Showing papers by "Princess Anne Hospital published in 2011"
Newcastle University1, Royal Melbourne Hospital2, University of Eastern Finland3, Princess Anne Hospital4, St Mary's Hospital5, University of Birmingham6, University of Copenhagen7, Western General Hospital8, Queen Mary University of London9, St George's Hospital10, Karolinska Institutet11, Queen's University Belfast12, University of Cape Town13, Churchill Hospital14, John Hunter Hospital15, Imperial College London16, Leiden University17, University of Leeds18, Leiden University Medical Center19, Erasmus University Rotterdam20, Creighton University Medical Center21
TL;DR: The CAPP2 trial aimed to investigate the antineoplastic effects of aspirin and a resistant starch in carriers of Lynch syndrome, the major form of hereditary colorectal cancer, and long-term follow-up of participants randomly assigned to aspirin or placebo is reported.
828 citations
University of Southern California1, Mayo Clinic2, German Cancer Research Center3, University of North Carolina at Chapel Hill4, Roswell Park Cancer Institute5, University of Melbourne6, Westmead Hospital7, Rutgers University8, University of Erlangen-Nuremberg9, National Institutes of Health10, City of Hope National Medical Center11, University of Helsinki12, Vanderbilt University13, University of Tübingen14, Bosch15, Harvard University16, University of Sydney17, University of Sheffield18, National and Kapodistrian University of Athens19, American Cancer Society20, Princess Anne Hospital21, University of California, Los Angeles22, Kaiser Permanente23, University of Hamburg24, Lund University25, Aristotle University of Thessaloniki26, University of Kansas27, Washington University in St. Louis28, University of Miami29, Agency for Science, Technology and Research30, Stanford University31, Cancer Prevention Institute of California32, University of Oulu33, University of Hawaii at Manoa34, University of Eastern Finland35, Katholieke Universiteit Leuven36, Flanders Institute for Biotechnology37, Karolinska Institutet38, QIMR Berghofer Medical Research Institute39, Boston University40, Fox Chase Cancer Center41, University of Pennsylvania42, University of London43, Guy's and St Thomas' NHS Foundation Trust44, Heidelberg University45, University of Oxford46, Imperial College London47
TL;DR: The results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations in multiple population of women.
Abstract: Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.
291 citations
TL;DR: This clinical trial is the largest ever conducted in the setting of FAP and found a trend of reduced polyp load (number and size) with 600 mg of aspirin daily and RS had no clinical effect on adenomas.
Abstract: Evidence supporting aspirin and resistant starch (RS) for colorectal cancer prevention comes from epidemiologic and laboratory studies (aspirin and RS) and randomized controlled clinical trials (aspirin). Familial adenomatous polyposis (FAP) strikes young people and, untreated, confers virtually a 100% risk of colorectal cancer and early death. We conducted an international, multicenter, randomized, placebo-controlled trial of aspirin (600 mg/d) and/or RS (30 g/d) for from 1 to 12 years to prevent disease progression in FAP patients from 10 to 21 years of age. In a 2 × 2 factorial design, patients were randomly assigned to the following four study arms: aspirin plus RS placebo; RS plus aspirin placebo; aspirin plus RS; RS placebo plus aspirin placebo; they were followed with standard annual clinical examinations including endoscopy. The primary endpoint was polyp number in the rectum and sigmoid colon (at the end of intervention), and the major secondary endpoint was size of the largest polyp. A total of 206 randomized FAP patients commenced intervention, of whom 133 had at least one follow-up endoscopy and were therefore included in the primary analysis. Neither intervention significantly reduced polyp count in the rectum and sigmoid colon: aspirin relative risk = 0.77 (95% CI, 0.54-1.10; versus nonaspirin arms); RS relative risk = 1.05 (95% CI, 0.73-1.49; versus non-RS arms). There was a trend toward a smaller size of largest polyp in patients treated with aspirin versus nonaspirin--mean 3.8 mm versus 5.5 mm for patients treated 1 or more years (adjusted P = 0.09) and mean 3.0 mm versus 6.0 mm for patients treated more than 1 year (P = 0.02); there were similar weaker trends with RS versus non-RS. Exploratory translational endpoints included crypt length (which was significantly shorter in normal-appearing mucosa in the RS group over time) and laboratory measures of proliferation (including Ki67). This clinical trial is the largest ever conducted in the setting of FAP and found a trend of reduced polyp load (number and size) with 600 mg of aspirin daily. RS had no clinical effect on adenomas.
193 citations
Family Research Institute1, Lawrence Berkeley National Laboratory2, Technion – Israel Institute of Technology3, European Institute of Oncology4, University of Turin5, Tel Aviv University6, Sheba Medical Center7, Pomeranian Medical University8, National Institutes of Health9, University of Pennsylvania10, Novartis11, Netherlands Cancer Institute12, Erasmus University Rotterdam13, Leiden University14, Radboud University Nijmegen15, Utrecht University16, University of Amsterdam17, VU University Amsterdam18, Maastricht University19, University of Cambridge20, Central Manchester University Hospitals NHS Foundation Trust21, The Royal Marsden NHS Foundation Trust22, Guy's and St Thomas' NHS Foundation Trust23, St James's University Hospital24, Princess Anne Hospital25, Newcastle upon Tyne Hospitals NHS Foundation Trust26, Royal Devon and Exeter Hospital27, University of Helsinki28, Mayo Clinic29, University of Kansas30, University of Pisa31, University of Gothenburg32, Uppsala University33, Karolinska Institutet34, German Cancer Research Center35, Memorial Hospital of South Bend36, Complutense University of Madrid37, University of Zaragoza38, University of Rostock39, University of Hamburg40, University of Michigan41, Memorial Sloan Kettering Cancer Center42, Pompeu Fabra University43, Latvian Biomedical Research and Study centre44, University of Utah45, Cancer Prevention Institute of California46, Harvard University47, University of Melbourne48, Fox Chase Cancer Center49, University of Cologne50, Technische Universität München51, University of Kiel52, University of Ulm53, Charité54, Heidelberg University55, University of Düsseldorf56, University of Paris57, University of Lyon58, University of Franche-Comté59, QIMR Berghofer Medical Research Institute60, New York University61
TL;DR: Cell biological analysis of the protein product suggests a function in regulating development of the mammary gland and genetic analysis identifies the HMMR gene as a modifier of the breast cancer risk associated with BRCA1 gene mutation.
Abstract: Differentiated mammary epithelium shows apicobasal polarity, and loss of tissue organization is an early hallmark of breast carcinogenesis. In BRCA1 mutation carriers, accumulation of stem and progenitor cells in normal breast tissue and increased risk of developing tumors of basal-like type suggest that BRCA1 regulates stem/progenitor cell proliferation and differentiation. However, the function of BRCA1 in this process and its link to carcinogenesis remain unknown. Here we depict a molecular mechanism involving BRCA1 and RHAMM that regulates apicobasal polarity and, when perturbed, may increase risk of breast cancer. Starting from complementary genetic analyses across families and populations, we identified common genetic variation at the low-penetrance susceptibility HMMR locus (encoding for RHAMM) that modifies breast cancer risk among BRCA1, but probably not BRCA2, mutation carriers: n = 7,584, weighted hazard ratio ((w)HR) = 1.09 (95% CI 1.02-1.16), p(trend) = 0.017; and n = 3,965, (w)HR = 1.04 (95% CI 0.94-1.16), p(trend) = 0.43; respectively. Subsequently, studies of MCF10A apicobasal polarization revealed a central role for BRCA1 and RHAMM, together with AURKA and TPX2, in essential reorganization of microtubules. Mechanistically, reorganization is facilitated by BRCA1 and impaired by AURKA, which is regulated by negative feedback involving RHAMM and TPX2. Taken together, our data provide fundamental insight into apicobasal polarization through BRCA1 function, which may explain the expanded cell subsets and characteristic tumor type accompanying BRCA1 mutation, while also linking this process to sporadic breast cancer through perturbation of HMMR/RHAMM.
190 citations
Institute of Cancer Research1, The Royal Marsden NHS Foundation Trust2, Royal Liverpool University Hospital3, Royal Melbourne Hospital4, Repatriation General Hospital5, University of Adelaide6, St Mary's Hospital7, Princess Anne Hospital8, Westmead Hospital9, St George's Hospital10, Churchill Hospital11, Guy's Hospital12, St. Michael's GAA, Sligo13, Royal Devon and Exeter Hospital14, NorthShore University HealthSystem15, Huntsman Cancer Institute16, King Edward Memorial Hospital17, Hospital de Sant Pau18, University of New South Wales19, University of Malaya20, Netherlands Cancer Institute21, Erasmus University Medical Center22, RMIT University23, Imperial College Healthcare24, Umeå University25, John Radcliffe Hospital26, Memorial Sloan Kettering Cancer Center27, Pomeranian Medical University28, Siemens29, Nottingham City Hospital30, University of Texas MD Anderson Cancer Center31, McGill University32, Karolinska University Hospital33, The Cyprus Institute of Neurology and Genetics34, Leiden University Medical Center35, Radboud University Nijmegen36
TL;DR: The IMPACT study as discussed by the authors showed that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer, which supports the rationale for continued screening in such men.
Abstract: What's known on the subject? and What does the study add? Scientists have found a number of genetic factors that increase prostate cancer risk, including heritable mutations in the genes BRCA1 and BRCA2. These mutations are not common but can have major impact, as a BRCA2 mutation increases risk by up to seven-fold while a BRCA1 mutation is thought to double risk in men under 65. The IMPACT study aims to determine whether targeted screening in men with a known BRCA1 or BRCA2 mutation would lead to earlier diagnosis of prostate cancers. This data from the IMPACT study adds to the increasing evidence that BRCA mutation carriers develop more aggressive disease. Although these are early results, it appears that PSA screening is more accurate at predicting potentially aggressive prostate cancer among men at higher risk of the disease due to a genetic predisposition than general population screening. This study provides support for continued screening in men with genetic mutations. OBJECTIVE To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported. PATIENTS AND METHODS Men aged 40-69 years from families with BRCA1 or BRCA2 mutations were offered annual prostate specific antigen (PSA) testing, and those with PSA > 3 ng/mL, were offered a prostate biopsy. Controls were men age-matched (+/- 5 years) who were negative for the familial mutation. RESULTS In total, 300 men were recruited (205 mutation carriers; 89 BRCA1, 116 BRCA2 and 95 controls) over 33 months. At the baseline screen (year 1), 7.0% (21/300) underwent a prostate biopsy. Prostate cancer was diagnosed in ten individuals, a prevalence of 3.3%. The positive predictive value of PSA screening in this cohort was 47 center dot 6% (10/21). One prostate cancer was diagnosed at year 2. Of the 11 prostate cancers diagnosed, nine were in mutation carriers, two in controls, and eight were clinically significant. CONCLUSIONS The present study shows that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer. These results support the rationale for continued screening in such men.
93 citations
Antonis C. Antoniou, Christiana Kartsonaki, Olga M. Sinilnikova1, Penny Soucy +180 more•Institutions (80)
TL;DR: The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.
Abstract: Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.
79 citations
TL;DR: BINOCAR registers can, uniquely, provide contemporary data on PND and birth prevalence rates to enable monitoring of the ultrasound component of FASP at a national and regional level, allowing comparisons between populationstobemade, planning of resourcesfacilitated and assistance for parents making informed decisions on whether to enter the screening programme.
Abstract: Objective: To provide current population-based prevalence and prenatal diagnosis rates (PND) for specified major congenital anomalies in England and Wales to enable monitoring of the Fetal Anomaly Screening Programme (FASP). Design Secondary analysis of prospectively collected registry data. Setting: Seven multiple-source, population-based congenital anomaly registers, members of the British Isles Network of Congenital Anomaly Registers (BINOCAR) in 2005 and 2006. Population: 2,883 births with congenital anomalies from a total of 601,545 live and stillbirths. Main outcome measures: PND and birth prevalence of selected congenital anomaly groups/subtypes (anencephaly, spina-bifida, serious cardiac, diaphragmatic hernia, gastroschisis, exomphalos, bilateral renal agenesis, lethal/severe skeletal dysplasia, cleft lip with or without cleft palate [CL + /–P]). Results: Of the selected anomaly groups, the most frequently reported were serious cardiac (14.1 per 10,000 births [95% CI 13.0–15.2]) and CL + /–P (9.7 per 10,000 births [8.9–10.5]); the least frequent were bilateral renal agenesis and lethal/severe skeletal dysplasia ( Conclusions: BINOCAR registers can, uniquely, provide contemporary data on PND and birth prevalence rates to enable monitoring of the ultrasound component of FASP at a national and regional level, allowing comparisons between populations to be made, planning of resources facilitated and assistance for parents making informed decisions on whether to enter the screening programme.
71 citations
TL;DR: In this paper, the authors describe five unrelated individuals with copy number abnormalities affecting distal chromosome 22q11.2, including diaphragmatic hernia and uterine didelphys associated with the distal microdeletion syndrome.
Abstract: The availability of microarray technology has led to the recent recognition of copy number abnormalities of distal chromosome 22q11.2 that are distinct from the better-characterized deletions and duplications of the proximal region. This report describes five unrelated individuals with copy number abnormalities affecting distal chromosome 22q11.2. We report on novel phenotypic features including diaphragmatic hernia and uterine didelphys associated with the distal microdeletion syndrome; and frontomedial polymicrogyria and callosal agenesis associated with the distal microduplication syndrome. We describe the third distal chromosome 22q11.2 microdeletion patient with Goldenhar syndrome. Patients with distal chromosome 22q11.2 copy number abnormalities exhibit inter- and intra-familial phenotypic variability, and challenge our ability to draw meaningful genotype-phenotype correlations.
55 citations
University of Cambridge1, Duke University2, University of Southern California3, University of Toronto4, University of California, Irvine5, National Institutes of Health6, University of California, San Francisco7, University of Erlangen-Nuremberg8, Harvard University9, Hannover Medical School10, University of North Carolina at Chapel Hill11, University of British Columbia12, Imperial College London13, University of Helsinki14, Complutense University of Madrid15, University of Pisa16, Peter MacCallum Cancer Centre17, University of Melbourne18, German Cancer Research Center19, University of South Florida20, University of New Mexico21, Mayo Clinic22, Katholieke Universiteit Leuven23, Fred Hutchinson Cancer Research Center24, University of Jena25, Princess Anne Hospital26, University of California, Los Angeles27, University of Sydney28, Tel Aviv University29, University of Kansas30, University of Hawaii at Manoa31, Cedars-Sinai Medical Center32, University of Copenhagen33, Netherlands Cancer Institute34, Pomeranian Medical University35, QIMR Berghofer Medical Research Institute36, Memorial Sloan Kettering Cancer Center37, Alberta Health Services38, Radboud University Nijmegen39, Bayfront Health St. Petersburg40, University College London41, Roswell Park Cancer Institute42, University of Pennsylvania43, University of Texas Health Science Center at Houston44, Carlos III Health Institute45, University of Glasgow46, Medical University of Vienna47, Karolinska Institutet48, University of Ulm49, University of Cologne50, Yale University51
TL;DR: These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer, and use of this SNP for ovarian cancer clinical risk prediction seems unwarranted.
Abstract: Purpose: An assay for the single-nucleotide polymorphism (SNP), rs61764370, has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3′-UTR miRNA binding site of the KRAS oncogene and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published article, analyzing fewer than 1,000 subjects in total, has examined this association. Experimental Design: Risk association was evaluated in 8,669 cases of invasive EOC and 10,012 controls from 19 studies participating in the Ovarian Cancer Association Consortium, and in 683 cases and 2,044 controls carrying BRCA1 mutations from studies in the Consortium of Investigators of Modifiers of BRCA1/2 . Prognosis association was also examined in a subset of five studies with progression-free survival (PFS) data and 18 studies with all-cause mortality data. Results: No evidence of association was observed between genotype and risk of unselected EOC (OR = 1.02, 95% CI: 0.95–1.10), serous EOC (OR = 1.08, 95% CI: 0.98–1.18), familial EOC (OR = 1.09, 95% CI: 0.78–1.54), or among women carrying deleterious mutations in BRCA1 (OR = 1.09, 95% CI: 0.88–1.36). There was little evidence for association with survival time among unselected cases (HR = 1.10, 95% CI: 0.99–1.22), among serous cases (HR = 1.12, 95% CI = 0.99–1.28), or with PFS in 540 cases treated with carboplatin and paclitaxel (HR = 1.18, 95% CI: 0.93–1.52). Conclusions: These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer. Use of this SNP for ovarian cancer clinical risk prediction, therefore, seems unwarranted. Clin Cancer Res; 17(11); 3742–50. ©2011 AACR .
52 citations
TL;DR: In this article, the authors report six patients with array deletions encompassing 12q14.3q15.1 and reported overlapping deletions of variable extent and size but primarily comprising chromosomal bands 12q13.3qs14.1.
Abstract: We report six patients with array deletions encompassing 12q14. Out of a total of 2538 array investigations carried out on children with developmental delay and dysmorphism in three diagnostic testing centres, six positive cases yielded a frequency of 1 in 423 for this deletion syndrome. The deleted region in each of the six cases overlaps significantly with previously reported cases with microdeletions of this region. The chromosomal range of the deletions extends from 12q13.3q15. In the current study, we report overlapping deletions of variable extent and size but primarily comprising chromosomal bands 12q13.3q14.1. Four of the six deletions were confirmed as de novo events. Two cases had deletions that included HMGA2, and both children had significant short stature. Neither case had osteopoikilosis despite both being deleted for LEMD3. Four cases had deletions that ended proximal to HMGA2 and all of these had much better growth. Five cases had congenital heart defects, including two with atrial septal defects, one each with pulmonary stenosis, sub-aortic stenosis and a patent ductus. Four cases had moderate delay, two had severe developmental delay and a further two had a diagnosis of autism. All six cases had significant speech delay with subtle facial dysmorphism.
38 citations
TL;DR: This patient is therefore the first described case with a primary epimutation consistent with AS accompanied by hypomethylation of other imprinted loci.
Abstract: Angelman syndrome (AS) and Prader–Willi syndrome (PWS) are caused by genetic and epigenetic mutations of the imprinted gene cluster on chromosome 15q13. Although the imprinting mutations causing PWS and AS are essentially opposite in nature, remarkably, a small number of patients have been reported with clinical features of PWS but epigenetic mutations consistent with AS. We report here a patient who presented with clinical features partially consistent with both PWS and Beckwith–Wiedemann syndrome (BWS). Epimutations were found at both the AS/PWS and BWS loci, and additionally at the H19, PEG3, NESPAS and GNAS loci. This patient is therefore the first described case with a primary epimutation consistent with AS accompanied by hypomethylation of other imprinted loci.
TL;DR: The study showed a continuous relationship between maternal glucose, either fasting or post-glucose challenge, and a number of important pregnancy outcomes, including birthweight greater than the 90th centile, clinical neonatal hypoglycaemia, primary Caesarean section and cord C-peptide (as a marker of fetal hyperinsulinaemia) across the whole range of blood glucose concentration with no obvious threshold.
Abstract: Gestational diabetes (GDM) is defined as carbohydrate intolerance, with onset or first recognition during pregnancy. Its importance was first recognized approximately 40 years ago, when it became apparent that women with gestational diabetes were more likely to develop diabetes in later life. More recently, thedangersofmaternalhyperglycaemia to the fetusandnewborn baby have been fully appreciated. There is a lack of international agreement regarding the diagnosis of gestational diabetes, in terms of the amount of glucose used (75 or 100 g) during the oral glucose tolerance test, the threshold values and the number of abnormal values required to make the diagnosis (Table 1). These discrepancies have largely arisen because of the absence of high-quality evidence regarding the effects of milder degrees of hyperglycaemia for the fetus and previous reports suggesting a continuum of risk between glucose and maternal and fetal outcomes [1]. TheHyperglycemiaandAdversePregnancyOutcome(HAPO) studywasundertakentoelucidate these issuesandclarify therisks to the mother, developing fetus and newborn baby [2]. The study showed a continuous relationship between maternal glucose, either fasting or post-glucose challenge, and a number of important pregnancy outcomes, including birthweight greater than the 90th centile, clinical neonatal hypoglycaemia, primary Caesarean section and cord C-peptide (as a marker of fetal hyperinsulinaemia) across the whole range of blood glucose concentration with no obvious threshold. The clinical implications were not immediately apparent, but the study provided evidence that lesser degrees of hyperglycaemia, not currently recognized by the World Health Organization criteria [3], are associated with adverse pregnancy outcomes.
TL;DR: Posterior fascial repair improves some domains of sexual function but not all in sexually active patients with symptomatic rectoceles, and local oestrogene treatment may contribute to this finding.
QIMR Berghofer Medical Research Institute1, University of Cambridge2, International Agency for Research on Cancer3, University of Pennsylvania4, Medical University of Vienna5, Baylor University Medical Center6, Harvard University7, City of Hope National Medical Center8, Creighton University9, The Royal Marsden NHS Foundation Trust10, Guy's and St Thomas' NHS Foundation Trust11, NHS Greater Glasgow and Clyde12, Princess Anne Hospital13, Fox Chase Cancer Center14, Georgetown University15, French Institute of Health and Medical Research16, University of Lyon17, Joseph Fourier University18, Erasmus University Rotterdam19, Netherlands Cancer Institute20, Radboud University Nijmegen21, Utrecht University22, Leiden University23, VU University Amsterdam24, Maastricht University25, University of Helsinki26, Pomeranian Medical University27, Laval University28, Mayo Clinic29, University of Southern Denmark30, University of Pisa31, Lund University32, Karolinska Institutet33, Uppsala University34, University of Gothenburg35, University of California, Los Angeles36, University of Chicago37, University of Texas at Dallas38
TL;DR: Evidence to date does not support a role for BARD1 variation, including the Cy557Ser variant, as a modifier of risk in BRCA1/2 mutation carriers, according to single SNP analysis.
Abstract: Background: Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies Methods: A cohort of 5,546 BRCA1 and 2,865 BRCA2 mutation carriers was used to evaluate risk of breast cancer associated with BARD1 Cys557Ser In a second nonindependent cohort of 1,537 of BRCA1 and 839 BRCA2 mutation carriers, BARD1 haplotypes were also evaluated Results: The BARD1 Cys557Ser variant was not significantly associated with risk of breast cancer from single SNP analysis, with a pooled effect estimate of 090 (95% CI: 071-115) in BRCA1 carriers and 087 (95% CI: 059-129) in BRCA2 carriers Further analysis of haplotypes at BARD1 also revealed no evidence that additional common genetic variation not captured by Cys557Ser was associated with breast cancer risk Conclusion: Evidence to date does not support a role for BARD1 variation, including the Cy557Ser variant, as a modifier of risk in BRCA1/2 mutation carriers Impact: Interactors of BRCA1/2 have been implicated as modifiers of BRCA1/2-associated cancer risk Our finding that BARD1 does not contribute to this risk modification may focus research on other genes that do modify BRCA1/2-associated cancer risk Cancer Epidemiol Biomarkers Prev; 20(5); 1032-38 (C) 2011 AACR
TL;DR: In summary, intra-abdominal pregnancy can be best managed by early diagnosis and prompt planned surgery, if any doubt exists about the safety of removing the placenta, it is a wiser option to leave it undisturbed.
Abstract: But, if the implantation site involves major vessels or vital organs, it is recommended that the placenta be left in situ (Delke et al. 1982). Maternal deaths may result from haemorrhage after inadvertent dislodgement of the placenta (Amritha et al. 2009). Possible consequences of leaving the placenta in situ include peritonitis, abscess formation and a second surgical procedure (Delke et al. 1982). In a survey of the literature, it was reported that some placentas which had been left in situ were absorbed without infection (Petrie and Duchin 1980). Methotrexate, a folic acid antagonist, has been used to destroy the residual placenta. However, it is suggested that methotrexate leads to rapid destruction of the abdominal placenta with accelerated accumulation of necrotic tissue, which provides a favourable medium for infection (Rahman et al. 1982; Costa et al. 1991). In summary, intra-abdominal pregnancy can be best managed by early diagnosis and prompt planned surgery. Diagnosis requires a high index of suspicion. Physical examination and ultrasound scans are often inconclusive. Complaints of recurrent abdominal pain in the gravid patient, unusual fetal lie, closed uneffaced cervix and oligohydramnios should increase the suspicion. At surgery, if any doubt exists about the safety of removing the placenta, it is a wiser option to leave it undisturbed. The patient should be closely monitored and examined for the signs of peritonitis or abscess formation.
Carlos III Health Institute1, University of Pennsylvania2, Netherlands Cancer Institute3, Erasmus University Rotterdam4, Utrecht University5, University of Amsterdam6, Leiden University7, VU University Medical Center8, Maastricht University9, Radboud University Nijmegen Medical Centre10, University of Cambridge11, Central Manchester University Hospitals NHS Foundation Trust12, The Royal Marsden NHS Foundation Trust13, Guy's and St Thomas' NHS Foundation Trust14, Princess Anne Hospital15, Newcastle upon Tyne Hospitals NHS Foundation Trust16, Royal Devon and Exeter Hospital17, Churchill Hospital18, University of Helsinki19, Mayo Clinic20, University of Kansas21, Georgetown University22, Lund University23, Karolinska Institutet24, Uppsala University25, Linköping University26, University of Iceland27, QIMR Berghofer Medical Research Institute28, University of Lyon29
TL;DR: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers.
Abstract: BACKGROUND: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2. METHODS: Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers. RESULTS: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. CONCLUSIONS AND INTERPRETATION: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers.
Alberta Health Services1, Duke University2, University College London3, Mayo Clinic4, QIMR Berghofer Medical Research Institute5, Katholieke Universiteit Leuven6, German Cancer Research Center7, University of Ulm8, University of California, Irvine9, Hannover Medical School10, Imperial College London11, Beatson West of Scotland Cancer Centre12, University of Helsinki13, Helsinki University Central Hospital14, Peter MacCallum Cancer Centre15, University of Melbourne16, Princess Anne Hospital17, Cedars-Sinai Medical Center18, University of Cambridge19, University of Copenhagen20, Radboud University Nijmegen Medical Centre21, BC Cancer Agency22, Simon Fraser University23, University of New Mexico24, University of Calgary25
TL;DR: It is concluded that variants in DCN and LUM are not directly associated with sEOC, and that confirmation of possible effect modification of the variants by non-genetic factors is required.
Abstract: Alterations in stromal tissue components can inhibit or promote epithelial tumorigenesis. Decorin (DCN) and lumican (LUM) show reduced stromal expression in serous epithelial ovarian cancer (sEOC). We hypothesized that common variants in these genes associate with risk. Associations with sEOC among Caucasians were estimated with odds ratios (OR) among 397 cases and 920 controls in two U.S.-based studies (discovery set), 436 cases and 1,098 controls in Australia (replication set 1) and a consortium of 15 studies comprising 1,668 cases and 4,249 controls (replication set 2). The discovery set and replication set 1 (833 cases and 2,013 controls) showed statistically homogeneous (Pheterogeneity≥0.48) decreased risks of sEOC at four variants: DCN rs3138165, rs13312816 and rs516115, and LUM rs17018765 (OR = 0.6 to 0.9; Ptrend = 0.001 to 0.03). Results from replication set 2 were statistically homogeneous (Pheterogeneity≥0.13) and associated with increased risks at DCN rs3138165 and rs13312816, and LUM rs17018765: all ORs = 1.2; Ptrend≤0.02. The ORs at the four variants were statistically heterogeneous across all 18 studies (Pheterogeneity≤0.03), which precluded combining. In post-hoc analyses, interactions were observed between each variant and recruitment period (Pinteraction≤0.003), age at diagnosis (Pinteraction = 0.04), and year of diagnosis (Pinteraction = 0.05) in the five studies with available information (1,044 cases, 2,469 controls). We conclude that variants in DCN and LUM are not directly associated with sEOC, and that confirmation of possible effect modification of the variants by non-genetic factors is required.
TL;DR: High-grade DCIS may be focally uncalcified, leading to underestimation of disease extent, which might be related to ER status, and exploration of additional biomarkers and targeted use of further diagnostic techniques may improve the preoperative staging of DCIS.
Abstract: INTRODUCTIONThe extent of calcified ductal carcinoma in situ (DCIS) detected by screening mammography is a determinant for treatment with breast conserving surgery (BCS). However, DCIS may be uncalcified and almost a quarter of patients with DCIS treated initially by BCS either require a second operation or are found to have unexpected invasive disease following surgery. Identification of these cases might guide selective implementation of additional diagnostic procedures. METHODSA retrospective review of patients with a preoperative diagnosis of pure high-grade DCIS at the Southampton and Salisbury Breast Screening Unit over a ten-year period was carried out. Mammograms were reviewed independently by a consultant radiologist and additional factors including the Breast Imaging Reporting and Data System (BI-RADS®) breast density score, DCIS extent and disease location within the breast recorded. RESULTSUnexpected invasive disease was found in 35 of 144 patients (24%). Within our unit the re-excision rate f...
TL;DR: A real but anonymous case history is described that highlights the need for mainstream medical specialties to acquire knowledge and skills in genetic medicine and incorporate genetics into their practice to receive prompt and appropriate attention.
Abstract: Several prominent reports and publications have highlighted the need for mainstream medical specialties to acquire knowledge and skills in genetic medicine and incorporate genetics into their practice.1–3 Good communication between clinical genetic services and mainstream specialties will be required as well as inclusion of genetic training in the continuing professional development of mainstream specialties. Here we describe a real but anonymous case history that highlights the need for such integration to receive prompt and appropriate attention.