Genetics and Epidemiology
Permanent URI for this collection
Browse
Recent Submissions
Item tPA supplementation preserves neurovascular and cognitive function in Tg2576 mice.(WILEY, 2024-07-01) Uekawa, K; Anfray, A; Ahn, SJ; Casey, N; Seo, J; Zhou, P; Iadecola, C; Park, LINTRODUCTION: Amyloid beta (Aβ) impairs the cerebral blood flow (CBF) increase induced by neural activity (functional hyperemia). Tissue plasminogen activator (tPA) is required for functional hyperemia, and in mouse models of Aβ accumulation tPA deficiency contributes to neurovascular and cognitive impairment. However, it remains unknown if tPA supplementation can rescue Aβ-induced neurovascular and cognitive dysfunction. METHODS: Tg2576 mice and wild-type littermates received intranasal tPA (0.8 mg/kg/day) or vehicle 5 days a week starting at 11 to 12 months of age and were assessed 3 months later. RESULTS: Treatment of Tg2576 mice with tPA restored resting CBF, prevented the attenuation in functional hyperemia, and improved nesting behavior. These effects were associated with reduced cerebral atrophy and cerebral amyloid angiopathy, but not parenchymal amyloid. DISCUSSION: These findings highlight the key role of tPA deficiency in the neurovascular and cognitive dysfunction associated with amyloid pathology, and suggest potential therapeutic strategies involving tPA reconstitution. HIGHLIGHTS: Amyloid beta (Aβ) induces neurovascular dysfunction and impairs the increase of cerebral blood flow induced by neural activity (functional hyperemia). Tissue plasminogen activator (tPA) deficiency contributes to the neurovascular and cognitive dysfunction caused by Aβ. In mice with florid amyloid pathology intranasal administration of tPA rescues the neurovascular and cognitive dysfunction and reduces brain atrophy and cerebral amyloid angiopathy. tPA deficiency plays a crucial role in neurovascular and cognitive dysfunction induced by Aβ and tPA reconstitution may be of therapeutic value.Item Extent of investigation and management of cases of 'unexplained' mismatch repair deficiency (u-dMMR): a UK Cancer Genetics Group consensus.(BMJ PUBLISHING GROUP, 2024-06-20) McVeigh, TP; Monahan, KJ; Christopher, J; West, N; Scott, M; Murray, J; Hanson, H; UKCGG dMMR Consensus Meeting Attendees; McVeigh, TerriBACKGROUND: Mismatch repair deficiency (dMMR) is a characteristic feature of cancers linked to Lynch syndrome. However, in most cases, it results from sporadic somatic events rather than hereditary factors. The term 'Lynch-like syndrome' (LLS) has been used to guide colorectal cancer surveillance for relatives of individuals with a dMMR tumour when somatic and germline genomic testing is uninformative. As the assessment of mismatch repair through immunohistochemistry and/or microsatellite instability is increasingly applied across various tumour types for treatment planning, dMMR is increasingly detected in tumours where suspicion of hereditary aetiology is low. Our objective was to establish current practices and develop national guidance for investigating, and managing relatives of, patients with cancers demonstrating unexplained dMMR. METHODS: This was achieved through a virtual consensus meeting involving key stakeholders from the UK, through premeeting surveys, structured discussions and in-meeting polling to formulate best practice guidance. RESULTS: We identified variability in the availability of diagnostic technologies across specialist centres. It was agreed that equitable access to baseline testing is required, acknowledging the need for a pragmatic approach to investigating dMMR cancers not traditionally associated with Lynch syndrome. Factors such as family history, age, tumour type, protein loss pattern and extent of the investigation were deemed crucial in guiding family management. The term 'unexplained dMMR' was recommended over LLS. CONCLUSION: Decisions regarding investigations and future cancer risk management in patients and relatives should be nuanced, considering factors like clinical suspicion of hereditary predisposition to allocate limited resources efficiently and avoid unnecessary investigations in low-suspicion families.Item Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants That Confer Risk for Breast Cancer.(AMER ASSOC CANCER RESEARCH, 2024-08-01) Sun, X; Verma, SP; Jia, G; Wang, X; Ping, J; Guo, X; Shu, X-O; Chen, J; Derkach, A; Cai, Q; Liang, X; Long, J; Offit, K; Oh, JH; Reiner, AS; Watt, GP; Woods, M; Yang, Y; Ambrosone, CB; Ambs, S; Chen, Y; Concannon, P; Garcia-Closas, M; Gu, J; Haiman, CA; Hu, JJ; Huo, D; John, EM; Knight, JA; Li, CI; Lynch, CF; Mellemkjær, L; Nathanson, KL; Nemesure, B; Olopade, OI; Olshan, AF; Pal, T; Palmer, JR; Press, MF; Sanderson, M; Sandler, DP; Troester, MA; Zheng, W; Bernstein, JL; Buas, MF; Shu, X; Garcia-Closas, MontserratBreast cancer includes several subtypes with distinct characteristic biological, pathologic, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate the development of improved prevention and treatment approaches. In this study, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case genome-wide association study (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead variants in 12 loci remained statistically significant after accounting for previously reported breast cancer susceptibility variants, among which, two were genome-wide significant. Fine mapping implicated putative functional/causal variants and risk genes at several loci, e.g., 3q26.31/TNFSF10, 8q22.3/NACAP1/GRHL2, and 8q23.3/LINC00536/TRPS1, for TNBC as compared with luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates the enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to two-fold increased risk of being diagnosed with TNBC instead of luminal cancers. The CC-GWAS PRS remained statistically significant after adjusting for TNBC PRS derived from traditional case-control GWAS in The Cancer Genome Atlas and the African Ancestry Breast Cancer Genetic Consortium. The CC-GWAS PRS was also associated with overall survival and disease-specific survival among patients with breast cancer. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC. Significance: The discovery of subtype-informative genetic risk variants for breast cancer advances our understanding of the etiologic heterogeneity of breast cancer, which could accelerate the identification of targets and personalized strategies for prevention and treatment.Item Weekly ultra-hypofractionated radiotherapy in localised prostate cancer.(ELSEVIER IRELAND LTD, 2024-07-01) Sundahl, N; Brand, D; Parker, C; Dearnaley, D; Tree, A; Pathmanathan, A; Suh, Y-E; Van As, N; Eeles, R; Khoo, V; Huddart, R; Murray, J; Brand, Douglas; Dearnaley, David; Eeles, Rosalind; Huddart, Robert; Murray, JuliaBACKGROUND: Moderately hypofractionated radiotherapy regimens or stereotactic body radiotherapy (SBRT) are standard of care for localised prostate cancer. However, some patients are unable or unwilling to travel daily to the radiotherapy department and do not have access to, or are not candidates for, SBRT. For many years, The Royal Marsden Hospital NHS Foundation Trust has offered a weekly ultra-hypofractionated radiotherapy regimen to the prostate (36 Gy in 6 weekly fractions) to patients unable/unwilling to travel daily. METHODS: The current study is a retrospective analysis of all patients with non-metastatic localised prostate cancer receiving this treatment schedule from 2010 to 2015. RESULTS: A total of 140 patients were included in the analysis, of whom 86 % presented with high risk disease, with 31 % having Gleason Grade Group 4 or 5 disease and 48 % T3 disease or higher. All patients received hormone treatment, and there was often a long interval between start of hormone treatment and start of radiotherapy (median of 11 months), with 34 % of all patients having progressed to non-metastatic castrate-resistant disease prior to start of radiotherapy. Median follow-up was 52 months. Median progression-free survival (PFS) and overall survival (OS) for the whole group was 70 months and 72 months, respectively. PFS and OS in patients with hormone-sensitive disease at time of radiotherapy was not reached and 75 months, respectively; and in patients with castrate-resistant disease at time of radiotherapy it was 20 months and 61 months, respectively. CONCLUSION: Our data shows that a weekly ultra-hypofractionated radiotherapy regimen for prostate cancer could be an option in those patients for whom daily treatment or SBRT is not an option.Item Deciphering the genetics and mechanisms of predisposition to multiple myeloma.(NATURE PORTFOLIO, 2024-08-05) Went, M; Duran-Lozano, L; Halldorsson, GH; Gunnell, A; Ugidos-Damboriena, N; Law, P; Ekdahl, L; Sud, A; Thorleifsson, G; Thodberg, M; Olafsdottir, T; Lamarca-Arrizabalaga, A; Cafaro, C; Niroula, A; Ajore, R; Lopez de Lapuente Portilla, A; Ali, Z; Pertesi, M; Goldschmidt, H; Stefansdottir, L; Kristinsson, SY; Stacey, SN; Love, TJ; Rognvaldsson, S; Hajek, R; Vodicka, P; Pettersson-Kymmer, U; Späth, F; Schinke, C; Van Rhee, F; Sulem, P; Ferkingstad, E; Hjorleifsson Eldjarn, G; Mellqvist, U-H; Jonsdottir, I; Morgan, G; Sonneveld, P; Waage, A; Weinhold, N; Thomsen, H; Försti, A; Hansson, M; Juul-Vangsted, A; Thorsteinsdottir, U; Hemminki, K; Kaiser, M; Rafnar, T; Stefansson, K; Houlston, R; Nilsson, B; Went, Molly; Gunnell, Andrea; Law, Philip; Sud, Amit; Kaiser, Martin; Houlston, RichardMultiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development.