Louise Izatt - Academia.edu (original) (raw)

Papers by Louise Izatt

Research paper thumbnail of X-Linked Dominant Chondrodysplasia Punctata

Keywords Disease name and synonyms Background-definition Prevalence and epidemiology Etiology and... more Keywords Disease name and synonyms Background-definition Prevalence and epidemiology Etiology and biological significance of antisynthetase antibodies Clinical picture Differential diagnosis Laboratory evaluation Prognosis and treatment References Abstract X-linked dominant chondrodysplasia punctata, (CDPX2 - MIM 302960) also known as Conradi- Hünermann-Happle syndrome, is a rare form of skeletal dysplasia that affects the skeleton producing short stature, asymmetric shortening of the limbs

Research paper thumbnail of Association of Type and Location of BRCA1 and BRCA2 Mutations With Risk of Breast and Ovarian Cancer

JAMA, Jan 7, 2015

Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2)... more Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. To identify mutation-specific cancer risks for carriers of BRCA1/2. Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. Mutations of BRCA1 or BRCA2. Breast and ovarian cancer risks. Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian c...

Research paper thumbnail of Genetics and the clinical approach to paragangliomas

Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et métabolisme, 2014

This study analyses new information on gene mutations in paragangliomas and puts them into a clin... more This study analyses new information on gene mutations in paragangliomas and puts them into a clinical context. A suspicion of malignancy is critical to determine the workup and surgical approach in adrenal (A-PGL) and extra-adrenal (E-PGL) paragangliomas (PGLs). Malignancy rates vary with location, family history, and gene tests results. Currently there is no algorithm incorporating the above information for clinical use. A sum of 1,821 articles were retrieved from PubMed using the search terms "paraganglioma genetics". Thirty-seven articles were selected of which 9 were analyzed. It was found that 599/2,487 (24%) patients affected with paragangliomas had a germline mutation. Of these 30.2% were mutations in SDHB, 25% VHL, 19.4% RET, 18.4% SDHD, 5.0% NF1, and 2.0% SDHC genes. A family history was positive in 18.1-64.3% of patients. Adrenal PGLs accounted for 55.1% in mutation (+) and 81.0% in mutation (-) patients (RR 1.2, p < 0.0001). Bilateral A-PGLs accounted for 56....

Research paper thumbnail of Chemical Cleavage of Mismatch

Medical Biomethods Handbook, 2005

ABSTRACT Direct nucleotide sequencing is the reference standard critical to all molecular biology... more ABSTRACT Direct nucleotide sequencing is the reference standard critical to all molecular biology whether it is used for the elucidation of an entire genome or the characterization of a specific mutation. Sequencing protocols were initially developed using either dideoxy nucleotides (1) or chemicals (2), although the latter became less attractive because of the toxic nature of the chemicals used. It is obvious that if sequencing was less expensive, then there would be no need for mutation-scanning techniques. However, although fluorescent technology is improving and capillary electrophoresis is replacing polyacrylamide gel electrophoresis, the cost of consumables is rising and laboratories are, therefore, forced to use other techniques to detect mutations. Mutation-scanning techniques need to detect new mutations within the entire coding region of a gene and there are several methods available to scan for sequence changes in either cellular RNA or genomic DNA. These include denaturing gradient gel electrophoresis (DGGE) (3) (see Chapter 8), chemical cleavage of mismatch (CCM) (4), enzyme mismatch cleavage (EMC) (5,6), single-stranded conformation polymorphism (SSCP) (see Chapter 7) (CR7), heteroduplex analysis (HA) (8), conformation-sensitive gel electrophoresis (CSGE) (9), the protein truncation test (PTT) (10); and, more recently, denaturing high-performance liquid chromatography (DHPLC) (11,CR12) (see Chapter24). The most critical factor that determines the success of any gene screening protocol is the sensitivity of the detection technique. The sensitivities of these methods vary greatly depending on the size of DNA/RNA template screened. For example, SSCP has a sensitivity of &gt;95‰ for fragments of 155 bp, but this is reduced to only 3‰ for 600 bp (13). Once optimised, DGGE has a sensitivity of approx 99‰ for fragments of up to 500 bp (14), and CSGE has a sensitivity of 90–100‰ for fragments of up to 450 bp (15). CCM and EMC, on the other hand, have sensitivities of 95–100‰ for fragments &gt;1.5 kb in size ( 16,17) and are ideal for screening compact genes where more than one exon can be amplified together using genomic DNA as the template. All of these techniques detect sequence changes such as nonsense, frame shift, splice site, and missense mutations, as well as polymorphisms, however, the PTT screens only for truncating mutations and is predicted to have a sensitivity of &gt;95‰ and can be used for RNA or DNA fragments in excess of 3 kb.

Research paper thumbnail of Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and o... more BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.

Research paper thumbnail of The Angelina Jolie effect: how high celebrity profile can have a major impact on provision of cancer related services

Breast cancer research : BCR, 2014

It is frequent for news items to lead to a short lived temporary increase in interest in a partic... more It is frequent for news items to lead to a short lived temporary increase in interest in a particular health related service, however it is rare for this to have a long lasting effect. In 2013, in the UK in particular, there has been unprecedented publicity in hereditary breast cancer, with Angelina Jolie's decision to have genetic testing for the BRCA1 gene and subsequently undergo risk reducing mastectomy (RRM), and a pre-release of the NICE guidelines on familial breast cancer in January and their final release on 26th June. The release of NICE guidelines created a lot of publicity over the potential for use of chemoprevention using tamoxifen or raloxifene. However, the longest lasting news story was the release of details of film actress Angelina Jolie's genetic test and surgery. To assess the potential effects of the 'Angelina Jolie' effect, referral data specific to breast cancer family history was obtained from around the UK for the years 2012 and 2013. A cons...

Research paper thumbnail of Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 exert dominant-negative effects

Endocrine Abstracts, 2014

Research paper thumbnail of Molecular prenatal diagnosis in a case of an X-linked dominant chondrodysplasia punctata

Prenatal Diagnosis, 2003

X-linked dominant chondrodysplasia punctata, (CDPX2-MIM302960) also known as Conradi-Hünermann-Ha... more X-linked dominant chondrodysplasia punctata, (CDPX2-MIM302960) also known as Conradi-Hünermann-Happle syndrome, is a rare form of skeletal dysplasia that affects the skeleton, skin, hair, and eyes. The disorder is caused by mutations within the emopamil binding protein (Ebp) that functions as a delta(8), delta(7) sterol isomerase in the cholesterol biosynthesis pathway. To date, over 40 separate mutations have been reported in the Ebp gene, EBP, with no obvious correlation between the molecular defects and the severity of the clinical phenotype. We have studied a 30-year-old woman who presented in adulthood with skin, hair, and mild skeletal defects but no ocular abnormalities and have identified a heterozygous missense mutation within the third transmembrane domain of the protein. In addition, we have performed molecular prenatal testing on her unborn fetus. The results demonstrate inter-familial variability for missense mutations within the emopamil binding protein and add to the molecular data for CDPX2.

Research paper thumbnail of DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Research paper thumbnail of Correction: Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer

PLoS Genetics, 2010

Copyright Public Library of Science. This is an open-access article distributed under the terms o... more Copyright Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Research paper thumbnail of Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer

PLoS Genetics, 2010

The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 ... more The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (,40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (l) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values,10 25 and 39 SNPs had p-values,10 24 . These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, p~3:8|10 {5 ) and for rs311499 was 0.72 (95% CI 0.61-0.85, p~6:6|10 {5 ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, p~1:2|10 {8 ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.

Research paper thumbnail of Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

PLoS Genetics, 2013

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To i... more BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7610 28 , HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4610 28 , HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4610 28 , HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2610 24 ). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

Research paper thumbnail of A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor–negative breast cancer in the general population

Nature Genetics, 2010

milgrom 57 , Irene l Andrulis 59-61 , gord glendon 59 , Hilmi ozcelik 60 , tomas kirchhoff 62,63 ... more milgrom 57 , Irene l Andrulis 59-61 , gord glendon 59 , Hilmi ozcelik 60 , tomas kirchhoff 62,63 , Joseph Vijai 62,63 , mia m gaudet 64,65 , david Altshuler 66 , candace guiducci 66 , swe-BRcA 67,133 , niklas loman 68 , katja Harbst 68 , Johanna Rantala 69 , Hans ehrencrona 70 , Anne-marie gerdes 71 , mads thomassen 72 , lone sunde 73 , l e t t e r s mod sQUAd 89,133 , Javier Benitez 90 , Ana osorio 90 , Heli nevanlinna 91 , tuomas Heikkinen 91 , maria A caligo 92 , mary s Beattie 93-95 , Ute Hamann 96 , Andrew k godwin 39 , marco montagna 97 , cinzia casella 97 , susan l neuhausen 98 , Beth Y karlan 99,100 , nadine tung 101 , Amanda e toland 102 , Jeffrey weitzel 103 , olofunmilayo olopade 104 , Jacques simard 105,106 , Penny soucy 105 , wendy s Rubinstein 107 , Adalgeir Arason 108 , gad Rennert 109 , nicholas g martin 110 , grant w montgomery 110 , Jenny chang-claude 111 , dieter Flesch-Janys 112 , Hiltrud Brauch 113,114 , genIcA 115,133 , gianluca severi 116 , laura Baglietto 116 , Angela cox 117 , simon s cross 118 , Penelope miron 119 , sue m gerty 7 , william tapper 7 , drakoulis Yannoukakos 120 , george Fountzilas 121,122 , Peter A Fasching 123 , matthias w Beckmann 124 , Isabel dos santos silva 125 , Julian Peto 125 , diether lambrechts 126 , Robert Paridaens 127 , thomas Rüdiger 128 , Asta Försti 96,129 , Robert winqvist 130 , katri Pylkäs 130 ,

Research paper thumbnail of Germline mutations in RAD51D confer susceptibility to ovarian cancer

Nature Genetics, 2011

Recently, RAD51C mutations were identified in families with breast and ovarian cancer 1 . This ob... more Recently, RAD51C mutations were identified in families with breast and ovarian cancer 1 . This observation prompted us to investigate the role of RAD51D in cancer susceptibility. We identified eight inactivating RAD51D mutations in unrelated individuals from 911 breast-ovarian cancer families compared with one inactivating mutation identified in 1,060 controls (P = 0.01). The association found here was principally with ovarian cancer, with three mutations identified in the 59 pedigrees with three or more individuals with ovarian cancer (P = 0.0005). The relative risk of ovarian cancer for RAD51D mutation carriers was estimated to be 6.30 (95% CI 2.86-13.85, P = 4.8 × 10 -6 ). By contrast, we estimated the relative risk of breast cancer to be 1.32 (95% CI 0.59-2.96, P = 0.50). These data indicate that RAD51D mutation testing may have clinical utility in individuals with ovarian cancer and their families. Moreover, we show that cells deficient in RAD51D are sensitive to treatment with a PARP inhibitor, suggesting a possible therapeutic approach for cancers arising in RAD51D mutation carriers.

Research paper thumbnail of Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer

Nature, 2012

Improved sequencing technologies offer unprecedented opportunities for investigating the role of ... more Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication 1 . Using pooled nextgeneration sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on proteintruncating variants (PTVs) and a large-scale sequencing casecontrol replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P 5 1.12 3 10 25 ), including 18 mutations in 6,912 individuals with breast cancer (P 5 2.42 3 10 24 ) and 12 mutations in 1,121 individuals with ovarian cancer (P 5 3.10 3 10 29 ). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.

Research paper thumbnail of Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk

Nature Genetics, 2012

Richard Houlston and colleagues report a genome-wide association study for colorectal cancer. The... more Richard Houlston and colleagues report a genome-wide association study for colorectal cancer. They report three loci newly associated with colorectal cancer, bringing the total number of common susceptibility loci to 20.

Research paper thumbnail of Cancer Risks for BRCA1 and BRCA2 Mutation Carriers: Results From Prospective Analysis of EMBRACE

JNCI Journal of the National Cancer Institute, 2013

Reliable estimates of cancer risk are critical for guiding management of BRCA1 and BRCA2 mutation... more 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.

Research paper thumbnail of Unexpected findings in cancer predisposition genes detected by array comparative genomic hybridisation: what are the issues?

Journal of Medical Genetics, 2011

Objective To calculate and discuss the percentage of imbalance for selected cancer predisposition... more Objective To calculate and discuss the percentage of imbalance for selected cancer predisposition genes in patients referred for routine diagnostic array comparative genomic hybridisation (CGH). Design Audit of findings from application of array CGH for patients referred for developmental delay, behavioural abnormalities and birth defects in 4805 patients referred to Guy's and St Thomas' NHS Foundation Trust for cytogenetic investigation from South East London, Kent and East Sussex and other genetic centres across the UK. Results 29 of 4805 (0.6%) patients examined by array CGH had genomic imbalance of <5 Mb involving cancer predisposition genes. Six patients were referred for syndromes involving cancer predisposition genes; none of the other 23 patients with array CGH findings in cancer predisposition genes had any symptoms/family history stated on their referral form suggestive for the respective syndrome. Twelve whole gene deletions, two partial deletions, 12 duplications, two partial duplications, and one mosaic duplication were observed. In 17/29 patients (59%), inheritance could not be established, eight imbalances were de novo, and four inherited. Conclusions This new technology raises the possibility of unexpected findings in cancer predisposition genes. Therefore, the possibility of such findings has to be addressed in pre-test and post-test counselling by genetically trained healthcare professionals. As many of these findings have not been described previously, their clinical significance is unknown and patients need longterm follow-up to determine their clinical relevance. This will enable genetic healthcare professionals to advise such people about their cancer risks and appropriate cancer risk management options.

Research paper thumbnail of Novel Mutations in X-Linked Dominant Chondrodysplasia Punctata (CDPX2)

Journal of Investigative Dermatology, 2003

Research paper thumbnail of Deficiency of the Cyclin-Dependent Kinase Inhibitor, CDKN1B, Results in Overgrowth and Neurodevelopmental Delay

Human Mutation, 2013

Germline mutations in the cyclin-dependent kinase inhibitor, CDKN1B, have been described in patie... more Germline mutations in the cyclin-dependent kinase inhibitor, CDKN1B, have been described in patients with multiple endocrine neoplasia (MEN), a cancer predisposition syndrome with adult onset neoplasia and no additional phenotypes. Here, we describe the first human case of CDKN1B deficiency, which recapitulates features of the murine CDKN1B knockout mouse model, including gigantism and neurodevelopmental defects. Decreased mRNA and protein expression of CDKN1B were confirmed in the proband's peripheral blood, which is not seen in MEN syndrome patients. We ascribed the decreased protein level to a maternally derived deletion on chromosome 12p13 encompassing the CDKN1B locus (which reduced mRNA expression) and a de novo allelic variant (c.-73G>A) in the CDKN1B promoter (which reduced protein translation). We propose a recessive model where decreased dosage of CDKN1B during development in humans results in a neuronal phenotype akin to that described in mice, placing CDKN1B as a candidate gene involved in developmental delay. Hum Mutat 34:864-868, 2013. C 2013 Wiley Periodicals, Inc.

Research paper thumbnail of X-Linked Dominant Chondrodysplasia Punctata

Keywords Disease name and synonyms Background-definition Prevalence and epidemiology Etiology and... more Keywords Disease name and synonyms Background-definition Prevalence and epidemiology Etiology and biological significance of antisynthetase antibodies Clinical picture Differential diagnosis Laboratory evaluation Prognosis and treatment References Abstract X-linked dominant chondrodysplasia punctata, (CDPX2 - MIM 302960) also known as Conradi- Hünermann-Happle syndrome, is a rare form of skeletal dysplasia that affects the skeleton producing short stature, asymmetric shortening of the limbs

Research paper thumbnail of Association of Type and Location of BRCA1 and BRCA2 Mutations With Risk of Breast and Ovarian Cancer

JAMA, Jan 7, 2015

Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2)... more Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. To identify mutation-specific cancer risks for carriers of BRCA1/2. Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. Mutations of BRCA1 or BRCA2. Breast and ovarian cancer risks. Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian c...

Research paper thumbnail of Genetics and the clinical approach to paragangliomas

Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et métabolisme, 2014

This study analyses new information on gene mutations in paragangliomas and puts them into a clin... more This study analyses new information on gene mutations in paragangliomas and puts them into a clinical context. A suspicion of malignancy is critical to determine the workup and surgical approach in adrenal (A-PGL) and extra-adrenal (E-PGL) paragangliomas (PGLs). Malignancy rates vary with location, family history, and gene tests results. Currently there is no algorithm incorporating the above information for clinical use. A sum of 1,821 articles were retrieved from PubMed using the search terms "paraganglioma genetics". Thirty-seven articles were selected of which 9 were analyzed. It was found that 599/2,487 (24%) patients affected with paragangliomas had a germline mutation. Of these 30.2% were mutations in SDHB, 25% VHL, 19.4% RET, 18.4% SDHD, 5.0% NF1, and 2.0% SDHC genes. A family history was positive in 18.1-64.3% of patients. Adrenal PGLs accounted for 55.1% in mutation (+) and 81.0% in mutation (-) patients (RR 1.2, p < 0.0001). Bilateral A-PGLs accounted for 56....

Research paper thumbnail of Chemical Cleavage of Mismatch

Medical Biomethods Handbook, 2005

ABSTRACT Direct nucleotide sequencing is the reference standard critical to all molecular biology... more ABSTRACT Direct nucleotide sequencing is the reference standard critical to all molecular biology whether it is used for the elucidation of an entire genome or the characterization of a specific mutation. Sequencing protocols were initially developed using either dideoxy nucleotides (1) or chemicals (2), although the latter became less attractive because of the toxic nature of the chemicals used. It is obvious that if sequencing was less expensive, then there would be no need for mutation-scanning techniques. However, although fluorescent technology is improving and capillary electrophoresis is replacing polyacrylamide gel electrophoresis, the cost of consumables is rising and laboratories are, therefore, forced to use other techniques to detect mutations. Mutation-scanning techniques need to detect new mutations within the entire coding region of a gene and there are several methods available to scan for sequence changes in either cellular RNA or genomic DNA. These include denaturing gradient gel electrophoresis (DGGE) (3) (see Chapter 8), chemical cleavage of mismatch (CCM) (4), enzyme mismatch cleavage (EMC) (5,6), single-stranded conformation polymorphism (SSCP) (see Chapter 7) (CR7), heteroduplex analysis (HA) (8), conformation-sensitive gel electrophoresis (CSGE) (9), the protein truncation test (PTT) (10); and, more recently, denaturing high-performance liquid chromatography (DHPLC) (11,CR12) (see Chapter24). The most critical factor that determines the success of any gene screening protocol is the sensitivity of the detection technique. The sensitivities of these methods vary greatly depending on the size of DNA/RNA template screened. For example, SSCP has a sensitivity of &gt;95‰ for fragments of 155 bp, but this is reduced to only 3‰ for 600 bp (13). Once optimised, DGGE has a sensitivity of approx 99‰ for fragments of up to 500 bp (14), and CSGE has a sensitivity of 90–100‰ for fragments of up to 450 bp (15). CCM and EMC, on the other hand, have sensitivities of 95–100‰ for fragments &gt;1.5 kb in size ( 16,17) and are ideal for screening compact genes where more than one exon can be amplified together using genomic DNA as the template. All of these techniques detect sequence changes such as nonsense, frame shift, splice site, and missense mutations, as well as polymorphisms, however, the PTT screens only for truncating mutations and is predicted to have a sensitivity of &gt;95‰ and can be used for RNA or DNA fragments in excess of 3 kb.

Research paper thumbnail of Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers

BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and o... more BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes. Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach. The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments. There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers. Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.

Research paper thumbnail of The Angelina Jolie effect: how high celebrity profile can have a major impact on provision of cancer related services

Breast cancer research : BCR, 2014

It is frequent for news items to lead to a short lived temporary increase in interest in a partic... more It is frequent for news items to lead to a short lived temporary increase in interest in a particular health related service, however it is rare for this to have a long lasting effect. In 2013, in the UK in particular, there has been unprecedented publicity in hereditary breast cancer, with Angelina Jolie's decision to have genetic testing for the BRCA1 gene and subsequently undergo risk reducing mastectomy (RRM), and a pre-release of the NICE guidelines on familial breast cancer in January and their final release on 26th June. The release of NICE guidelines created a lot of publicity over the potential for use of chemoprevention using tamoxifen or raloxifene. However, the longest lasting news story was the release of details of film actress Angelina Jolie's genetic test and surgery. To assess the potential effects of the 'Angelina Jolie' effect, referral data specific to breast cancer family history was obtained from around the UK for the years 2012 and 2013. A cons...

Research paper thumbnail of Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 exert dominant-negative effects

Endocrine Abstracts, 2014

Research paper thumbnail of Molecular prenatal diagnosis in a case of an X-linked dominant chondrodysplasia punctata

Prenatal Diagnosis, 2003

X-linked dominant chondrodysplasia punctata, (CDPX2-MIM302960) also known as Conradi-Hünermann-Ha... more X-linked dominant chondrodysplasia punctata, (CDPX2-MIM302960) also known as Conradi-Hünermann-Happle syndrome, is a rare form of skeletal dysplasia that affects the skeleton, skin, hair, and eyes. The disorder is caused by mutations within the emopamil binding protein (Ebp) that functions as a delta(8), delta(7) sterol isomerase in the cholesterol biosynthesis pathway. To date, over 40 separate mutations have been reported in the Ebp gene, EBP, with no obvious correlation between the molecular defects and the severity of the clinical phenotype. We have studied a 30-year-old woman who presented in adulthood with skin, hair, and mild skeletal defects but no ocular abnormalities and have identified a heterozygous missense mutation within the third transmembrane domain of the protein. In addition, we have performed molecular prenatal testing on her unborn fetus. The results demonstrate inter-familial variability for missense mutations within the emopamil binding protein and add to the molecular data for CDPX2.

Research paper thumbnail of DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Research paper thumbnail of Correction: Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer

PLoS Genetics, 2010

Copyright Public Library of Science. This is an open-access article distributed under the terms o... more Copyright Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Research paper thumbnail of Common Genetic Variants and Modification of Penetrance of BRCA2-Associated Breast Cancer

PLoS Genetics, 2010

The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 ... more The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (,40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (l) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values,10 25 and 39 SNPs had p-values,10 24 . These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, p~3:8|10 {5 ) and for rs311499 was 0.72 (95% CI 0.61-0.85, p~6:6|10 {5 ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, p~1:2|10 {8 ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.

Research paper thumbnail of Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

PLoS Genetics, 2013

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To i... more BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7610 28 , HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4610 28 , HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4610 28 , HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2610 24 ). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

Research paper thumbnail of A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor–negative breast cancer in the general population

Nature Genetics, 2010

milgrom 57 , Irene l Andrulis 59-61 , gord glendon 59 , Hilmi ozcelik 60 , tomas kirchhoff 62,63 ... more milgrom 57 , Irene l Andrulis 59-61 , gord glendon 59 , Hilmi ozcelik 60 , tomas kirchhoff 62,63 , Joseph Vijai 62,63 , mia m gaudet 64,65 , david Altshuler 66 , candace guiducci 66 , swe-BRcA 67,133 , niklas loman 68 , katja Harbst 68 , Johanna Rantala 69 , Hans ehrencrona 70 , Anne-marie gerdes 71 , mads thomassen 72 , lone sunde 73 , l e t t e r s mod sQUAd 89,133 , Javier Benitez 90 , Ana osorio 90 , Heli nevanlinna 91 , tuomas Heikkinen 91 , maria A caligo 92 , mary s Beattie 93-95 , Ute Hamann 96 , Andrew k godwin 39 , marco montagna 97 , cinzia casella 97 , susan l neuhausen 98 , Beth Y karlan 99,100 , nadine tung 101 , Amanda e toland 102 , Jeffrey weitzel 103 , olofunmilayo olopade 104 , Jacques simard 105,106 , Penny soucy 105 , wendy s Rubinstein 107 , Adalgeir Arason 108 , gad Rennert 109 , nicholas g martin 110 , grant w montgomery 110 , Jenny chang-claude 111 , dieter Flesch-Janys 112 , Hiltrud Brauch 113,114 , genIcA 115,133 , gianluca severi 116 , laura Baglietto 116 , Angela cox 117 , simon s cross 118 , Penelope miron 119 , sue m gerty 7 , william tapper 7 , drakoulis Yannoukakos 120 , george Fountzilas 121,122 , Peter A Fasching 123 , matthias w Beckmann 124 , Isabel dos santos silva 125 , Julian Peto 125 , diether lambrechts 126 , Robert Paridaens 127 , thomas Rüdiger 128 , Asta Försti 96,129 , Robert winqvist 130 , katri Pylkäs 130 ,

Research paper thumbnail of Germline mutations in RAD51D confer susceptibility to ovarian cancer

Nature Genetics, 2011

Recently, RAD51C mutations were identified in families with breast and ovarian cancer 1 . This ob... more Recently, RAD51C mutations were identified in families with breast and ovarian cancer 1 . This observation prompted us to investigate the role of RAD51D in cancer susceptibility. We identified eight inactivating RAD51D mutations in unrelated individuals from 911 breast-ovarian cancer families compared with one inactivating mutation identified in 1,060 controls (P = 0.01). The association found here was principally with ovarian cancer, with three mutations identified in the 59 pedigrees with three or more individuals with ovarian cancer (P = 0.0005). The relative risk of ovarian cancer for RAD51D mutation carriers was estimated to be 6.30 (95% CI 2.86-13.85, P = 4.8 × 10 -6 ). By contrast, we estimated the relative risk of breast cancer to be 1.32 (95% CI 0.59-2.96, P = 0.50). These data indicate that RAD51D mutation testing may have clinical utility in individuals with ovarian cancer and their families. Moreover, we show that cells deficient in RAD51D are sensitive to treatment with a PARP inhibitor, suggesting a possible therapeutic approach for cancers arising in RAD51D mutation carriers.

Research paper thumbnail of Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer

Nature, 2012

Improved sequencing technologies offer unprecedented opportunities for investigating the role of ... more Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication 1 . Using pooled nextgeneration sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on proteintruncating variants (PTVs) and a large-scale sequencing casecontrol replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1D are associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P 5 1.12 3 10 25 ), including 18 mutations in 6,912 individuals with breast cancer (P 5 2.42 3 10 24 ) and 12 mutations in 1,121 individuals with ovarian cancer (P 5 3.10 3 10 29 ). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.

Research paper thumbnail of Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk

Nature Genetics, 2012

Richard Houlston and colleagues report a genome-wide association study for colorectal cancer. The... more Richard Houlston and colleagues report a genome-wide association study for colorectal cancer. They report three loci newly associated with colorectal cancer, bringing the total number of common susceptibility loci to 20.

Research paper thumbnail of Cancer Risks for BRCA1 and BRCA2 Mutation Carriers: Results From Prospective Analysis of EMBRACE

JNCI Journal of the National Cancer Institute, 2013

Reliable estimates of cancer risk are critical for guiding management of BRCA1 and BRCA2 mutation... more 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.

Research paper thumbnail of Unexpected findings in cancer predisposition genes detected by array comparative genomic hybridisation: what are the issues?

Journal of Medical Genetics, 2011

Objective To calculate and discuss the percentage of imbalance for selected cancer predisposition... more Objective To calculate and discuss the percentage of imbalance for selected cancer predisposition genes in patients referred for routine diagnostic array comparative genomic hybridisation (CGH). Design Audit of findings from application of array CGH for patients referred for developmental delay, behavioural abnormalities and birth defects in 4805 patients referred to Guy's and St Thomas' NHS Foundation Trust for cytogenetic investigation from South East London, Kent and East Sussex and other genetic centres across the UK. Results 29 of 4805 (0.6%) patients examined by array CGH had genomic imbalance of <5 Mb involving cancer predisposition genes. Six patients were referred for syndromes involving cancer predisposition genes; none of the other 23 patients with array CGH findings in cancer predisposition genes had any symptoms/family history stated on their referral form suggestive for the respective syndrome. Twelve whole gene deletions, two partial deletions, 12 duplications, two partial duplications, and one mosaic duplication were observed. In 17/29 patients (59%), inheritance could not be established, eight imbalances were de novo, and four inherited. Conclusions This new technology raises the possibility of unexpected findings in cancer predisposition genes. Therefore, the possibility of such findings has to be addressed in pre-test and post-test counselling by genetically trained healthcare professionals. As many of these findings have not been described previously, their clinical significance is unknown and patients need longterm follow-up to determine their clinical relevance. This will enable genetic healthcare professionals to advise such people about their cancer risks and appropriate cancer risk management options.

Research paper thumbnail of Novel Mutations in X-Linked Dominant Chondrodysplasia Punctata (CDPX2)

Journal of Investigative Dermatology, 2003

Research paper thumbnail of Deficiency of the Cyclin-Dependent Kinase Inhibitor, CDKN1B, Results in Overgrowth and Neurodevelopmental Delay

Human Mutation, 2013

Germline mutations in the cyclin-dependent kinase inhibitor, CDKN1B, have been described in patie... more Germline mutations in the cyclin-dependent kinase inhibitor, CDKN1B, have been described in patients with multiple endocrine neoplasia (MEN), a cancer predisposition syndrome with adult onset neoplasia and no additional phenotypes. Here, we describe the first human case of CDKN1B deficiency, which recapitulates features of the murine CDKN1B knockout mouse model, including gigantism and neurodevelopmental defects. Decreased mRNA and protein expression of CDKN1B were confirmed in the proband's peripheral blood, which is not seen in MEN syndrome patients. We ascribed the decreased protein level to a maternally derived deletion on chromosome 12p13 encompassing the CDKN1B locus (which reduced mRNA expression) and a de novo allelic variant (c.-73G>A) in the CDKN1B promoter (which reduced protein translation). We propose a recessive model where decreased dosage of CDKN1B during development in humans results in a neuronal phenotype akin to that described in mice, placing CDKN1B as a candidate gene involved in developmental delay. Hum Mutat 34:864-868, 2013. C 2013 Wiley Periodicals, Inc.