ORCID Profile
0000-0003-3324-4338
Current Organisations
University of Oxford
,
University of Southampton
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Springer Science and Business Media LLC
Date: 14-02-2012
DOI: 10.1038/BJC.2012.31
Publisher: Springer Science and Business Media LLC
Date: 07-08-2011
DOI: 10.1038/NG.893
Publisher: Springer Science and Business Media LLC
Date: 30-03-2008
DOI: 10.1038/NG.111
Abstract: To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.
Publisher: Springer Science and Business Media LLC
Date: 15-05-2012
DOI: 10.1038/BJC.2012.160
Publisher: Oxford University Press (OUP)
Date: 27-08-2008
DOI: 10.1093/HMG/DDN267
Abstract: The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10 638 cases and 10 457 healthy in iduals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17 95% confidence interval [CI]: 1.12-1.22 P = 1.08 x 10(-12)) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (OR(per allele) = 1.19 95% CI: 1.15-1.23 P(trend) = 7.4 x 10(-24)). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2007
DOI: 10.1158/1055-9965.EPI-06-0829
Abstract: Background: Early menarche and late menopause are important risk factors for breast cancer, but their effects on breast cancer risk in BRCA1 and BRCA2 carriers are unknown. Methods: We assessed breast cancer risk in a large series of 1,187 BRCA1 and 414 BRCA2 carriers from the International BRCA1/2 Carrier Cohort Study. Rate ratios were estimated using a weighted Cox-regression approach. Results: Breast cancer risk was not significantly related to age at menopause {hazard ratio [HR] for menopause below age 35 years, 0.60 [95% confidence interval (95% CI), 0.25-1.44] 35 to 40 years, 1.15 [0.65-2.04] 45 to 54 years, 1.02 [0.65-1.60] ≥55 years, 1.12 [0.12-5.02], as compared with premenopausal women}. However, there was some suggestion of a reduction in risk after menopause in BRCA2 carriers. There was some evidence of a protective effect of oophorectomy (HR, 0.56 95% CI, 0.29-1.09) and a significant trend of decreasing risk with increasing time since oophorectomy, but no apparent effect of natural menopause. There was no association between age at menarche and breast cancer risk, nor any apparent association with the estimated total duration of breast mitotic activity. Conclusions: These results are consistent with other observations suggesting a protective effect of oophorectomy, similar in relative effect to that in the general population. The absence of an effect of age at natural menopause is, however, not consistent with findings in the general population and may reflect the different natural history of the disease in carriers. (Cancer Epidemiol Biomarkers Prev 2007 (4):740–6)
Publisher: Elsevier BV
Date: 07-2021
Publisher: Springer Science and Business Media LLC
Date: 17-11-2022
DOI: 10.1186/S12910-022-00853-1
Abstract: Public health scholars have long called for preparedness to help better negotiate ethical issues that emerge during public health emergencies. In this paper we argue that the concept of ethical preparedness has much to offer other areas of health beyond pandemic emergencies, particularly in areas where rapid technological developments have the potential to transform aspects of health research and care, as well as the relationship between them. We do this by viewing the ethical decision-making process as a behaviour, and conceptualising ethical preparedness as providing a health research/care setting that can facilitate the promotion of this behaviour. We draw on an implementation science and behaviour change model, COM-B, to demonstrate that to be ethically prepared requires having the capability (ability), opportunity , and motivation (willingness) to work in an ethically prepared way. We use two case ex les from our empirical research—one pandemic and one non-pandemic related—to illustrate how our conceptualisation of ethical preparedness can be applied in practice. The first case study was of the UK NHSX COVID-19 contact tracing application case study involved eight in-depth interviews with people involved with the development/governance of this application. The second case involved a complex case regarding familial communication discussed at the UK Genethics Forum. We used deductive qualitative analysis based on the COM-B model categories to analyse the transcripbed data from each case study. Our analysis highlighted that being ethically prepared needs to go beyond merely equipping health professionals with skills and knowledge, or providing research governance actors with ethical principles and/or frameworks. To allow or support these different actors to utilise their skills and knowledge (or principles and frameworks), a focus on the physical and social opportunity is important, as is a better understanding the role of motivation. To understand ethical preparedness, we need to view the process of ethical decision-making as a behaviour. We have provided insight into the specific factors that are needed to promote this behaviour—using ex les from both in the pandemic context as well as in areas of health research and medicine where there have been rapid technological developments. This offers a useful starting point for further conceptual work around the notion of being ethically prepared.
Publisher: BMJ
Date: 13-03-2020
DOI: 10.1136/JMEDGENET-2019-106759
Abstract: Advances in technology have led to a massive expansion in the capacity for genomic analysis, with a commensurate fall in costs. The clinical indications for genomic testing have evolved markedly the volume of clinical sequencing has increased dramatically and the range of clinical professionals involved in the process has broadened. There is general acceptance that our early dichotomous paradigms of variants being pathogenic–high risk and benign–no risk are overly simplistic. There is increasing recognition that the clinical interpretation of genomic data requires significant expertise in disease–gene-variant associations specific to each disease area. Inaccurate interpretation can lead to clinical mismanagement, inconsistent information within families and misdirection of resources. It is for this reason that ‘national subspecialist multidisciplinary meetings’ (MDMs) for genomic interpretation have been articulated as key for the new NHS Genomic Medicine Service, of which Cancer Variant Interpretation Group UK (CanVIG-UK) is an early exemplar. CanVIG-UK was established in 2017 and now has UK members, including at least one clinical diagnostic scientist and one clinical cancer geneticist from each of the 25 regional molecular genetics laboratories of the UK and Ireland. Through CanVIG-UK, we have established national consensus around variant interpretation for cancer susceptibility genes via monthly national teleconferenced MDMs and collaborative data sharing using a secure online portal. We describe here the activities of CanVIG-UK, including exemplar outputs and feedback from the membership.
Publisher: Springer Science and Business Media LLC
Date: 20-05-2011
Publisher: Public Library of Science (PLoS)
Date: 27-03-2013
Publisher: Springer Science and Business Media LLC
Date: 04-06-2008
Publisher: Oxford University Press (OUP)
Date: 04-2013
DOI: 10.1093/JNCI/DJT095
Abstract: Reliable estimates of cancer risk are critical for guiding management of BRCA1 and BRCA2 mutation carriers. The aims of this study were to derive penetrance estimates for breast cancer, ovarian cancer, and contralateral breast cancer in a prospective series of mutation carriers and to assess how these risks are modified by common breast cancer susceptibility alleles. Prospective cancer risks were estimated using a cohort of 978 BRCA1 and 909 BRCA2 carriers from the United Kingdom. Nine hundred eighty-eight women had no breast or ovarian cancer diagnosis at baseline, 1509 women were unaffected by ovarian cancer, and 651 had been diagnosed with unilateral breast cancer. Cumulative risks were obtained using Kaplan-Meier estimates. Associations between cancer risk and covariables of interest were evaluated using Cox regression. All statistical tests were two-sided. The average cumulative risks by age 70 years for BRCA1 carriers were estimated to be 60% (95% confidence interval [CI] = 44% to 75%) for breast cancer, 59% (95% CI = 43% to 76%) for ovarian cancer, and 83% (95% CI = 69% to 94%) for contralateral breast cancer. For BRCA2 carriers, the corresponding risks were 55% (95% CI = 41% to 70%) for breast cancer, 16.5% (95% CI = 7.5% to 34%) for ovarian cancer, and 62% (95% CI = 44% to 79.5%) for contralateral breast cancer. BRCA2 carriers in the highest tertile of risk, defined by the joint genotype distribution of seven single nucleotide polymorphisms associated with breast cancer risk, were at statistically significantly higher risk of developing breast cancer than those in the lowest tertile (hazard ratio = 4.1, 95% CI = 1.2 to 14.5 P = .02). Prospective risk estimates confirm that BRCA1 and BRCA2 carriers are at high risk of developing breast, ovarian, and contralateral breast cancer. Our results confirm findings from retrospective studies that common breast cancer susceptibility alleles in combination are predictive of breast cancer risk for BRCA2 carriers.
Publisher: Springer Science and Business Media LLC
Date: 17-11-2009
Publisher: Springer Science and Business Media LLC
Date: 11-10-2018
Publisher: Mary Ann Liebert Inc
Date: 06-2023
Abstract: The past few decades have seen rapid increases in the size and scope of biobanks, with large-scale publicly funded ventures supporting health-related research becoming the norm. As these biobanks are increasingly asked to share their data, including for ex le, genome-wide analyses, questions arise about how such decisions are made, including whether applicants' research aligns with the aims of the biobank. To better understand how biobanks make decisions relating to their data use, we sought the views and experiences of those involved in decision-making relating to data access at 11 large-scale publicly funded health biobanks. We were particularly interested in how potentially contentious applications were approached. Interviewees had some concerns about decisions on applications they felt their governance structures could not reach. We ask broader questions about the responsibility of those involved in biobank access decisions-those working early in the research process-when considering such issues.
Publisher: Springer Science and Business Media LLC
Date: 04-2012
DOI: 10.1186/BCR3169
Publisher: American Association for Cancer Research (AACR)
Date: 11-2010
DOI: 10.1158/1055-9965.EPI-10-0517
Abstract: Background: The genes caspase-8 (CASP8) and caspase-10 (CASP10) functionally cooperate and play a key role in the initiation of apoptosis. Suppression of apoptosis is one of the major mechanisms underlying the origin and progression of cancer. Previous case-control studies have indicated that the polymorphisms CASP8 D302H and CASP10 V410I are associated with a reduced risk of breast cancer in the general population. Methods: To evaluate whether the CASP8 D302H (CASP10 V410I) polymorphisms modify breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers, we analyzed 7,353 (7,227) subjects of white European origin provided by 19 (18) study groups that participate in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A weighted cohort approach was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). Results: The minor allele of CASP8 D302H was significantly associated with a reduced risk of breast cancer (per-allele HR, 0.85 95% CI, 0.76-0.97 Ptrend = 0.011) and ovarian cancer (per-allele HR, 0.69 95% CI, 0.53-0.89 Ptrend = 0.004) for BRCA1 but not for BRCA2 mutation carriers. The CASP10 V410I polymorphism was not associated with breast or ovarian cancer risk for BRCA1 or BRCA2 mutation carriers. Conclusions: CASP8 D302H decreases breast and ovarian cancer risk for BRCA1 mutation carriers but not for BRCA2 mutation carriers. Impact: The combined application of these and other recently identified genetic risk modifiers could in the future allow better in idual risk calculation and could aid in the in idualized counseling and decision making with respect to preventive options in BRCA1 mutation carriers. Cancer Epidemiol Biomarkers Prev 19(11) 2859–68. ©2010 AACR.
Publisher: Oxford University Press (OUP)
Date: 30-01-2012
Publisher: Springer Science and Business Media LLC
Date: 23-12-2012
DOI: 10.1038/NG.2503
Publisher: Springer Science and Business Media LLC
Date: 11-12-2008
Publisher: Springer Science and Business Media LLC
Date: 10-06-2009
DOI: 10.1007/S10549-008-0083-5
Abstract: The p27(kip1) protein functions as an inhibitor of cyclin dependent kinase-2, and shows loss of expression in a large percentage of BRCA1 and BRCA2 breast cancer cases. We investigated the association between CDKN1B gene variants and breast cancer risk in 2359 female BRCA1 and BRCA2 mutation carriers from Australia, the UK, and the USA. S les were genotyped for five single nucleotide polymorphisms, including coding variant rs2066827 (V109G). Cox regression provided no convincing evidence that any of the polymorphisms modified disease risk for BRCA1 or BRCA2 carriers, either alone or as a haplotype. Borderline associations were observed for homozygote carriers of the rs3759216 rare allele, but were opposite in effect for BRCA1 and BRCA2 carriers (adjusted hazard ratio (HR) 0.72 (95% CI = 0.53-0.99 P = 0.04 for BRCA1, HR 1.47 (95% CI = 0.99-2.18 P = 0.06 for BRCA2). The 95% confidence intervals for per allele risk estimates excluded a twofold risk, indicating that common CDKN1B polymorphisms do not markedly modify breast cancer risk among BRCA1 or BRCA2 carriers.
Publisher: Informa UK Limited
Date: 24-02-2022
Publisher: Cambridge University Press (CUP)
Date: 26-09-2023
DOI: 10.1017/PCM.2022.1
Abstract: Opportunities offered by precision medicine have long been promised in the medical and health literature. However, precision medicine – and the methodologies and approaches it relies on – also has adverse environmental impacts. As research into precision medicine continues to expand, there is a compelling need to consider these environmental impacts and develop means to mitigate them. In this article, we review the adverse environmental impacts associated with precision medicine, with a particular focus on those associated with its underlying need for data-intensive approaches. We illustrate the importance of considering the environmental impacts of precision medicine and describe the adverse health outcomes that are associated with climate change. We follow this with a description of how these environmental impacts are being addressed in both the health and data-driven technology sector. We then describe the (scant) literature on environmental impacts associated with data-driven precision medicine specifically. We finish by highlighting various environmental considerations that precision medicine researchers, and the field more broadly, should take into account.
Publisher: Springer Science and Business Media LLC
Date: 16-12-2012
DOI: 10.1038/NATURE11725
Publisher: SAGE Publications
Date: 2022
DOI: 10.1177/20552076221111297
Abstract: Data-Driven and Artificial Intelligence technologies are rapidly changing the way that health research is conducted, including offering new opportunities. This will inevitably have adverse environmental impacts. These include carbon dioxide emissions linked to the energy required to generate and process large amounts of data the impact on the material environment (in the form of data centres) the unsustainable extraction of minerals for technological components and e-waste (discarded electronic appliances) disposal. The growth of Data-Driven and Artificial Intelligence technologies means there is now a compelling need to consider these environmental impacts and develop means to mitigate them. Here, we offer a scoping review of how the environmental impacts of data storage and processing during Data-Driven and Artificial Intelligence health-related research are being discussed in the academic literature. Using the UK as a case study, we also offer a review of policies and initiatives that consider the environmental impacts of data storage and processing during Data-Driven and Artificial Intelligence health-related research in the UK. Our findings suggest little engagement with these issues to date. We discuss the implications of this and suggest ways that the Data-Driven and Artificial Intelligence health research sector needs to move to become more environmentally sustainable.
Publisher: Elsevier BV
Date: 12-2007
DOI: 10.1086/522611
Publisher: Wiley
Date: 29-11-2019
DOI: 10.1002/PD.5611
Abstract: Reproductive carrier screening started in some countries in the 1970s for hemoglobinopathies and Tay-Sachs disease. Cystic fibrosis carrier screening became possible in the late 1980s and with technical advances, screening of an ever increasing number of genes has become possible. The goal of carrier screening is to inform people about their risk of having children with autosomal recessive and X-linked recessive disorders, to allow for informed decision making about reproductive options. The consequence may be a decrease in the birth prevalence of these conditions, which has occurred in several countries for some conditions. Different programs target different groups (high school, premarital, couples before conception, couples attending fertility clinics, and pregnant women) as does the governance structure (public health initiative and user pays). Ancestry-based offers of screening are being replaced by expanded carrier screening panels with multiple genes that is independent of ancestry. This review describes screening in Australia, Cyprus, Israel, Italy, Malaysia, the Netherlands, Saudi Arabia, the United Kingdom, and the United States. It provides an insight into the enormous variability in how reproductive carrier screening is offered across the globe. This largely relates to geographical variation in carrier frequencies of genetic conditions and local health care, financial, cultural, and religious factors.
Publisher: Springer Science and Business Media LLC
Date: 18-11-2009
Publisher: Mary Ann Liebert Inc
Date: 06-2022
Abstract: Low levels of public trust in biobanks are perceived to be a deterrent to participation and a threat to their sustainability. Acting in a "trustworthy" manner is seen to be one approach to ensuring public trust in biobanks. Striving to improve public trust in biobanks and prioritizing the need for institutional trustworthiness are both vital endeavors. However, there has been little discussion in the context of biobanking about the meaning of these two concepts, and the relationship between them. In this article, we argue that it is important to examine this, to ensure clarity around their meaning, as well as their relationship with each other as they apply to biobanking. We conclude by making a series of recommendations for biobanks.
Publisher: BMJ
Date: 18-11-2020
DOI: 10.1136/JMEDGENET-2020-107248
Abstract: Accurate classification of variants in cancer susceptibility genes (CSGs) is key for correct estimation of cancer risk and management of patients. Consistency in the weighting assigned to in idual elements of evidence has been much improved by the American College of Medical Genetics (ACMG) 2015 framework for variant classification, UK Association for Clinical Genomic Science (UK-ACGS) Best Practice Guidelines and subsequent Cancer Variant Interpretation Group UK (CanVIG-UK) consensus specification for CSGs. However, considerable inconsistency persists regarding practice in the combination of evidence elements. CanVIG-UK is a national subspecialist multidisciplinary network for cancer susceptibility genomic variant interpretation, comprising clinical scientist and clinical geneticist representation from each of the 25 diagnostic laboratories/clinical genetic units across the UK and Republic of Ireland. Here, we summarise the aggregated evidence elements and combinations possible within different variant classification schemata currently employed for CSGs (ACMG, UK-ACGS, CanVIG-UK and ClinGen gene-specific guidance for PTEN, TP53 and CDH1). We present consensus recommendations from CanVIG-UK regarding (1) consistent scoring for combinations of evidence elements using a validated numerical ‘exponent score’ (2) new combinations of evidence elements constituting likely pathogenic’ and ‘pathogenic’ classification categories, (3) which evidence elements can and cannot be used in combination for specific variant types and (4) classification of variants for which there are evidence elements for both pathogenicity and benignity.
Publisher: Springer Science and Business Media LLC
Date: 08-08-2017
Publisher: Springer Science and Business Media LLC
Date: 03-1995
DOI: 10.1038/NG0395-284
Abstract: The IDDM2 locus encoding susceptibility to type 1 diabetes was mapped previously to a 4.1-kb region spanning the insulin gene and a minisatellite or variable number of tandem repeats (VNTR) locus on human chromosome 11p15.5. By 'cross-match' haplotype analysis and linkage disequilibrium mapping, we have mapped the mutation IDDM2 to within the VNTR itself. Other polymorphisms were systematically excluded as primary disease determinants. Transmission of IDDM2 may be influenced by parent-of-origin phenomena. Although we show that the insulin gene is expressed biallelically in the adult pancreas, we present preliminary evidence that the level of transcription in vivo is correlated with allelic variation within the VNTR. Allelic variation at VNTRs may play an important general role in human disease.
Publisher: Oxford University Press (OUP)
Date: 23-04-2010
DOI: 10.1093/HMG/DDQ174
Publisher: BMJ
Date: 20-06-2022
DOI: 10.1136/MEDETHICS-2021-108102
Abstract: Centralised, compliance-focused approaches to research ethics have been normalised in practice. In this paper, we argue that the dominance of such systems has been driven by neoliberal approaches to governance, where the focus on controlling and in idualising risk has led to an overemphasis of decontextualised ethical principles and the conflation of ethical requirements with the documentation of ‘informed consent’. Using a UK-based case study, involving a point-of-care-genetic test as an illustration, we argue that rather than ensuring ethical practice such compliance-focused approaches may obstruct valuable research. We call for an approach that encourages researchers and research communities—including regulators, ethics committees, funders and publishers of academic research—to acquire skills to make morally appropriate decisions, and not base decision-making solely on compliance with prescriptive regulations. We call this ‘ethical preparedness’ and outline how a research ethics system might make space for this approach.
Publisher: Springer Science and Business Media LLC
Date: 27-05-2012
DOI: 10.1038/NG.2293
Publisher: Oxford University Press (OUP)
Date: 02-09-2011
DOI: 10.1093/HMG/DDR388
Publisher: Informa UK Limited
Date: 03-07-2018
Publisher: BMJ
Date: 03-2018
DOI: 10.1136/MEDETHICS-2017-104588
Abstract: Clinical practice and research are governed by distinct rules and regulations and have different approaches to, for ex le, consent and providing results. However, genomics is an ex le of where research and clinical practice have become codependent. The 100 000 genomes project (100kGP) is a hybrid venture where a person can obtain a clinical investigation only if he or she agrees to also participate in ongoing research—including research by industry and commercial companies. In this paper, which draws on 20 interviews with professional stakeholders involved in 100kGP, we investigate the ethical issues raised by this project’s hybrid nature. While some interviewees thought the hybrid nature of 100kGP was its vanguard, interviewees identified several tensions around hybrid practice: how to decide who should be able to participate how to determine whether offering results might unduly influence participation into wide-ranging but often as yet unknown research and how to ensure that patients/families do not develop false expectations about receiving results. These areas require further debate as 100kGP moves into routine healthcare in the form of the national genomic medicine service. To address the tensions identified, we explore the appropriateness of Faden et al.’s framework of ethical obligations for when research and clinical care are completely integrated. We also argue that enabling ongoing transparent and trustworthy communication between patients/families and professionals around the kinds of research that should be permitted in 100kGP will help to understand and ensure that expectations remain realistic. Our paper aims to encourage a focused discussion about these issues and to inform a new ‘social contract’ for research and clinical care in the health service.
Publisher: Springer Science and Business Media LLC
Date: 12-01-2015
DOI: 10.1038/NG.3185
Publisher: Springer Science and Business Media LLC
Date: 08-1995
DOI: 10.1038/NG0895-379
Publisher: The Endocrine Society
Date: 10-2008
DOI: 10.1210/JC.2008-1003
Abstract: Germline mutations in AIP have been recently shown to cause pituitary adenoma predisposition (PAP). Subsequently, many intragenic germline mutations have been reported, both in familial and in sporadic settings. Our objective was to evaluate the possible contribution of large genomic germline AIP deletions, an important mutation type in tumor predisposition syndromes, in PAP. Here, we applied the multiplex ligation-dependent probe lification assay to examine whether large genomic AIP or MEN1 alterations account for a subset of PAP cases. The study was performed on familial and sporadic pituitary adenoma cases of European origin, which had previously tested negative for germline AIP and MEN1 mutations by sequencing. Two of 21 pituitary adenoma families (9.5%) were found to harbor an AIP deletion. No copy number changes were detected among 67 sporadic pituitary adenoma patients. No MEN1 deletions were found. The present study shows that large genomic AIP deletions account for a subset of PAP. Therefore, in suspected PAP cases undergoing counseling and AIP genetic testing, multiplex ligation-dependent probe lification could be considered if direct sequencing does not identify a mutation.
Publisher: Public Library of Science (PLoS)
Date: 29-06-2012
Publisher: Elsevier BV
Date: 11-2021
Publisher: Springer Science and Business Media LLC
Date: 25-04-2015
Publisher: The Endocrine Society
Date: 08-2007
DOI: 10.1210/JC.2006-2843
Abstract: Context: Germline mutations in the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome, but in up to 20–25% of clinical MEN1 cases, no MEN1 mutations can be found. Recently, a germline mutation in the CDKN1B gene, encoding p27Kip1, was reported in one suspected MEN1 family with two acromegalic patients. Objective: Our objective was to evaluate the role of CDKN1B 27Kip1 in human tumor predisposition in patients clinically suspected of MEN1 but testing negative for MEN1 germline mutation as well as in familial and sporadic acromegaly ituitary adenoma patients. Design: Genomic DNA was analyzed for germline mutations in the CDKN1B 27Kip1 gene by PCR lification and direct sequencing. Setting: The study was conducted at nonprofit academic research and medical centers. Patients: Thirty-six Dutch and one German suspected MEN1 patient, who previously tested negative for germline MEN1 gene mutations, were analyzed. In addition, 19 familial and 50 sporadic acromegaly ituitary adenoma patients from Europe and the United States were included in the study. Main Outcome Measures: We analyzed germline CDKN1B 27Kip1 mutations in in iduals with pituitary adenoma and MEN1-like features. Results: A heterozygous 19-bp duplication (c.59_77dup19) leading to a truncated protein product was identified in one Dutch patient with suspected MEN1 phenotype, pituitary adenoma, carcinoid tumor, and hyperparathyroidism (one of 36, 2.8%). No mutations were detected in either familial or sporadic acromegaly ituitary adenoma patients. Conclusions: Our results support the previous finding that germline CDKN1B 27Kip1 mutations predispose to a human MEN1-like condition. However, such mutations appear uncommon in suspected MEN1 cases and rare or nonexistent in familial or sporadic acromegaly ituitary adenoma patients.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Anneke Lucassen.