BACKGROUND:In CAPP2, 600 mg aspirin daily significantly reduced the incidence of colorectal cancer and the incidence of all Lynch syndrome cancers among participants with Lynch syndrome. CaPP3 aimed to assess the efficacy of two lower doses of aspirin. METHODS:CaPP3 was a multicentre, parallel-group, randomised, double-blind, dose non-inferiority trial that compared 100 mg or 300 mg daily aspirin with 600 mg daily aspirin in Lynch syndrome carriers aged older than 18 years; patients were recruited from clinical genetics centres in the UK, Australia, Finland, Israel, and Spain. The trial was double-blinded for 2 years, and open label on the same dose for three subsequent years with consent for cancer follow-up (except in the UK, where 75 mg aspirin replaced the 100 mg dose in the open phase). Participants from the five countries were randomly assigned by the Newcastle Clinical Trials Unit in a 3:3:4 ratio to receive daily doses of 100 mg, 300 mg, and 600 mg. Participants received blinded doses of aspirin, identically packaged so as not to indicate dose, every 6 months. Information on compliance was collected on a self-report basis. The dose was revealed at 2 years of recruitment; subsequently, aspirin was obtained via hospital prescriptions during this open-label phase. The primary outcome was the number of new primary mismatch repair-deficient cancers (referred to as Lynch syndrome cancers) developing in participants and diagnosed in the period from the start of the intervention for each participant. The safety outcome was the number of adverse events of interest in the first 2 years of blinded treatment. Aspirin-specific adverse events were recorded at regular participant interviews as a measure of harm during the blinded phase. A non-inferiority margin of 1·5 was chosen for each lower dose against 600 mg daily for the primary endpoint. The effects of the two lower doses (compared to 600 mg daily) were examined with Cox proportional hazards examining time to first Lynch syndrome cancer, with the effect being assessed by hazard ratios (HRs), while negative binomial regression examined the relative cancer burden assessed by incidence rate ratios (IRRs). Non-inferiority was proposed with either lower dose if the upper 95% CI of both the HR and IRR in comparison with 600 mg were below the non-inferiority boundary of 1·5. Participants were deemed per protocol if they had adhered to the protocol and continued taking aspirin into the unblinded phase (ie, they agreed to remain in the study at the 2-year review); non-inferiority required consistency of effects within both intention-to-treat and per-protocol populations and for both HR and IRR analyses. CaPP3 is registered on the ISRCTN registry (ISRCTN16261285) and ClinicalTrials.gov (NCT02497820), and was closed to recruitment in March 2019; this analysis was timed for when all participants reached 5 years past recruitment. Further follow-up is planned until all participants reach 10 years past recruitment. FINDINGS:Between October, 2014, and March, 2019, 1879 patients with Lynch syndrome were recruited and randomly assigned: 564 (30·0%) to 100 mg aspirin daily, 565 (30·1%) to 300 mg daily, and 750 (39·9%) to 600 mg daily. Following the exclusion of 13 participants, the intention-to-treat population consisted of 1866 participants; 559 (30·0%) received 100 mg, 562 (30·1%) received 300 mg, and 745 (39·9%) received 600 mg. 730 (39·1%) of 1866 participants stopped taking aspirin within the 2-year blinded phase, while 937 (50·2%) completed 5 years of aspirin, taking aspirin during the subsequent 3-year unblinded open phase. The per-protocol population consisted of 1136 participants: 336 (29·6%) on 100 mg, 357 (31·4%) on 300 mg, and 443 (39·0%) on 600 mg. Up to a median of 66·4 months (IQR 32·1-84·0) of follow-up, 176 participants had been diagnosed with 216 Lynch syndrome cancers (57 cancers in patients on 100 mg, 75 in those on 300 mg, and 84 in those on 600 mg), including 83 of 1846 participants with colorectal cancer (21 participants on 100 mg, 30 on 300 mg, and 32 on 600 mg). For Lynch syndrome cancers, the 100 mg dose was non-inferior to 600 mg in the intention-to-treat analysis (HR for time to first Lynch syndrome cancer 0·97 [95% CI 0·67-1·42], IRR for cancer burden 0·94 [95% CI 0·65-1·38]). For the per-protocol analysis, the cancer burden was non-inferior with the 100 mg dose (IRR 0·90 [95% CI 0·55-1·46]) but time to first Lynch syndrome cancer was not (HR 1·00 [95% CI 0·61-1·63]). Non-inferiority was not established for the 300 mg dose for either time to first Lynch syndrome cancer or cancer burden, in both intention-to-treat and per-protocol analyses (intention-to-treat population: HR 1·28 [95% CI 0·91-1·80], IRR 1·12 [95% CI 0·79-1·61]; per-protocol population: HR 1·42 [0·91-2·19], IRR 1·28 [0·82-1·98]). The proportion of participants with any reported adverse events of interest increased modestly but significantly with dose: 140 (25·0%) of 561 participants on 100 mg, 151 (26·8%) of 564 on 300 mg, and 234 (31·2%) of 750 on 600 mg (p=0·03 for heterogeneity). Over the 5 years, serious adverse events due to bleeding occurred in no patients on 100 mg, three (0·5%) on 300 mg, and 11 (1·5%) participants on 600 mg (p=0·004 for heterogeneity). INTERPRETATION:Although non-inferiority could not formally be concluded for either 100 mg or 300 mg of aspirin daily by comparison with 600 mg aspirin daily, there was evidence that the 100 mg dose had similar characteristics to 600 mg in terms of cancer risk but with fewer side-effects and less risk of bleeding. FUNDING:Cancer Research UK; Bayer Pharma; Newcastle Hospitals NHS Foundation Trust.

PURPOSE:To quantify the impact of noncanonical FBN1 splice site variants in undiagnosed Marfan syndrome (MFS), a connective tissue disorder associated with skeletal abnormalities and familial thoracic aortic aneurysm disease (FTAAD). METHODS:A systematic analysis of ultrarare FBN1 variants was performed using genome sequencing data from the 100,000 Genomes Project. Variants were annotated with SpliceAI and the significance of enrichment among individuals with FTAAD was assessed using Fisher's exact test. Experimental validation used RNA sequencing, reverse transcriptase polymerase chain reaction, minigene constructs, and replication analysis was with data from UK Biobank. RESULTS:Using aggregate data for 78,195 individuals, we identified 13,864 singleton single-nucleotide variants in FBN1 of which 21 were predicted to affect splicing (SpliceAI > 0.5). Incidence of candidate splice variants in individuals recruited with FTAAD (9/703) was significantly elevated compared with that seen in non-FTAAD participants (12/77,492; odds ratio = 84, P = 9.7 × 10-14). Additional analysis uncovered a further 14 families harboring 11 different FBN1 splice variants. A total of 20 candidate splice variants in 23 families were identified, of which 70% lay beyond the ±8 splice regions. RNA testing confirmed the predicted splice aberration in 16 of 20 and for 9 of 20, pseudoexonization was the likely splicing anomaly. CONCLUSION:Our findings indicate that noncanonical splice variants may account for approximately 3% of families with undiagnosed FTAAD, highlighting the importance of incorporating analysis of introns and confirmatory RNA testing into genetic testing for Marfan syndrome.

Background Carriers of germline pathogenic variants (PVs) in the BRCA1 and BRCA2 genes are at higher risk of developing breast and ovarian cancer than the general population. It is unclear if these PVs influence other breast or ovarian cancer risk factors, including age at menopause (ANM), age at menarche (AAM), menstrual cycle length, BMI or height. There is a biological rationale for associations between BRCA1 and BRCA2 PVs and reproductive traits, for example involving DNA damage and repair mechanisms. The evidence for or against such associations is limited. Methods We used data on 3,046 BRCA1 and 3,264 BRCA2 PV carriers, and 2,857 non-carrier female relatives of PV carriers from the Epidemiological Study of Familial Breast Cancer (EMBRACE). Associations between ANM and PV carrier status was evaluated using linear regression models allowing for censoring. AAM, menstrual cycle length, BMI, and height in carriers and non-carriers were compared using linear and multinomial logistic regression. Analyses were adjusted for potential confounders, and weighted analyses carried out to account for non-random sampling with respect to cancer status. Results No statistically significant difference in ANM between carriers and non-carriers was observed in analyses accounting for censoring. Linear regression effect sizes for ANM were -0.002 (95%CI: -0.401, 0.397) and -0.172 (95%CI: -0.531, 0.188), for BRCA1 and BRCA2 PV carriers respectively, compared with non-carrier women. The distributions of AAM, menstrual cycle length and BMI were similar between PV carriers and non-carriers, but BRCA1 PV carriers were slightly taller on average than non-carriers (0.5 cm difference, p = 0.003). Conclusion Information on the distribution of cancer risk factors in PV carriers is needed for incorporating these factors into multifactorial cancer risk prediction algorithms. Contrary to previous reports, we found no evidence that BRCA1 or BRCA2 PV are associated with hormonal or anthropometric factors, except for a weak association with height. We highlight methodological considerations and data limitations inherent in studies aiming to address this question.

BACKGROUND:The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP3 ) receptor type 1 (IP3 R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. OBJECTIVES:We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. METHODS:Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. RESULTS:We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP3 -binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype-phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. CONCLUSIONS:This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

CONTEXT:Head and neck paragangliomas (HNPGLs) are rare, usually benign, slow-growing tumours arising from neural crest-derived tissue. Definitive management pathways for HNPGLs have yet to be clearly defined. OBJECTIVE:To review our experience of the clinical features and management of these tumours and to analyse outcomes of different treatment modalities. METHODS:Demographic and clinical data were obtained from The Northern Ireland Electronic Care Record (NIECR) as well from a prospectively maintained HNPGL database between January 2011 through December 2023. RESULTS:There were 87 patients; 50 females: 37 males with a mean age of 52.3 ± 14.2 years old (range 17-91 years old). 58.6% (n = 51) of patients had carotid body tumours, 25.2% (n = 22) glomus vagal tumours, 6.8% (n = 6) tumours in the middle ear, 2.2% (n = 2) in the parapharyngeal space and 1.1% (n = 1) in the sphenoid sinus. 5.7% (n = 5) of patients had multifocal disease. The mean tumour size at presentation was 3.2 ± 1.4 cm (range 0.5-6.9 cm). Pathogenic SDHD mutations were identified in 41.3% (n = 36), SDHB in 12.6% (n = 11), SDHC in 2.2% (n = 2) and SDHA in 1.1% (n = 1) of the patients. Overall treatment modalities included surgery alone in 51.7% (n = 45) of patients, radiotherapy in 14.9% (n = 13), observation in 28.7% (n = 25), and somatostatin analogue therapy with octreotide in 4.5% (n = 4) of patients. Factors associated with a significantly higher risk of recurrence included age over 60 years (p = .04), tumour size exceeding 2 cm (p = .03), positive SDHx variants (p = .01), and vagal and jugular tumours (p = .04). CONCLUSION:The majority of our patients underwent initial surgical intervention and achieved disease stability. Our results suggest that carefully selected asymptomatic or medically unfit patients can be safely observed provided lifelong surveillance is maintained. We advocate for the establishment of a UK and Ireland national HNPGL registry, to delineate optimal management strategies for these rare tumours and improve long term outcomes.

Abstract Background and Aims The incidence of Renal Cell Carcinoma (RCC) is the 9th commonest cancer worldwide. It originates from the renal tubular epithelium and to date has been subclassified into five different categories. Of which, papillary carcinoma is one subclassification and it includes two variants: sporadic and hereditary. This case report aims to outline a rare case of hereditary papillary RCC and the implications for the family involved. Method We performed a retrospective assessment of clinical and radiological characteristics of the index patient and affected relatives. Genetic diagnosis and management have been summarised. Results A 62-year-old male (II.1) was diagnosed with RCC after presenting with right-sided flank pain and multiple complex cystic lesions within both kidneys. A kidney biopsy revealed a papillary structure with foamy histocytes and clear cell-type epithelium clusters. Immunostaining of tumour cells demonstrated CK7 and P504S positivity consistent with RCC. Subsequently, he underwent bilateral nephrectomies and being rendered anephric, was commenced on haemodialysis. He underwent deceased donor renal transplantation four years later at the age of 66 (HLA 1:2:1, CMV -/-, cRF 35%) and remains dialysis independent six years on. After the diagnosis of the index patient, his son (III.1) was found to have multifocal papillary RCC, having also presented with flank pain, but this time in his 30s (Fig. 1). Patient III.1 underwent genetic testing which revealed a missense variant in the MET gene (NM_000245.4 c.3308G>A; p.Gly1103Glu). The variant affects a highly conserved residue in the Tyrosine Kinase domain of the MET protein. Pathogenic activating variants are associated with RCC. Identification of the same variant in the affected father with bilateral disease allowed classification of the variant as likely pathogenic according to the ACMG criteria [1]. The father has seven children, all of whom have now been tested. 5/7 of them have been found to carry the likely pathogenic MET missense variant. Of the 4 asymptomatic carriers, all are under surveillance by regular renal imaging and (one has had radiofrequency ablation). Conclusion The case outlines a rare form of hereditary RCC and the implications that detection of the genetic variant has meant in terms of early diagnosis of disease. Incidence of RCC is increasing worldwide. Hereditary papillary RCC is rare, it is typically inherited in an autosomal dominant pattern. Germline mutations in the MET proto-oncogene are located at 7q31, which encodes for the tyrosine kinase signaling pathway. Variants lead to uncontrolled activation of MET protein and aberrant cell growth [2]. Discussion Hereditary papillary RCC has an estimated incidence of < 1:1500000, its rarity highlighted by the fact that only ∼35 families have been reported worldwide in literature. In these cases it exhibits 100% penetrance, with patients developing renal cell carcinoma typically between their fifth and sixth decade [3]. We would like to acknowledge the family involved in this case report. As with many cancers, early diagnosis is helped by detection of a genetic variant, leading to improved long-term disease-free survival. In the case of metastatic papillary RCC 2-year survival is still estimated at 18% (3).

Supplementary Table 3. Results of the statistical analyses of SNPs from project 12 in BRCA-mutation carriers affected or non-affected with breast cancer and according to their estrogen receptor status.

The Ehlers Danlos syndromes are identified by their connective tissue features and are not rich in dysmorphic handles. Vascular Ehlers Danlos syndrome (vEDS) however, is characterised by a recognisable phenotypic constellation of internal and external dysmorphology. This review charts the paediatric and adult phenotypes of vEDS due primarily to COL3A1 gene variants and the potential recognition of some other EDS subtypes, including COL1A1 and COL25A1 that can present with vEDS-like features, with certain dysmorphic handles as clues to the diagnosis and the adjunct of gene testing in patients presenting with vEDS features.

Supplementary Methods, Tables 1-3, Figure 1 from Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for <i>BRCA1</i> and <i>BRCA2</i> Mutation Carriers: Implications for Risk Prediction

Supplementary Data from BRCA1 and c-Myc Associate to Transcriptionally Repress Psoriasin, a DNA Damage–Inducible Gene

Supplementary Table 2. Results of the statistical analyses in BRCA mutation carriers.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Supplementary Table 1. The 3,248 SNPs included in the study

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes ( path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.