likely not markedly increased for individuals who carry a truncating variant in BRCA1 exons 9 or 10, or any other BRCA1 allele that permits 20-30% of tumor suppressor function. More generally, our findings highlight the importance of assessing naturally occurring alternative splicing for clinical evaluation of variants in disease-causing genes.The research described was supported by Spanish Instituto de Salud Carlos III funding, an initiative of the Spanish Ministry of Economy and Innovation partially supported by European Regional Development FEDER Funds [PI12/00539 and PI15/00059 to M.d.H., PI13/02030 to A.V.]; the French Ministry of Higher Education and Research [to O.S.]; the University of Otago, Mackenzie Charitable Foundation, Maria Lupton, and .Health Research Council of New Zealand [to L.W.]; UK Higher Education Funding Council Senior Fellowship Scheme, the University of Southampton [to D.B.]; Cancer research UK [to D.B., M.R.]; FamilienHede Nielsen Foundation fund [to T.V.O.H.]; Cancer Research-UK Senior Cancer Research Fellowship [to A.C.A.]; National Institute of Health [CA128978 and CA11616 to F.J.C.]; an NIH specialized program of research excellence in breast cancer to the Mayo Clinic [P50 CA116201 to F.J.C.]; and the US Breast Cancer Research Foundation [to F.J.C.]; translational grant from the French National Cancer Institute and Direction Générale de l'Offre des Soins (INCa-DGOS AAP/CFB/CI) and a grant from the French North-West Canceropole (CNO) [to A.M.]; The Cancer Council Queensland [APP1086286 to A.B.S.]; the NHMRC Senior Research Fellowship Scheme [ID 1061779 to A.B.S.]; NHMRC Project grant scheme [ID 1010719 to A.B.S.]. EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer (recently merged with Breast Cancer Campaign forming Breast Cancer Now) and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). SEARCH was supported by grants CRUK A490/A11021, C490/A16561. CIMBA data management was supported by Cancer Research-UK grant C12292/A11174 and C1287/A10118. BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Communitýs Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS).This is the author accepted manuscript. The final version is available from Oxford University Press via http://dx.doi.org/10.1093/hmg/ddw09