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The discovery in 2005 of the JAK2 V617F gain-of-function mutation in myeloproliferative neoplasms and more particularly in polycythemia vera has deeply changed the diagnostic and therapeutic approaches to polycythemia. More recently, the use of NGS in routine practice has revealed a large number of variants, although it is not always possible to classify them as pathogenic. This is notably the case for the JAK2 E846D variant for which for which questions remain unanswered. In a large French national cohort of 650 patients with well-characterized erythrocytosis, an isolated germline heterozygous JAK2 E846D substitution was observed in only two cases. For one of the patients, a family study could be performed, without segregation of the variant with the erythrocytosis phenotype. On the other hand, based on the large UK Biobank resource cohort including more than half a million UK participants, the JAK2 E846D variant was found in 760 individuals, associated with a moderate increase in hemoglobin and hematocrit values, but with no significant difference to the mean values of the rest of the studied population. Altogether, our data as well as UK Biobank cohort analyses suggest that the occurrence of an absolute polycythemia cannot be attributed to the sole demonstration of an isolated JAK2 E846D variant. However, it must be accompanied by other stimuli or favoring factors in order to generate absolute erythrocytosis. [ABSTRACT FROM AUTHOR]

The previous lack of national UK guidance on the use of Prenatal and Pre-implantation Genetic Testing (PND and PGT-M) for Monogenic Disorders for Germline Cancer Susceptibility Gene Variants (gCSGV) has led to disparities in care across the UK, and inequitable access to reproductive options for families living with cancer susceptibility syndromes. In 2023, the UK Cancer Genetics Group and Fetal Genomics Group of the British Society of Genetic Medicine developed joint consensus guidance seeking to provide healthcare professionals with a clear counselling framework to support individuals/couples during their reproductive decision-making process. The guidance is for healthcare professionals, individuals and couples with a gCSGV and their families, policy makers and charities supporting people with cancer susceptibility syndromes. Details about the consensus group participants, the main workshop's format, and the pre- and post-workshop nationwide surveys, are available in the full document. [ABSTRACT FROM AUTHOR]

Background: Testing for germline pathogenic variants (GPVs) in cancer predisposition genes is increasingly offered as part of routine care for patients with cancer. This is often urgent in oncology clinics due to potential implications on treatment and surgical decisions. This also allows identification of family members who should be offered predictive genetic testing. In the UK, it is common practice for healthcare professionals to provide a patient information leaflet (PIL) at point of care for diagnostic genetic testing in patients with cancer, after results disclosure when a GPV is identified, and for predictive testing of at-risk relatives. Services usually create their own PIL, resulting in duplication of effort and wide variability regarding format, content, signposting and patient input in co-design and evaluation., Methods: Representatives from UK Cancer Genetics Group (UKCGG), Cancer Research UK (CRUK) funded CanGene-CanVar programme and Association of Genetic Nurse Counsellors (AGNC) held a 2-day meeting with the aim of making recommendations for clinical practice regarding co-design of PIL for germline cancer susceptibility genetic testing. Lynch syndrome and haematological malignancies were chosen as exemplar conditions., Results: Meeting participants included patient representatives including as co-chair, multidisciplinary clinicians and other experts from across the UK. High-level consensus for UK recommendations for clinical practice was reached on several aspects of PIL using digital polling, including that PIL should be offered, accessible, co-designed and evaluated with patients., Conclusions: Recommendations from the meeting are likely to be applicable for PIL co-design for a wide range of germline genetic testing scenarios., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Mendelian randomization (MR) is a widely used method that exploits the unique properties of germline genetic variation to strengthen causal inference in relationships between exposures and outcomes. Nonlinear MR allows estimation of the shape of these relationships. In a previous paper, the authors applied linear and nonlinear MR to estimate the effect of BMI on mortality in UK Biobank, providing evidence for a J‐shaped association. However, it is now clear that there are problems with widely used nonlinear MR methods, which draws attention to the likely erroneous nature of the conclusions regarding the shapes of several explored relationships. Here, the authors explore the utility and likely biases of these nonlinear MR methods with the use of a negative control design. Although there remains good evidence for a causal effect of higher BMI increasing the risk of mortality, the pattern of this association across different levels of BMI requires further characterization. [ABSTRACT FROM AUTHOR]

The finding of the enigmatic pathogen Anisolpidium rosenvingei in the filamentous brown macroalga Pylaiella littoralis presented a unique opportunity to histochemically study the distribution of chitin in this little-known pathogen using FUNGALASE™-F, a fluorescein-labelled chitinase. Chitin was found localised to the exit tube of this pathogen, which infects exclusively reproductive cells of its host. The cytological and phylogenetic implications of this finding are discussed. This paper also reports the first record of this pathogen in the United Kingdom, on the west coast of Scotland. [ABSTRACT FROM AUTHOR]

Background: Our study aimed to establish 'real-world' performance and cost-effectiveness of ovarian cancer (OC) surveillance in women with pathogenic germline BRCA1/2 variants who defer risk-reducing bilateral salpingo-oophorectomy (RRSO)., Methods: Our study recruited 875 female BRCA1/2 -heterozygotes at 13 UK centres and via an online media campaign, with 767 undergoing at least one 4-monthly surveillance test with the Risk of Ovarian Cancer Algorithm (ROCA) test. Surveillance performance was calculated with modelling of occult cancers detected at RRSO. The incremental cost-effectiveness ratio (ICER) was calculated using Markov population cohort simulation., Results: Our study identified 8 OCs during 1277 women screen years: 2 occult OCs at RRSO (both stage 1a), and 6 screen-detected; 3 of 6 (50%) were ≤stage 3a and 5 of 6 (83%) were completely surgically cytoreduced. Modelled sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) for OC were 87.5% (95% CI, 47.3 to 99.7), 99.9% (99.9-100), 75% (34.9-96.8) and 99.9% (99.9-100), respectively. The predicted number of quality-adjusted life years (QALY) gained by surveillance was 0.179 with an ICER cost - saving of -£102,496/QALY., Conclusion: OC surveillance for women deferring RRSO in a 'real-world' setting is feasible and demonstrates similar performance to research trials; it down-stages OC, leading to a high complete cytoreduction rate and is cost-saving in the UK National Health Service (NHS) setting. While RRSO remains recommended management, ROCA-based surveillance may be considered for female BRCA -heterozygotes who are deferring such surgery., Competing Interests: Competing interests: The project was co-funded by Abcodia Ltd and North Central London Cancer Alliance. Abcodia Ltd had no role in the design of the project, nor in the interpretation of the findings or the drafting/editing of the manuscript. Sue Philpott has previously held a consulting role with Abcodia Ltd Adam Rosenthal has previously held a consulting role with Abcodia Ltd and Everything Genetic Ltd. Ranjit Manchanda has received funding from Yorkshire Cancer Research, GSK, Eve Appeal, Cancer Research UK, NHS Innovation Accelerator (NIA), Barts & the London Charity, Rose Trees Trust outside this work for research related to genetic testing and honorarium for advisory board membership or lectures from Astrazeneca/MSD/GSK/EGL. Naveena Singh has served on advisory boards for Astra-Zeneca-MSD and Glaxo SmithKline. Gareth Evans has a consultancy role with AstraZeneca. Helen Hanson has served on advisory boards for AstraZeneca. Steve Skates works at Massachusetts General Hospital which has co-licensed the software for early detection of ovarian cancer to Abcodia and has served on clinical advisory boards for Guardant Health and LUNGevity, has collaborated on early detection research with Freenome, participates in the Independent Data Monitoring Committee for GRAIL and has stock option for serving on the scientific Advisory Board for SISCAPA Assay Technologies. The other authors declare no competing interests., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Germline pathogenic variants (GPVs) in the cancer predisposition genes BRCA1 , BRCA2 , MLH1 , MSH2 , MSH6 , BRIP1 , PALB2 , RAD51D and RAD51C are identified in approximately 15% of patients with ovarian cancer (OC). While there are clear guidelines around clinical management of cancer risk in patients with GPV in BRCA1 , BRCA2 , MLH1 , MSH2 and MSH6 , there are few guidelines on how to manage the more moderate OC risk in patients with GPV in BRIP1 , PALB2 , RAD51D and RAD51C , with clinical questions about appropriateness and timing of risk-reducing gynaecological surgery. Furthermore, while recognition of RAD51C and R AD51D as OC predisposition genes has been established for several years, an association with breast cancer (BC) has only more recently been described and clinical management of this risk has been unclear. With expansion of genetic testing of these genes to all patients with non-mucinous OC, new data on BC risk and improved estimates of OC risk, the UK Cancer Genetics Group and CanGene-CanVar project convened a 2-day meeting to reach a national consensus on clinical management of BRIP1 , PALB2 , RAD51D and RAD51C carriers in clinical practice. In this paper, we present a summary of the processes used to reach and agree on a consensus, as well as the key recommendations from the meeting., Competing Interests: Competing interests: HH received honoraria from AstraZeneca for advisory roles. CT received honoraria from AstraZeneca and Roche for advisory roles, which were donated in full to charity (https://tukongote.com/, registration number 11511580, charity number 1186151). RM declares research funding from Barts & the London Charity, Rosetrees Trust, GSK, Eve Appeal, CRUK and Yorkshire Cancer Research outside this work; and honorarium for advisory board membership from AstraZeneca/MSD/GSK/EGL. DME was in receipt of research funding from AstraZeneca. ANR had prior consultancy arrangements with Abcodia and Everything Genetic. ACA was listed as a creator of BOADICEA, which was licensed by Cambridge Enterprise for commercial purposes., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Pituitary adenomas (PAs) are common, usually benign tumors of the anterior pituitary gland which, for the most part, have no known genetic cause. PAs are associated with major clinical effects due to hormonal dysregulation and tumoral impingement on vital brain structures. PAM encodes a multifunctional protein responsible for the essential C-terminal amidation of secreted peptides.. Methods: Following the identification of a loss-of-function variant (p.Arg703Gln) in the peptidylglycine a-amidating monooxygenase (PAM) gene in a family with pituitary gigantism, we investigated 299 individuals with sporadic PAs and 17 familial isolated PA kindreds for PAM variants. Genetic screening was performed by germline and tumor sequencing and germline copy number variation (CNV) analysis.. Results: In germline DNA, we detected seven heterozygous, likely pathogenic missense, truncating, and regulatory SNVs. These SNVs were found in sporadic subjects with growth hormone excess (p.Gly552Arg and p.Phe759Ser), pediatric Cushing disease (c.-133T>C and p.His778fs), or different types of PAs (c.-361G>A, p.Ser539Trp, and p.Asp563Gly). The SNVs were functionally tested in vitro for protein expression and trafficking by Western blotting, splicing by minigene assays, and amidation activity in cell lysates and serum samples. These analyses confirmed a deleterious effect on protein expression and/or function. By interrogating 200,000 exomes from the UK Biobank, we confirmed a significant association of the PAM gene and rare PAM SNVs with diagnoses linked to pituitary gland hyperfunction. Conclusion: The identification of PAM as a candidate gene associated with pituitary hypersecretion opens the possibility of developing novel therapeutics based on altering PAM function. [ABSTRACT FROM AUTHOR]

Lynch syndrome (LS), caused by heterozygous germline mutation in one of the key mismatch repair (MMR) genes, is the primary cause of inherited colorectal cancer (CRC). LS also increases susceptibility to several other cancers. It is estimated that just 5% of patients with LS are aware of their diagnosis. Therefore, in an attempt to increase the identification of cases within the UK population, the 2017 NICE guidelines recommend offering immunohistochemistry for MMR proteins or microsatellite instability (MSI) testing to all people with CRC when first diagnosed. Following identification of MMR deficiency, eligible patients should be assessed for underlying causes, including potential referral to the genetics service and/or germline LS testing (if appropriate). In our regional centre for CRC, we audited local pathways to identify what proportion of patients are being correctly referred, in line with national guidelines. Reflecting on these results, we highlight our practical concerns by identifying the pitfalls and issues faced with the recommended referral pathway. We also propose possible solutions to improve the efficacy of the system for both referrers and patients. Finally, we discuss the ongoing interventions that national bodies and regional centres are implementing to improve and further streamline this process. [ABSTRACT FROM AUTHOR]

Summary: The implementation of whole genome sequencing and large somatic gene panels in haematological malignancies is identifying an increasing number of individuals with either potential or confirmed germline predisposition to haematological malignancy. There are currently no national or international best practice guidelines with respect to management of carriers of such variants or of their at‐risk relatives. To address this gap, the UK Cancer Genetics Group (UKCGG), CanGene‐CanVar and the NHS England Haematological Oncology Working Group held a workshop over two days on 28–29th April 2022, with the aim of establishing consensus guidelines on relevant clinical and laboratory pathways. The workshop focussed on the management of disease‐causing germline variation in the following genes: DDX41, CEBPA, RUNX1, ANKRD26, ETV6, GATA2. Using a pre‐workshop survey followed by structured discussion and in‐meeting polling, we achieved consensus for UK best practice in several areas. In particular, high consensus was achieved on issues regarding standardised reporting, variant classification, multidisciplinary team working and patient support. The best practice recommendations from this meeting may be applicable to an expanding number of other genes in this setting. [ABSTRACT FROM AUTHOR]

The rationale for performing bilateral oophorectomy during cystectomy in females diagnosed with bladder cancer (BC) is multifaceted;however, the incidence of ovarian cancer (OC) germline mutations in females diagnosed with BC remains unknown. Additionally, there is a scarcity of data regarding the co-occurrence and;timing of these two malignancies. Given the well-established benefits of retaining the ovaries, including in postmenopausal women, our study sought to achieve three objectives: determine the frequency of recognized OC germline variants among females with BC, evaluate;the temporal and simultaneous occurrence of these two malignancies, and assess;the risk of other neoplastic conditions and family history in women harboring OC germline mutations and with a diagnosis of BC. Using the UK Biobank, a long-term prospective population-based database;from the United Kingdom encompassing both;genotypic and phenotypic data from 501,232 patients, we analyzed OC germline variants as reported by NCCN in a cohort of females diagnosed with bladder cancer (n=1,346). We restricted the analysis to high and moderate-impact variants for initial regression and pathogenic/likely pathogenic (P/LP) variants as reported by ClinVar, and evaluated the concomitant presence of other malignancies, family history, and age of presentation. 3.4% of women in our cohort exhibited the presence of 15 distinct germline variants which were previously established to be linked with varying degrees of OC development. CHEK2 and PALB2 mutations represented the highest ratio of overall/pathogenic variants (15.8% and 6.6% respectively) (Figure 1). Although females with P/LP OC germline mutations demonstrated a significantly amplified risk of development of OC, the diagnosis of OC preceded that of bladder cancer by 11.3 (±12.5 years) and 15.6 (±11.3 years) in all cases;(Figure 2), even in those without established OC germline mutations. Females who exhibited P/LP OC germline variants were also observed to have a higher likelihood of reporting maternal and sibling breast cancer (14.63% vs. 8.12%, p=0.04 and 9.76% vs. 3.98%, p=0.02, respectively), maternal colon cancer (9.76% vs. 4.21%), and reduced maternal life expectancy compared to non-P/LP patients (75.34 vs. 68.15 years, p=0.0014). Our study provides evidence against routine recommendation for bilateral oophorectomy during cystectomy in female BC patients. Furthermore, the study highlights that females with OC germline mutations who have been diagnosed with BC may be at a heightened risk of developing other malignancies, including breast cancer and melanoma, following their bladder cancer diagnosis, accentuating the necessity of devising personalized oncological management approaches in our female BC patients. [ABSTRACT FROM AUTHOR]

Background and aims: Summarised in polygenic risk scores (PRS), the effect of common, low penetrant genetic variants associated with colorectal cancer (CRC), can be used for risk stratification. Methods: To assess the combined impact of the PRS and other main factors on CRC risk, 163,516 individuals from the UK Biobank were stratified as follows: 1. carriers status for germline pathogenic variants (PV) in CRC susceptibility genes (APC, MLH1, MSH2, MSH6, PMS2), 2. low (< 20%), intermediate (20–80%), or high PRS (> 80%), and 3. family history (FH) of CRC. Multivariable logistic regression and Cox proportional hazards models were applied to compare odds ratios and to compute the lifetime incidence, respectively. Results: Depending on the PRS, the CRC lifetime incidence for non-carriers ranges between 6 and 22%, compared to 40% and 74% for carriers. A suspicious FH is associated with a further increase of the cumulative incidence reaching 26% for non-carriers and 98% for carriers. In non-carriers without FH, but high PRS, the CRC risk is doubled, whereas a low PRS even in the context of a FH results in a decreased risk. The full model including PRS, carrier status, and FH improved the area under the curve in risk prediction (0.704). Conclusion: The findings demonstrate that CRC risks are strongly influenced by the PRS for both a sporadic and monogenic background. FH, PV, and common variants complementary contribute to CRC risk. The implementation of PRS in routine care will likely improve personalized risk stratification, which will in turn guide tailored preventive surveillance strategies in high, intermediate, and low risk groups. [ABSTRACT FROM AUTHOR]

Deucravacitinib, a novel, selective inhibitor of TYK2 is currently under review at the FDA and EMA for treatment of moderate‐to‐severe plaque psoriasis. It is unclear whether recent safety concerns (ie, elevated rates of lung cancer and lymphoma) related to similar medications (ie, other JAK inhibitors) are shared with this novel TYK2 inhibitor. We used a partial loss‐of‐function variant in TYK2 (rs34536443), previously shown to protect against psoriasis and other autoimmune diseases, to evaluate the potential effect of therapeutic TYK2 inhibition on risk of lung cancer and non‐Hodgkin lymphoma. Summary genetic association data on lung cancer risk were obtained from a GWAS meta‐analysis of 29 266 cases and 56 450 controls in the Integrative Analysis of Lung Cancer Risk and Aetiology (INTEGRAL) consortium. Summary genetic association data on non‐Hodgkin lymphoma risk were obtained from a GWAS meta‐analysis of 8489 cases and 374 506 controls in the UK Biobank and InterLymph consortium. In the primary analysis, each copy of the minor allele of rs34536443, representing partial TYK2 inhibition, was associated with an increased risk of lung cancer (OR 1.15, 95% CI 1.09‐1.23, P = 2.29 × 10−6) and non‐Hodgkin lymphoma (OR 1.18, 95% CI 1.05‐1.33, P = 5.25 × 10−3). Our analyses using an established partial loss‐of‐function mutation to mimic TYK2 inhibition provide genetic evidence that therapeutic TYK2 inhibition may increase risk of lung cancer and non‐Hodgkin lymphoma. These findings, consistent with recent reports from postmarketing trials of similar JAK inhibitors, could have important implications for future safety assessment of deucravacitinib and other TYK2 inhibitors in development. What's new? Increased rates of lymphoma and lung cancer associated with Janus kinase (JAK) inhibitors used in the treatment of chronic inflammatory conditions have raised significant concern. A promising alternative, particularly for the treatment of plaque psoriasis, is deucravacitinib, a selective inhibitor of JAK family member TYK2. Here, the authors explored possible carcinogenic effects of TYK2 inhibition by genetic proxy based on a partial loss‐of‐function variant in TYK2 that provides protection against psoriasis. Analyses show that genetically proxied TYK2 inhibition increases lung cancer and non‐Hodgkin lymphoma risk. The findings could impact safety assessments of deucravacitinib and future novel TYK2 inhibitors. [ABSTRACT FROM AUTHOR]

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a component of familial melanoma due to germline pathogenic variants (GPVs) in CDKN2A. However, it is unclear what role this gene or other genes play in its etiology. MATERIALS AND METHODS: We analyzed 189 cancer predisposition genes using parametric rare-variant association (RVA) tests and nonparametric permutation tests to identify gene-level associations in PDAC for patients with (CDKN2A +) and without (CDKN2A–) GPV. Exome sequencing was performed on 84 patients with PDAC, 47 CDKN2A+ and 37 CDKN2A–. After variant filtering, various RVA tests and permutation tests were run separately by CDKN2A status. Genes with the strongest nominal associations were evaluated in patients with PDAC from The Cancer Genome Atlas and the UK Biobank (UKB). A secondary analysis including only GPV from UKB was also performed. RESULTS: In RVA tests, ERCC4 and RET showed the most compelling evidence as plausible PDAC candidate genes for CDKN2A+ patients. In contrast, the findings in CDKN2A– patients provided evidence for HMBS , EPCAM , and MRE11 as potential new candidate genes and confirmed ATM, BRCA2 , and PALB2 as PDAC genes, consistent with findings in The Cancer Genome Atlas and the UKB. As expected, CDKN2A– patients were more likely to harbor GPVs from the 189 genes investigated. When including only GPVs from UKB, significant associations with PDAC were seen for ATM, BRCA2, and CDKN2A. CONCLUSION: These results suggest that variants in other genes likely play a role in PDAC in all patients and that PDAC in CDKN2A+ patients has a distinct etiology from PDAC in CDKN2A– patients. Our study reports on the complex genetics of #pancreaticcancer in an international cohort of patients with and without germline pathogenic variants in the CDKN2A gene. [ABSTRACT FROM AUTHOR]

Background: The relationship between leukocyte telomere length (LTL) and female reproductive endocrine diseases has gained significant attention and research interest in recent years. However, there is still limited understanding of the exact impacts of LTL on these diseases. Therefore, the primary objective of this study was to investigate the genetic causal association between LTL and female reproductive endocrine diseases by employing Mendelian randomization (MR) analysis. Methods: Instruments for assessing genetic variation associated with exposure and outcome were derived from summary data of published genome-wide association studies (GWAS). Inverse-variance weighted (IVW) was utilized as the main analysis method to investigate the causal relationship between LTL and female reproductive endocrine diseases. The exposure data were obtained from the UK Biobanks GWAS dataset, comprising 472,174 participants of European ancestry. The outcome data were acquired from the FinnGen consortium, including abnormal uterine bleeding (menorrhagia and oligomenorrhea), endometriosis (ovarian endometrioma and adenomyosis), infertility, polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI) and premenstrual syndrome (PMS). Furthermore, to account for potential confounding factors such as smoking, alcohol consumption, insomnia, body mass index (BMI) and a history of pelvic inflammatory disease (PID), multivariable MR (MVMR) analysis was also conducted. Lastly, a series of pleiotropy tests and sensitivity analyses were performed to ensure the reliability and robustness of our findings. P < 0.0063 was considered to indicate statistically significant causality following Bonferroni correction. Results: Our univariable MR analysis demonstrated that longer LTL was causally associated with an increased risk of menorrhagia (IVW: odds ratio [OR]: 1.1803; 95% confidence interval [CI]: 1.0880–1.2804; P = 0.0001) and ovarian endometrioma (IVW: OR: 1.2946; 95%CI: 1.0970–1.5278; P = 0.0022) at the Bonferroni significance level. However, no significant correlation was observed between LTL and oligomenorrhea (IVW: OR: 1.0124; 95%CI: 0.7350–1.3946; P = 0.9398), adenomyosis (IVW: OR: 1.1978; 95%CI: 0.9983–1.4372; P = 0.0522), infertility (IVW: OR: 1.0735; 95%CI: 0.9671–1.1915; P = 0.1828), PCOS (IVW: OR: 1.0633; 95%CI: 0.7919–1.4278; P = 0.6829), POI (IVW: OR: 0.8971; 95%CI: 0.5644–1.4257; P = 0.6459) or PMS (IVW: OR: 0.7749; 95%CI: 0.4137–1.4513; P = 0.4256). Reverse MR analysis indicated that female reproductive endocrine diseases have no causal effect on LTL. MVMR analysis suggested that the causal effect of LTL on menorrhagia and ovarian endometrioma remained significant after accounting for smoking, alcohol consumption, insomnia, BMI and a history of PID. Pleiotropic and sensitivity analyses also showed robustness of our results. Conclusion: The results of our bidirectional two-sample MR analysis revealed that genetically predicted longer LTL significantly increased the risk of menorrhagia and ovarian endometrioma, which is consistent with the findings from MVMR studies. However, we did not notice any significant effects of LTL on oligomenorrhea, adenomyosis, infertility, PCOS, POI or PMS. Additionally, reproductive endocrine disorders were found to have no impact on LTL. To enhance our understanding of the effect and underlying mechanism of LTL on female reproductive endocrine diseases, further large-scale studies are warranted in the future. [ABSTRACT FROM AUTHOR]

Female Corynorhinus mexicanus bats store sperm for three months. One cause of the death of sperm is the action of reactive oxygen species (ROS). Three antioxidant enzymes - superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) - regulate the REDOX state of the environment in which gametes are stored. The aim of this study was to evaluate antioxidant enzymatic activity in female genital fluid during the period of sperm storage (October-December). The activity of the enzymes in the female bats' genital fluid was determined by spectrophotometry. SOD activity was 20 USOD/ml/min in each month. Total GPX activity was 70 UGPX/ml/min in October, but increased in November and December to 145 UGPX/ml/min. Specific CAT activity was 2000 UK/ml/min in October, but in November it increased to 16 000 UK/ml/min, then to 32 000 UK/ml/min in December. The ROS fluorescence indices in the sperm ranged from 3000 to 8000 with no significant differences. These data show that antioxidant enzymes participate in the maintenance of sperm viability in the female reproductive tract of C. mexicanus. [ABSTRACT FROM AUTHOR]

Background: Telomere length shortening can cause senescence and apoptosis in various immune cells, resulting in immune destabilization and ageing of the organism. In this study, we aimed to systematically assess the causal relationship of leukocyte telomere length (LTL) with ankylosing spondylitis (AS) and rheumatoid arthritis (RA) using a Mendelian randomization study. Methods: LTL (n=472174) was obtained from the UK Biobank genome-wide association study pooled data. AS (n=229640), RA (n=212472) were obtained from FinnGen database. MR-Egger, inverse variance weighting, and weighted median methods were used to estimate the effects of causes. Cochran’s Q test, MR Egger intercept test, MR-PRESSO, leave-one-out analysis, and funnel plots were used to look at sensitivity, heterogeneity, and multiple effects. Forward MR analysis considered LTL as the exposure and AS, RA as the outcome. Reverse MR analysis considered AS, RA as the exposure and LTL as the outcome. Results: In the forward MR analysis, inverse variance-weighted and weighted median analysis results indicated that longer LTL might be associated with increased risk of AS (IVW: OR = 1.55, 95% CI: 1.14-2.11, p = 0.006). MR Egger regression analysis showed no pleiotropy between instrumental variables (IVs) (Egger intercept= 0.008, p = 0.294). The leave-one-out analysis showed that each single nucleotide polymorphism (SNP) of AS was robust to each outcome. No significant causal effects were found between AS, RA and LTL in the reverse MR analysis. Conclusion: Longer LTL may be related with an increased risk of developing AS, and these findings provide a foundation for future clinical research on the causal association between LTL and AS. [ABSTRACT FROM AUTHOR]

Objective: To review the current state of genetic risk models for predicting the development of kidney cancer, by identifying and comparing the performance of published models. Methods: Risk models were identified from a recent systematic review and the Cancer‐PRS web directory. A narrative synthesis of the models, previous validation studies and related genome‐wide association studies (GWAS) was carried out. The discrimination and calibration of the identified models was then assessed and compared in the UK Biobank (UKB) cohort (cases, 452; controls, 487 925). Results: A total of 39 genetic models predicting the development of kidney cancer were identified and 31 were validated in the UKB. Several of the genetic‐only models (seven of 25) and most of the mixed genetic‐phenotypic models (five of six) had some discriminatory ability (area under the receiver operating characteristic curve >0.5) in this cohort. In general, models containing a larger number of genetic variants identified in GWAS performed better than models containing a small number of variants associated with known causal pathways. However, the performance of the included models was consistently poorer than genetic risk models for other cancers. Conclusions: Although there is potential for genetic models to identify those at highest risk of developing kidney cancer, their performance is poorer than the best genetic risk models for other cancers. This may be due to the comparatively small number of genetic variants associated with kidney cancer identified in GWAS to date. The development of improved genetic risk models for kidney cancer is dependent on the identification of more variants associated with this disease. Whether these will have utility within future kidney cancer screening pathways is yet to determined. [ABSTRACT FROM AUTHOR]

Women with ovarian cancer who have a pathogenic germline variant in BRCA 1 or BRCA 2 (BRCA) have been shown to have better 5-year survival after diagnosis than women who are BRCA -wildtype (non-carriers). Modifiable lifestyle factors, including smoking, physical activity and body mass index (BMI) have previously been associated with ovarian cancer survival; however, it is unknown whether these associations differ by germline BRCA status. We investigated measures of lifestyle prior to diagnosis in two cohorts of Australian women with invasive epithelial ovarian cancer, using Cox proportional hazards regression to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). In the combined studies (n = 1923), there was little association between physical activity, BMI or alcohol intake and survival, and no difference by BRCA status. However, the association between current smoking status before diagnosis and poorer survival was stronger for BRCA variant carriers (HR 1.98; 95% CI 1.20–3.27) than non-carriers (HR 1.18; 95% CI 0.96–1.46; p-interaction 0.02). We saw a similar differential association with smoking when we pooled results from two additional cohorts from the USA and UK (n = 2120). Combining the results from all four studies gave a pooled-HR of 1.94 (95% CI 1.28–2.94) for current smoking among BRCA variant carriers compared to 1.08 (0.90–1.29) for non-carriers. Our results suggest that the adverse effect of smoking on survival may be stronger for women with a BRCA variant than those without. Thus, while smoking cessation may improve outcomes for all women with ovarian cancer, it might provide a greater benefit for BRCA variant carriers. • It is unknown whether associations between lifestyle factors and ovarian cancer survival differ by BRCA variant status. • The adverse effects of smoking on ovarian cancer survival may be stronger for women with a BRCA variant than those without. • There was no differential association in survival by BRCA variant status for physical activity, BMI or alcohol intake. [ABSTRACT FROM AUTHOR]

Introduction: Recent consensus statements recommend that orchidopexy for undescended testis is performed between 6 and 12 months of age. We designed a survey to determine what age consultant surgeons believe is the optimal age for orchidopexy as well as surveying other aspects of surgery for testicular maldescent. Methods: An anonymous survey was distributed to 122 UK consultants who participated in an international prospective audit of orchidopexy outcomes. Preferences and management strategies were compared between different groups of surgeons (specialist paediatric general surgeons, specialist paediatric urologists and general surgeons/urologists with an interest in general surgery of childhood [but who mainly treat adult patients]). Results: There were 105 responses (62 specialist paediatric surgeons, 30 specialist paediatric urologists and 13 general surgeons/urologists) from 25 centres. The overall response rate was 86%. The median preferred age for orchidopexy was 10.5 months (range: 3–24 months). This differed significantly between groups, with a median of 12 months among specialist paediatric surgeons, 9 months among specialist paediatric urologists and 12 months among general surgeons/urologists (p = 0.001). Fifty-one consultants (49%) stated that the optimal age to perform orchidopexy was twelve months or more. Respondents cited concerns about the possible long-term effects of general anaesthesia at a young age and higher atrophy rates in younger children as the main reasons for postponing orchidopexy until 12 months. Conclusions: There remains no consensus among surgeons as to the optimal age for orchidopexy. Management practice of undescended testis varies across different surgical specialties, particularly with regard to optimal age of surgery. [ABSTRACT FROM AUTHOR]

Haemophagocytic lymphohistiocytosis is a life-threatening systemic inflammatory syndrome defined by persistent fever, cytopenia and multi-organ dysfunction. Primary haemophagocytic lymphohistiocytosis classically presents in childhood as a result of genetically abnormal perforin or inflammasome function, leading to the aberrant release of pro-inflammatory cytokines causing a hyperinflammatory state. Secondary haemophagocytic lymphohistiocytosis is an acquired phenomenon occurring at any age as a result of immune dysregulation to a specific trigger such as infection, haematological malignancy or autoimmune disease. Secondary haemophagocytic lymphohistiocytosis occurring in the pregnant woman represents a diagnostic challenge and carries a significant mortality. This has led to its first inclusion in the fourth Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries across the United Kingdom annual maternal report in 2017. This article presents an overview of haemophagocytic lymphohistiocytosis, reviews the literature on haemophagocytic lymphohistiocytosis in pregnancy, suggests diagnostic pathways and explores the safety and efficacy of existing and potential treatment strategies for haemophagocytic lymphohistiocytosis occurring during pregnancy. [ABSTRACT FROM AUTHOR]

Mitochondria, the organelles providing the cell with energy, have recently gained greater public visibility in the UK and beyond, through the introduction of two reproductive technologies which involve their manipulation, specifically 'mitochondrial donation' to prevent the maternal transmission of inherited disorders, and 'Augment' to improve egg quality and fertility. Focusing on these two 'MitoTechnologies' and mobilising the conceptual framework of "bio-objectification", we examine three key processes whereby mitochondria are made to appear to have a life of their own: their transferability, their optimisation of life processes and their capitalisation. We then explore the implications of their bio-objectification in the bioeconomy of reproduction. Drawing on publicly available material collected in two research projects, we argue that mitochondria become a biopolitical agent by contributing to the redefinition of life as something that can be boosted at the cellular level and in reproduction. Mitochondria are now presented as playing a key role for a successful and healthy conception through the development and promotion of MitoTechnologies. We also show how their "revitalising power" is invested with great promissory capital, mainly deriving from their ethical and scientific biovalue in the case of mitochondrial donation, and from the logics of assetisation, in the case of Augment. [ABSTRACT FROM AUTHOR]

Background: Women facing increased energetic demands in childhood commonly have altered adult ovarian activity and shorter reproductive lifespan, possibly comprising a strategy to optimize reproductive success. Here, we sought to understand the mechanisms of early-life programming of reproductive function, by integrating analysis of reproductive tissues in an appropriate mouse model with methylation analysis of proxy tissue DNA in a well-characterized population of Bangladeshi migrants in the UK. Bangladeshi women whose childhood was in Bangladesh were found to have later pubertal onset and lower age-matched ovarian reserve than Bangladeshi women who grew-up in England. Subsequently, we aimed to explore the potential relevance to the altered reproductive phenotype of one of the genes that emerged from the screens. Results: Of the genes associated with differential methylation in the Bangladeshi women whose childhood was in Bangladesh as compared to Bangladeshi women who grew up in the UK, 13 correlated with altered expression of the orthologous gene in the mouse model ovaries. These mice had delayed pubertal onset and a smaller ovarian reserve compared to controls. The most relevant of these genes for reproductive function appeared to be SRD5A1, which encodes the steroidogenic enzyme 5α reductase-1. SRD5A1 was more methylated at the same transcriptional enhancer in mice ovaries as in the women's buccal DNA, and its expression was lower in the hypothalamus of the mice as well, suggesting a possible role in the central control of reproduction. The expression of Kiss1 and Gnrh was also lower in these mice compared to controls, and inhibition of 5α reductase-1 reduced Kiss1 and Gnrh mRNA levels and blocked GnRH release in GnRH neuronal cell cultures. Crucially, we show that inhibition of this enzyme in female mice in vivo delayed pubertal onset. Conclusions: SRD5A1/5α reductase-1 responds epigenetically to the environment and its downregulation appears to alter the reproductive phenotype. These findings help to explain diversity in reproductive characteristics and how they are shaped by early-life environment and reveal novel pathways that might be targeted to mitigate health issues caused by life-history trade-offs. [ABSTRACT FROM AUTHOR]

Two major reports in the UK and USA have recently sanctioned as ethically acceptable genome editing of future generations for the treatment of serious rare inherited conditions. This marks an important turning point in the application of recombinant DNA techniques to humans. The central question this paper addresses is how did it became possible for human genetic engineering (HGE) of future generations to move from an illegitimate idea associated with eugenics in the 1980s to a concrete proposal sanctioned by scientists and bioethicists in 2020? The paper uses the concept of a regime of normativity to understand the co-evolution and mutual shaping of technology, imaginaries, norms and governance processes in debates about HGE in the USA and UK. It will be argued that interlinked discursive, institutional, political and technological changes have made proposals for the use of genome editing in the genetic engineering of future generations both "thinkable" and legitimate. [ABSTRACT FROM AUTHOR]

Human genetic studies of common variants have provided substantial insight into the biological mechanisms that govern ovarian ageing 1 . Here we report analyses of rare protein-coding variants in 106,973 women from the UK Biobank study, implicating genes with effects around five times larger than previously found for common variants (ETAA1, ZNF518A, PNPLA8, PALB2 and SAMHD1). The SAMHD1 association reinforces the link between ovarian ageing and cancer susceptibility 1 , with damaging germline variants being associated with extended reproductive lifespan and increased all-cause cancer risk in both men and women. Protein-truncating variants in ZNF518A are associated with shorter reproductive lifespan-that is, earlier age at menopause (by 5.61 years) and later age at menarche (by 0.56 years). Finally, using 8,089 sequenced trios from the 100,000 Genomes Project (100kGP), we observe that common genetic variants associated with earlier ovarian ageing associate with an increased rate of maternally derived de novo mutations. Although we were unable to replicate the finding in independent samples from the deCODE study, it is consistent with the expected role of DNA damage response genes in maintaining the genetic integrity of germ cells. This study provides evidence of genetic links between age of menopause and cancer risk., (© 2024. The Author(s).)

Background: Diagnosis of a child with a genetic condition leads to parents asking whether there is a risk the condition could occur again with future pregnancies. If the cause is identified as an apparent de novo mutation (DNM), couples are currently given a generic, population average, recurrence risk of ~1%-2%, depending on the condition. Although DNMs usually arise as one-off events, they can also originate through the process of mosaicism in either parent; in this instance, the DNM is present in multiple germ cells and the actual recurrence risk could theoretically be as high as 50%., Methods: Our qualitative interview study examined the views and reflections on current practice provided by UK practitioners working in clinical genetics (n=20) regarding the potential impact of PREcision Genetic Counselling And REproduction (PREGCARE)-a new preconception personalised recurrence risk assessment strategy., Results: Those interviewed regarded PREGCARE as a very useful addition to risk management, especially for cases where it revised the risk downwards or clarified that a couple's personalised recurrence risk meets National Health Service thresholds for non-invasive prenatal testing, otherwise inaccessible based on the generic DNM recurrence risk., Conclusion: Participants said it could release some couples requiring reassurance from undergoing unnecessary invasive testing in future pregnancies. However, they regarded mosaicism and PREGCARE as complex concepts to communicate, requiring further training and additional appointment time for pre-test genetic counselling to prepare couples for all the possible outcomes of a personalised risk assessment, including potentially identifying the parental origin of the DNM, and to ensure informed consent., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)