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1.  Cardiovascular disease relates to intestinal uptake of p-cresol in patients with chronic kidney disease 
BMC Nephrology  2014;15:87.
Serum p-cresyl sulfate (PCS) associates with cardiovascular disease in patients with chronic kidney disease. PCS concentrations are determined by intestinal uptake of p-cresol, human metabolism to PCS and renal clearance. Whether intestinal uptake of p-cresol itself is directly associated with cardiovascular disease in patients with renal dysfunction has not been studied to date.
We performed a prospective study in patients with chronic kidney disease stage 1 – 5 (NCT00441623). Intestinal uptake of p-cresol, under steady state conditions, was estimated from 24 h urinary excretion of PCS. Primary endpoint was time to first cardiovascular event, i.e., cardiac death, myocardial infarction/ischemia, ventricular arrhythmia, cardiovascular surgery, ischemic stroke or symptomatic peripheral arterial disease. Statistical analysis was done using Kaplan-Meier estimates and Cox proportional hazard analyses.
In a cohort of 200 patients, median 24 h urinary excretion of PCS amounted to 457.47 μmol (IQR 252.68 – 697.17). After a median follow-up of 52 months, 25 patients reached the primary endpoint (tertile 1/2/3: 5/6/14 events, log rank P 0.037). Higher urinary excretion of PCS was directly associated with cardiovascular events (univariate hazard ratio per 100 μmol increase: 1.112, P 0.002). In multivariate analysis, urinary excretion of PCS remained a predictor of cardiovascular events, independent of eGFR (hazard ratio 1.120, P 0.002).
In patients with chronic kidney disease, intestinal uptake of p-cresol associates with cardiovascular disease independent of renal function. The intestinal generation and absorption of p-cresol may be therapeutic targets to reduce cardiovascular disease risk in patients with renal dysfunction.
PMCID: PMC4064102  PMID: 24912660
Cardiovascular disease; Gut; P-cresyl sulfate
2.  SVA retrotransposon insertion-associated deletion represents a novel mutational mechanism underlying large genomic copy number changes with non-recurrent breakpoints 
Genome Biology  2014;15(6):R80.
Genomic disorders are caused by copy number changes that may exhibit recurrent breakpoints processed by nonallelic homologous recombination. However, region-specific disease-associated copy number changes have also been observed which exhibit non-recurrent breakpoints. The mechanisms underlying these non-recurrent copy number changes have not yet been fully elucidated.
We analyze large NF1 deletions with non-recurrent breakpoints as a model to investigate the full spectrum of causative mechanisms, and observe that they are mediated by various DNA double strand break repair mechanisms, as well as aberrant replication. Further, two of the 17 NF1 deletions with non-recurrent breakpoints, identified in unrelated patients, occur in association with the concomitant insertion of SINE/variable number of tandem repeats/Alu (SVA) retrotransposons at the deletion breakpoints. The respective breakpoints are refractory to analysis by standard breakpoint-spanning PCRs and are only identified by means of optimized PCR protocols designed to amplify across GC-rich sequences. The SVA elements are integrated within SUZ12P intron 8 in both patients, and were mediated by target-primed reverse transcription of SVA mRNA intermediates derived from retrotranspositionally active source elements. Both SVA insertions occurred during early postzygotic development and are uniquely associated with large deletions of 1 Mb and 867 kb, respectively, at the insertion sites.
Since active SVA elements are abundant in the human genome and the retrotranspositional activity of many SVA source elements is high, SVA insertion-associated large genomic deletions encompassing many hundreds of kilobases could constitute a novel and as yet under-appreciated mechanism underlying large-scale copy number changes in the human genome.
PMCID: PMC4229983  PMID: 24958239
3.  Heritability and Clinical Determinants of Serum Indoxyl Sulfate and p-Cresyl Sulfate, Candidate Biomarkers of the Human Microbiome Enterotype 
PLoS ONE  2014;9(5):e79682.
Indoxyl sulfate and p-cresyl sulfate are unique microbial co-metabolites. Both co-metabolites have been involved in the pathogenesis of accelerated cardiovascular disease and renal disease progression. Available evidence suggests that indoxyl sulfate and p-cresyl sulfate may be considered candidate biomarkers of the human enterotype and may help to explain the link between diet and cardiovascular disease burden.
Objective and Design
Information on clinical determinants and heritability of indoxyl sulfate and p-cresyl sulfate serum is non-existing. To clarify this issue, the authors determined serum levels of indoxyl sulfate and p-cresyl sulfate in 773 individuals, recruited in the frame of the Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO study).
Serum levels of indoxyl sulfate and p-cresyl sulfate amounted to 3.1 (2.4–4.3) and 13.0 (7.4–21.5) μM, respectively. Regression analysis identified renal function, age and sex as independent determinants of both co-metabolites. Both serum indoxyl sulfate (h2 = 0.17) and p-cresyl sulfate (h2 = 0.18) concentrations showed moderate but significant heritability after adjustment for covariables, with significant genetic and environmental correlations for both co-metabolites.
Family studies cannot provide conclusive evidence for a genetic contribution, as confounding by shared environmental effects can never be excluded.
The heritability of indoxyl sulfate and p-cresyl sulfate is moderate. Besides genetic host factors and environmental factors, also renal function, sex and age influence the serum levels of these co-metabolites.
PMCID: PMC4029585  PMID: 24850265
4.  DNA Glycosylases Involved in Base Excision Repair May Be Associated with Cancer Risk in BRCA1 and BRCA2 Mutation Carriers 
Osorio, Ana | Milne, Roger L. | Kuchenbaecker, Karoline | Vaclová, Tereza | Pita, Guillermo | Alonso, Rosario | Peterlongo, Paolo | Blanco, Ignacio | de la Hoya, Miguel | Duran, Mercedes | Díez, Orland | Ramón y Cajal, Teresa | Konstantopoulou, Irene | Martínez-Bouzas, Cristina | Andrés Conejero, Raquel | Soucy, Penny | McGuffog, Lesley | Barrowdale, Daniel | Lee, Andrew | SWE-BRCA,  | Arver, Brita | Rantala, Johanna | Loman, Niklas | Ehrencrona, Hans | Olopade, Olufunmilayo I. | Beattie, Mary S. | Domchek, Susan M. | Nathanson, Katherine | Rebbeck, Timothy R. | Arun, Banu K. | Karlan, Beth Y. | Walsh, Christine | Lester, Jenny | John, Esther M. | Whittemore, Alice S. | Daly, Mary B. | Southey, Melissa | Hopper, John | Terry, Mary B. | Buys, Saundra S. | Janavicius, Ramunas | Dorfling, Cecilia M. | van Rensburg, Elizabeth J. | Steele, Linda | Neuhausen, Susan L. | Ding, Yuan Chun | Hansen, Thomas v. O. | Jønson, Lars | Ejlertsen, Bent | Gerdes, Anne-Marie | Infante, Mar | Herráez, Belén | Moreno, Leticia Thais | Weitzel, Jeffrey N. | Herzog, Josef | Weeman, Kisa | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Scuvera, Giulietta | Bonanni, Bernardo | Mariette, Frederique | Volorio, Sara | Viel, Alessandra | Varesco, Liliana | Papi, Laura | Ottini, Laura | Tibiletti, Maria Grazia | Radice, Paolo | Yannoukakos, Drakoulis | Garber, Judy | Ellis, Steve | Frost, Debra | Platte, Radka | Fineberg, Elena | Evans, Gareth | Lalloo, Fiona | Izatt, Louise | Eeles, Ros | Adlard, Julian | Davidson, Rosemarie | Cole, Trevor | Eccles, Diana | Cook, Jackie | Hodgson, Shirley | Brewer, Carole | Tischkowitz, Marc | Douglas, Fiona | Porteous, Mary | Side, Lucy | Walker, Lisa | Morrison, Patrick | Donaldson, Alan | Kennedy, John | Foo, Claire | Godwin, Andrew K. | Schmutzler, Rita Katharina | Wappenschmidt, Barbara | Rhiem, Kerstin | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Plendl, Hans Jörg | Niederacher, Dieter | Sutter, Christian | Wang-Gohrke, Shan | Steinemann, Doris | Preisler-Adams, Sabine | Kast, Karin | Varon-Mateeva, Raymonda | Gehrig, Andrea | Stoppa-Lyonnet, Dominique | Sinilnikova, Olga M. | Mazoyer, Sylvie | Damiola, Francesca | Poppe, Bruce | Claes, Kathleen | Piedmonte, Marion | Tucker, Kathy | Backes, Floor | Rodríguez, Gustavo | Brewster, Wendy | Wakeley, Katie | Rutherford, Thomas | Caldés, Trinidad | Nevanlinna, Heli | Aittomäki, Kristiina | Rookus, Matti A. | van Os, Theo A. M. | van der Kolk, Lizet | de Lange, J. L. | Meijers-Heijboer, Hanne E. J. | van der Hout, A. H. | van Asperen, Christi J. | Gómez Garcia, Encarna B. | Hoogerbrugge, Nicoline | Collée, J. Margriet | van Deurzen, Carolien H. M. | van der Luijt, Rob B. | Devilee, Peter | HEBON,  | Olah, Edith | Lázaro, Conxi | Teulé, Alex | Menéndez, Mireia | Jakubowska, Anna | Cybulski, Cezary | Gronwald, Jacek | Lubinski, Jan | Durda, Katarzyna | Jaworska-Bieniek, Katarzyna | Johannsson, Oskar Th. | Maugard, Christine | Montagna, Marco | Tognazzo, Silvia | Teixeira, Manuel R. | Healey, Sue | Investigators, kConFab | Olswold, Curtis | Guidugli, Lucia | Lindor, Noralane | Slager, Susan | Szabo, Csilla I. | Vijai, Joseph | Robson, Mark | Kauff, Noah | Zhang, Liying | Rau-Murthy, Rohini | Fink-Retter, Anneliese | Singer, Christian F. | Rappaport, Christine | Geschwantler Kaulich, Daphne | Pfeiler, Georg | Tea, Muy-Kheng | Berger, Andreas | Phelan, Catherine M. | Greene, Mark H. | Mai, Phuong L. | Lejbkowicz, Flavio | Andrulis, Irene | Mulligan, Anna Marie | Glendon, Gord | Toland, Amanda Ewart | Bojesen, Anders | Pedersen, Inge Sokilde | Sunde, Lone | Thomassen, Mads | Kruse, Torben A. | Jensen, Uffe Birk | Friedman, Eitan | Laitman, Yael | Shimon, Shani Paluch | Simard, Jacques | Easton, Douglas F. | Offit, Kenneth | Couch, Fergus J. | Chenevix-Trench, Georgia | Antoniou, Antonis C. | Benitez, Javier
PLoS Genetics  2014;10(4):e1004256.
Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03–1.16), p = 2.7×10−3) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03–1.21, p = 4.8×10−3). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.
Author Summary
Women harboring a germ-line mutation in the BRCA1 or BRCA2 genes have a high lifetime risk to develop breast and/or ovarian cancer. However, not all carriers develop cancer and high variability exists regarding age of onset of the disease and type of tumor. One of the causes of this variability lies in other genetic factors that modulate the phenotype, the so-called modifier genes. Identification of these genes might have important implications for risk assessment and decision making regarding prevention of the disease. Given that BRCA1 and BRCA2 participate in the repair of DNA double strand breaks, here we have investigated whether variations, Single Nucleotide Polymorphisms (SNPs), in genes participating in other DNA repair pathway may be associated with cancer risk in BRCA carriers. We have selected the Base Excision Repair pathway because BRCA defective cells are extremely sensitive to the inhibition of one of its components, PARP1. Thanks to a large international collaborative effort, we have been able to identify at least two SNPs that are associated with increased cancer risk in BRCA1 and BRCA2 mutation carriers respectively. These findings could have implications not only for risk assessment, but also for treatment of BRCA1/2 mutation carriers with PARP inhibitors.
PMCID: PMC3974638  PMID: 24698998
5.  Multiple orbital neurofibromas, painful peripheral nerve tumors, distinctive face and marfanoid habitus: a new syndrome 
Four unrelated patients having an unusual clinical phenotype, including multiple peripheral nerve sheath tumors, are reported. Their clinical features were not typical of any known familial tumor syndrome. The patients had multiple painful neurofibromas, including bilateral orbital plexiform neurofibromas, and spinal as well as mucosal neurofibromas. In addition, they exhibited a marfanoid habitus, shared similar facial features, and had enlarged corneal nerves as well as neuronal migration defects. Comprehensive NF1, NF2 and SMARCB1 mutation analyses revealed no mutation in blood lymphocytes and in schwann cells cultured from plexiform neurofibromas. Furthermore, no mutations in RET, PRKAR1A, PTEN and other RAS-pathway genes were found in blood leukocytes. Collectively, the clinical and pathological findings in these four cases fit no known syndrome and likely represent a new disorder.
PMCID: PMC3355267  PMID: 22258529
orbital neurofibroma; plexiform neurofibroma; enlarged corneal nerves; marfanoid habitus
6.  Mitotic Recombination of Chromosome Arm 17q as a Cause of Loss of Heterozygosity of NF1 in Neurofibromatosis type 1-associated Glomus Tumors 
Genes, chromosomes & cancer  2012;51(5):429-437.
Neurofibromatosis type 1 (NF1) is a common, autosomal dominant, tumor-predisposition syndrome that arises secondary to mutations in NF1. Glomus tumors are painful benign tumors that originate from the glomus body in the fingers and toes due to biallelic inactivation of NF1. We karyotyped cultures from four previously reported and one new glomus tumor and hybridized tumor (and matching germline) DNA on Illumina HumanOmni1-Quad SNP arrays (~1 × 106 SNPs). Two tumors displayed evidence of copy-neutral loss of heterozygosity of chromosome arm 17q not observed in the germline sample, consistent with a mitotic recombination event. One of these two tumors, NF1-G12, featured extreme polyploidy (near-tetraploidy, near-hexaploidy, or near-septaploidy) across all chromosomes. In the remaining four tumors, there were few cytogenetic abnormalities observed, and copy-number analysis was consistent with diploidy in all chromosomes. This is the first study of glomus tumors cytogenetics, to our knowledge, and the first to report biallelic inactivation of NF1 secondary to mitotic recombination of chromosome arm 17q in multiple NF1-associated glomus tumors. We have observed mitotic recombination in 22% of molecularly-characterized NF1-associated glomus tumors, suggesting that it is a not uncommon mechanism in the reduction to homozygosity of the NF1 germline mutation in these tumors. In tumor NF1-G12, we hypothesize that mitotic recombination also “unmasked” (reduced to homozygosity) a hypomorphic germline allele in a gene on chromosome arm 17q associated with chromosomal instability, resulting in the extreme polyploidy.
PMCID: PMC3295917  PMID: 22250039
7.  Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk 
Couch, Fergus J. | Wang, Xianshu | McGuffog, Lesley | Lee, Andrew | Olswold, Curtis | Kuchenbaecker, Karoline B. | Soucy, Penny | Fredericksen, Zachary | Barrowdale, Daniel | Dennis, Joe | Gaudet, Mia M. | Dicks, Ed | Kosel, Matthew | Healey, Sue | Sinilnikova, Olga M. | Lee, Adam | Bacot, François | Vincent, Daniel | Hogervorst, Frans B. L. | Peock, Susan | Stoppa-Lyonnet, Dominique | Jakubowska, Anna | Investigators, kConFab | Radice, Paolo | Schmutzler, Rita Katharina | Domchek, Susan M. | Piedmonte, Marion | Singer, Christian F. | Friedman, Eitan | Thomassen, Mads | Hansen, Thomas V. O. | Neuhausen, Susan L. | Szabo, Csilla I. | Blanco, Ignacio | Greene, Mark H. | Karlan, Beth Y. | Garber, Judy | Phelan, Catherine M. | Weitzel, Jeffrey N. | Montagna, Marco | Olah, Edith | Andrulis, Irene L. | Godwin, Andrew K. | Yannoukakos, Drakoulis | Goldgar, David E. | Caldes, Trinidad | Nevanlinna, Heli | Osorio, Ana | Terry, Mary Beth | Daly, Mary B. | van Rensburg, Elizabeth J. | Hamann, Ute | Ramus, Susan J. | Ewart Toland, Amanda | Caligo, Maria A. | Olopade, Olufunmilayo I. | Tung, Nadine | Claes, Kathleen | Beattie, Mary S. | Southey, Melissa C. | Imyanitov, Evgeny N. | Tischkowitz, Marc | Janavicius, Ramunas | John, Esther M. | Kwong, Ava | Diez, Orland | Balmaña, Judith | Barkardottir, Rosa B. | Arun, Banu K. | Rennert, Gad | Teo, Soo-Hwang | Ganz, Patricia A. | Campbell, Ian | van der Hout, Annemarie H. | van Deurzen, Carolien H. M. | Seynaeve, Caroline | Gómez Garcia, Encarna B. | van Leeuwen, Flora E. | Meijers-Heijboer, Hanne E. J. | Gille, Johannes J. P. | Ausems, Margreet G. E. M. | Blok, Marinus J. | Ligtenberg, Marjolijn J. L. | Rookus, Matti A. | Devilee, Peter | Verhoef, Senno | van Os, Theo A. M. | Wijnen, Juul T. | Frost, Debra | Ellis, Steve | Fineberg, Elena | Platte, Radka | Evans, D. Gareth | Izatt, Louise | Eeles, Rosalind A. | Adlard, Julian | Eccles, Diana M. | Cook, Jackie | Brewer, Carole | Douglas, Fiona | Hodgson, Shirley | Morrison, Patrick J. | Side, Lucy E. | Donaldson, Alan | Houghton, Catherine | Rogers, Mark T. | Dorkins, Huw | Eason, Jacqueline | Gregory, Helen | McCann, Emma | Murray, Alex | Calender, Alain | Hardouin, Agnès | Berthet, Pascaline | Delnatte, Capucine | Nogues, Catherine | Lasset, Christine | Houdayer, Claude | Leroux, Dominique | Rouleau, Etienne | Prieur, Fabienne | Damiola, Francesca | Sobol, Hagay | Coupier, Isabelle | Venat-Bouvet, Laurence | Castera, Laurent | Gauthier-Villars, Marion | Léoné, Mélanie | Pujol, Pascal | Mazoyer, Sylvie | Bignon, Yves-Jean | Złowocka-Perłowska, Elżbieta | Gronwald, Jacek | Lubinski, Jan | Durda, Katarzyna | Jaworska, Katarzyna | Huzarski, Tomasz | Spurdle, Amanda B. | Viel, Alessandra | Peissel, Bernard | Bonanni, Bernardo | Melloni, Giulia | Ottini, Laura | Papi, Laura | Varesco, Liliana | Tibiletti, Maria Grazia | Peterlongo, Paolo | Volorio, Sara | Manoukian, Siranoush | Pensotti, Valeria | Arnold, Norbert | Engel, Christoph | Deissler, Helmut | Gadzicki, Dorothea | Gehrig, Andrea | Kast, Karin | Rhiem, Kerstin | Meindl, Alfons | Niederacher, Dieter | Ditsch, Nina | Plendl, Hansjoerg | Preisler-Adams, Sabine | Engert, Stefanie | Sutter, Christian | Varon-Mateeva, Raymonda | Wappenschmidt, Barbara | Weber, Bernhard H. F. | Arver, Brita | Stenmark-Askmalm, Marie | Loman, Niklas | Rosenquist, Richard | Einbeigi, Zakaria | Nathanson, Katherine L. | Rebbeck, Timothy R. | Blank, Stephanie V. | Cohn, David E. | Rodriguez, Gustavo C. | Small, Laurie | Friedlander, Michael | Bae-Jump, Victoria L. | Fink-Retter, Anneliese | Rappaport, Christine | Gschwantler-Kaulich, Daphne | Pfeiler, Georg | Tea, Muy-Kheng | Lindor, Noralane M. | Kaufman, Bella | Shimon Paluch, Shani | Laitman, Yael | Skytte, Anne-Bine | Gerdes, Anne-Marie | Pedersen, Inge Sokilde | Moeller, Sanne Traasdahl | Kruse, Torben A. | Jensen, Uffe Birk | Vijai, Joseph | Sarrel, Kara | Robson, Mark | Kauff, Noah | Mulligan, Anna Marie | Glendon, Gord | Ozcelik, Hilmi | Ejlertsen, Bent | Nielsen, Finn C. | Jønson, Lars | Andersen, Mette K. | Ding, Yuan Chun | Steele, Linda | Foretova, Lenka | Teulé, Alex | Lazaro, Conxi | Brunet, Joan | Pujana, Miquel Angel | Mai, Phuong L. | Loud, Jennifer T. | Walsh, Christine | Lester, Jenny | Orsulic, Sandra | Narod, Steven A. | Herzog, Josef | Sand, Sharon R. | Tognazzo, Silvia | Agata, Simona | Vaszko, Tibor | Weaver, Joellen | Stavropoulou, Alexandra V. | Buys, Saundra S. | Romero, Atocha | de la Hoya, Miguel | Aittomäki, Kristiina | Muranen, Taru A. | Duran, Mercedes | Chung, Wendy K. | Lasa, Adriana | Dorfling, Cecilia M. | Miron, Alexander | Benitez, Javier | Senter, Leigha | Huo, Dezheng | Chan, Salina B. | Sokolenko, Anna P. | Chiquette, Jocelyne | Tihomirova, Laima | Friebel, Tara M. | Agnarsson, Bjarni A. | Lu, Karen H. | Lejbkowicz, Flavio | James, Paul A. | Hall, Per | Dunning, Alison M. | Tessier, Daniel | Cunningham, Julie | Slager, Susan L. | Wang, Chen | Hart, Steven | Stevens, Kristen | Simard, Jacques | Pastinen, Tomi | Pankratz, Vernon S. | Offit, Kenneth | Easton, Douglas F. | Chenevix-Trench, Georgia | Antoniou, Antonis C.
PLoS Genetics  2013;9(3):e1003212.
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 = 2.7×10−8, HR = 1.14, 95% CI: 1.09–1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10−8, HR = 1.27, 95% CI: 1.17–1.38) and 4q32.3 (rs4691139, P = 3.4×10−8, 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 = 2×10−4). 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.
Author Summary
BRCA1 mutation carriers have increased and variable risks of breast and ovarian cancer. To identify modifiers of breast and ovarian cancer risk in this population, a multi-stage GWAS of 14,351 BRCA1 mutation carriers was performed. Loci 1q32 and TCF7L2 at 10q25.3 were associated with breast cancer risk, and two loci at 4q32.2 and 17q21.31 were associated with ovarian cancer risk. The 4q32.3 ovarian cancer locus was not associated with ovarian cancer risk in the general population or in BRCA2 carriers and is the first indication of a BRCA1-specific risk locus for either breast or ovarian cancer. Furthermore, modeling the influence of these modifiers on cumulative risk of breast and ovarian cancer in BRCA1 mutation carriers for the first time showed that a wide range of individual absolute risks of each cancer can be estimated. These differences suggest that genetic risk modifiers may be incorporated into the clinical management of BRCA1 mutation carriers.
PMCID: PMC3609646  PMID: 23544013
8.  Functional redundancy of exon 12 of BRCA2 revealed by a comprehensive analysis of the c.6853A>G p.I2285V variant 
Human mutation  2009;30(11):1543-1550.
Variants of Unknown Significance (VUS) in BRCA1 and BRCA2 are common, and present significant challenges for genetic counseling. We observed that BRCA2: c.6853A>G (p.I2285V) (Brest cancer Information Core [BIC] name: 7081A>G; co-occurs in trans with the founder mutation c.5946delT (p.S1982RfsX22) (BIC name: 6174delT), supporting the published classification of p.I2285V as a neutral variant. However, we also noted that when compared with wild-type BRCA2, p.I2285V resulted in increased exclusion of exon 12. Functional assay using allelic complementation in Brca2-null mouse embryonic stem cells revealed that p.I2285V, an allele with exon 12 deleted and wild-type BRCA2 were all phenotypically indistinguishable, as measured by sensitivity to DNA-damaging agents, effect on irradiation-induced Rad51 foci formation, homologous recombination and overall genomic integrity. An allele frequency study showed the p.I2285V variant was identified in 15/722 (2.1%) Ashkenazi Jewish cases and 10/475 (2.1%) ethnically-matched controls, odds ratio: 0.99 (95% confidence interval: 0.44–2.21), P = 0.97. Thus the p.I2285V variant is not associated with an increased risk for breast cancer. Taken together, our clinical and functional studies strongly suggest that exon 12 is functionally redundant and therefore missense variants in this exon are likely to be neutral. Such comprehensive functional studies will be important adjuncts to genetic studies of variants.
PMCID: PMC3501199  PMID: 19795481
BRCA2; unclassified variants; co-occurrence; exon splicing enhancer; exon skipping; in-frame deletion; neutral variant; Embryonic Stem (ES) cells
9.  Renal Cell Carcinoma in the Allograft: What Is the Role of Polyomavirus? 
BK virus (BKV) is known to cause subclinical infection in childhood. The virus remains latent in the human body, mainly in the urinary tract epithelium. After initiation of an immunosuppressive treatment, reactivation can occur in renal transplant recipients. BKV can cause hemorrhagic cystitis, ureteral stenosis and BKV nephropathy in immunocompromised patients. Furthermore, a number of case reports suggest an association between BKV infection and the development of urinary tract cancer. So far, an oncogenic potential of BKV has been observed in vitro and in animal models; however, its oncogenic capacity in humans remains unclear. We report the case of a 59-year-old patient who developed a poorly differentiated renal cell carcinoma in her renal allograft, with pulmonary and abdominal metastasis. Surgical removal of the allograft and cessation of the immunosuppressive therapy resulted in complete resolution of the metastatic disease.
PMCID: PMC3482068  PMID: 23197968
BK virus; Polyoma; Renal cell carcinoma; Kidney transplant
10.  An observational cohort study of extended dosing (once every 2 weeks or once monthly) regimens with darbepoetin alfa in patients with chronic kidney disease not on dialysis: the EXTEND study 
Nephrology Dialysis Transplantation  2011;27(6):2303-2311.
Darbepoetin alfa (DA) has been shown to be an effective treatment of anaemia in patients with chronic kidney disease (CKD) not on dialysis (NoD). EXTEND is an observational study assessing the effectiveness of DA administered once biweekly (Q2W) or monthly (QM) in a general CKD-NoD population.
Adult CKD-NoD patients starting DA Q2W/QM treatment in June 2006 or later were eligible. Retrospective and/or prospective data including haemoglobin levels and erythropoiesis-stimulating agent (ESA) dosing were collected for 6 months before and 12 months after DA initiation. Mean Hb levels were calculated every 3 months, and ESA dose was converted to a geometric mean weekly DA equivalent dose and summarized monthly.
Data from 4278 patients showed that patients receiving ESA treatment before DA Q2W/QM initiation had a mean (95% confidence interval) Hb level of 11.9 g/dL (11.8–12.0 g/dL) at initiation and 11.6 g/dL (11.6–11.7 g/dL) at Months 10–12, with mean ESA dose of 22 μg/week (21–23 μg/week) prior to initiation, 16 μg/week (15–16 μg/week) at initiation and 16 μg/week (15–16 μg/week) at Month 12. In ESA-naive patients, Hb levels increased from 10.3 g/dL (10.2–10.3 g/dL) at initiation to 11.7 g/dL at Months 4–6 and were maintained at a mean level of 11.7 g/dL (11.7–11.8 g/dL) at Months 10–12, with mean ESA dose of 16 μg/week (16–17 μg/week) at initiation and 16 μg/week (16–17 μg/week) at Month 12. In the 85% of patients receiving DA at extended intervals (Q2W or less frequently) at Month 12, 12 patients (0.3%) experienced DA-related adverse reactions.
DA Q2W/QM was an effective treatment of anaemia in the general CKD-NoD patient population and a dose increase was not required in patients switching from a previous ESA regimen.
PMCID: PMC3363980  PMID: 22140136
anaemia; chronic kidney disease; darbepoetin alfa; erythropoiesis-stimulating agent
11.  Practical Tools to Implement Massive Parallel Pyrosequencing of PCR Products in Next Generation Molecular Diagnostics 
PLoS ONE  2011;6(9):e25531.
Despite improvements in terms of sequence quality and price per basepair, Sanger sequencing remains restricted to screening of individual disease genes. The development of massively parallel sequencing (MPS) technologies heralded an era in which molecular diagnostics for multigenic disorders becomes reality. Here, we outline different PCR amplification based strategies for the screening of a multitude of genes in a patient cohort. We performed a thorough evaluation in terms of set-up, coverage and sequencing variants on the data of 10 GS-FLX experiments (over 200 patients). Crucially, we determined the actual coverage that is required for reliable diagnostic results using MPS, and provide a tool to calculate the number of patients that can be screened in a single run. Finally, we provide an overview of factors contributing to false negative or false positive mutation calls and suggest ways to maximize sensitivity and specificity, both important in a routine setting. By describing practical strategies for screening of multigenic disorders in a multitude of samples and providing answers to questions about minimum required coverage, the number of patients that can be screened in a single run and the factors that may affect sensitivity and specificity we hope to facilitate the implementation of MPS technology in molecular diagnostics.
PMCID: PMC3184136  PMID: 21980484
12.  Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers 
Human Molecular Genetics  2010;19(14):2886-2897.
Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P < 1 × 10−3) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutation carriers from nine centers. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (Ptrend < 0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR = 0.78, 95% CI: 0.69–0.90, Ptrend = 3.6 × 10−4 and HR = 1.25, 95% CI: 1.10–1.41, Ptrend = 4.2 × 10−4), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the strongest associations in BRCA2 carriers (HR = 1.55, 95% CI: 1.25–1.92, Ptrend = 6 × 10−5 and HR = 1.37, 95% CI: 1.16–1.62, Ptrend = 1.7 × 10−4). The magnitude and direction of the associations were consistent with the original GWAS. In subsequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations.
PMCID: PMC2893806  PMID: 20418484
13.  Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction 
Antoniou, Antonis C | Beesley, Jonathan | McGuffog, Lesley | Sinilnikova, Olga M. | Healey, Sue | Neuhausen, Susan L. | Ding, Yuan Chun | Rebbeck, Timothy R. | Weitzel, Jeffrey N. | Lynch, Henry T. | Isaacs, Claudine | Ganz, Patricia A. | Tomlinson, Gail | Olopade, Olufunmilayo I. | Couch, Fergus J. | Wang, Xianshu | Lindor, Noralane M. | Pankratz, Vernon S. | Radice, Paolo | Manoukian, Siranoush | Peissel, Bernard | Zaffaroni, Daniela | Barile, Monica | Viel, Alessandra | Allavena, Anna | Dall’Olio, Valentina | Peterlongo, Paolo | Szabo, Csilla I. | Zikan, Michal | Claes, Kathleen | Poppe, Bruce | Foretova, Lenka | Mai, Phuong L. | Greene, Mark H. | Rennert, Gad | Lejbkowicz, Flavio | Glendon, Gord | Ozcelik, Hilmi | Andrulis, Irene L. | Thomassen, Mads | Gerdes, Anne-Marie | Sunde, Lone | Cruger, Dorthe | Jensen, Uffe Birk | Caligo, Maria | Friedman, Eitan | Kaufman, Bella | Laitman, Yael | Milgrom, Roni | Dubrovsky, Maya | Cohen, Shimrit | Borg, Ake | Jernström, Helena | Lindblom, Annika | Rantala, Johanna | Stenmark-Askmalm, Marie | Melin, Beatrice | Nathanson, Kate | Domchek, Susan | Jakubowska, Ania | Lubinski, Jan | Huzarski, Tomasz | Osorio, Ana | Lasa, Adriana | Durán, Mercedes | Tejada, Maria-Isabel | Godino, Javier | Benitez, Javier | Hamann, Ute | Kriege, Mieke | Hoogerbrugge, Nicoline | van der Luijt, Rob B | van Asperen, Christi J | Devilee, Peter | Meijers-Heijboer, E.J. | Blok, Marinus J | Aalfs, Cora M. | Hogervorst, Frans | Rookus, Matti | Cook, Margaret | Oliver, Clare | Frost, Debra | Conroy, Don | Evans, D. Gareth | Lalloo, Fiona | Pichert, Gabriella | Davidson, Rosemarie | Cole, Trevor | Cook, Jackie | Paterson, Joan | Hodgson, Shirley | Morrison, Patrick J. | Porteous, Mary E. | Walker, Lisa | Kennedy, M. John | Dorkins, Huw | Peock, Susan | Godwin, Andrew K. | Stoppa-Lyonnet, Dominique | de Pauw, Antoine | Mazoyer, Sylvie | Bonadona, Valérie | Lasset, Christine | Dreyfus, Hélène | Leroux, Dominique | Hardouin, Agnès | Berthet, Pascaline | Faivre, Laurence | Loustalot, Catherine | Noguchi, Tetsuro | Sobol, Hagay | Rouleau, Etienne | Nogues, Catherine | Frénay, Marc | Vénat-Bouvet, Laurence | Hopper, John L. | Daly, Mary B. | Terry, Mary B. | John, Esther M. | Buys, Saundra S. | Yassin, Yosuf | Miron, Alex | Goldgar, David | Singer, Christian F. | Dressler, Anne Catharina | Gschwantler-Kaulich, Daphne | Pfeiler, Georg | Hansen, Thomas V. O. | Jønson, Lars | Agnarsson, Bjarni A. | Kirchhoff, Tomas | Offit, Kenneth | Devlin, Vincent | Dutra-Clarke, Ana | Piedmonte, Marion | Rodriguez, Gustavo C. | Wakeley, Katie | Boggess, John F. | Basil, Jack | Schwartz, Peter E. | Blank, Stephanie V. | Toland, Amanda Ewart | Montagna, Marco | Casella, Cinzia | Imyanitov, Evgeny | Tihomirova, Laima | Blanco, Ignacio | Lazaro, Conxi | Ramus, Susan J. | Sucheston, Lara | Karlan, Beth Y. | Gross, Jenny | Schmutzler, Rita | Wappenschmidt, Barbara | Engel, Christoph | Meindl, Alfons | Lochmann, Magdalena | Arnold, Norbert | Heidemann, Simone | Varon-Mateeva, Raymonda | Niederacher, Dieter | Sutter, Christian | Deissler, Helmut | Gadzicki, Dorothea | Preisler-Adams, Sabine | Kast, Karin | Schönbuchner, Ines | Caldes, Trinidad | de la Hoya, Miguel | Aittomäki, Kristiina | Nevanlinna, Heli | Simard, Jacques | Spurdle, Amanda B. | Holland, Helene | Chen, Xiaoqing | Platte, Radka | Chenevix-Trench, Georgia | Easton, Douglas F.
Cancer research  2010;70(23):9742-9754.
The known breast cancer (BC) susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1,LSP1 and 2q35 confer increased risks of BC for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of three additional SNPs, rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11 and rs10941679 at 5p12 and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased BC risk for BRCA2 carriers (per-allele Hazard Ratio (HR)=1.10, 95%CI:1.03-1.18, p=0.006 and HR=1.09, 95%CI:1.01-1.19, p=0.03, respectively). Neither SNP was associated with BC risk for BRCA1 carriers and rs6504950 was not associated with BC for either BRCA1 or BRCA2 carriers. Of the nine polymorphisms investigated, seven were associated with BC for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, p-values:7×10−11-0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (p=0.0049, 0.03 respectively). All risk associated polymorphisms appear to interact multiplicatively on BC risk for mutation carriers. Based on the joint genotype distribution of the seven risk associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e. between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing BC by age 80, compared with 42-50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences may be sufficient to influence the clinical management of mutation carriers.
PMCID: PMC2999830  PMID: 21118973
BRCA1; BRCA2; genetic modifier; common variant; genome-wide association study; penetrance; genetic counseling
14.  Fluid Status in Peritoneal Dialysis Patients: The European Body Composition Monitoring (EuroBCM) Study Cohort 
PLoS ONE  2011;6(2):e17148.
Euvolemia is an important adequacy parameter in peritoneal dialysis (PD) patients. However, accurate tools to evaluate volume status in clinical practice and data on volume status in PD patients as compared to healthy population, and the associated factors, have not been available so far.
We used a bio-impedance spectroscopy device, the Body Composition Monitor (BCM) to assess volume status in a cross-sectional cohort of prevalent PD patients in different European countries. The results were compared to an age and gender matched healthy population.
Only 40% out of 639 patients from 28 centres in 6 countries were normovolemic. Severe fluid overload was present in 25.2%. There was a wide scatter in the relation between blood pressure and volume status. In a multivariate analysis in the subgroup of patients from countries with unrestricted availability of all PD modalities and fluid types, older age, male gender, lower serum albumin, lower BMI, diabetes, higher systolic blood pressure, and use of at least one exchange per day with the highest hypertonic glucose were associated with higher relative tissue hydration. Neither urinary output nor ultrafiltration, PD fluid type or PD modality were retained in the model (total R2 of the model = 0.57).
The EuroBCM study demonstrates some interesting issues regarding volume status in PD. As in HD patients, hypervolemia is a frequent condition in PD patients and blood pressure can be a misleading clinical tool to evaluate volume status. To monitor fluid balance, not only fluid output but also dietary input should be considered. Close monitoring of volume status, a correct dialysis prescription adapted to the needs of the patient and dietary measures seem to be warranted to avoid hypervolemia.
PMCID: PMC3044747  PMID: 21390320
15.  Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers 
Antoniou, Antonis C. | Sinilnikova, Olga M. | McGuffog, Lesley | Healey, Sue | Nevanlinna, Heli | Heikkinen, Tuomas | Simard, Jacques | Spurdle, Amanda B. | Beesley, Jonathan | Chen, Xiaoqing | Neuhausen, Susan L. | Ding, Yuan C. | Couch, Fergus J. | Wang, Xianshu | Fredericksen, Zachary | Peterlongo, Paolo | Peissel, Bernard | Bonanni, Bernardo | Viel, Alessandra | Bernard, Loris | Radice, Paolo | Szabo, Csilla I. | Foretova, Lenka | Zikan, Michal | Claes, Kathleen | Greene, Mark H. | Mai, Phuong L. | Rennert, Gad | Lejbkowicz, Flavio | Andrulis, Irene L. | Ozcelik, Hilmi | Glendon, Gord | Gerdes, Anne-Marie | Thomassen, Mads | Sunde, Lone | Caligo, Maria A. | Laitman, Yael | Kontorovich, Tair | Cohen, Shimrit | Kaufman, Bella | Dagan, Efrat | Baruch, Ruth Gershoni | Friedman, Eitan | Harbst, Katja | Barbany-Bustinza, Gisela | Rantala, Johanna | Ehrencrona, Hans | Karlsson, Per | Domchek, Susan M. | Nathanson, Katherine L. | Osorio, Ana | Blanco, Ignacio | Lasa, Adriana | Benítez, Javier | Hamann, Ute | Hogervorst, Frans B.L. | Rookus, Matti A. | Collee, J. Margriet | Devilee, Peter | Ligtenberg, Marjolijn J. | van der Luijt, Rob B. | Aalfs, Cora M. | Waisfisz, Quinten | Wijnen, Juul | van Roozendaal, Cornelis E.P. | Peock, Susan | Cook, Margaret | Frost, Debra | Oliver, Clare | Platte, Radka | Evans, D. Gareth | Lalloo, Fiona | Eeles, Rosalind | Izatt, Louise | Davidson, Rosemarie | Chu, Carol | Eccles, Diana | Cole, Trevor | Hodgson, Shirley | Godwin, Andrew K. | Stoppa-Lyonnet, Dominique | Buecher, Bruno | Léoné, Mélanie | Bressac-de Paillerets, Brigitte | Remenieras, Audrey | Caron, Olivier | Lenoir, Gilbert M. | Sevenet, Nicolas | Longy, Michel | Ferrer, Sandra Fert | Prieur, Fabienne | Goldgar, David | Miron, Alexander | John, Esther M. | Buys, Saundra S. | Daly, Mary B. | Hopper, John L. | Terry, Mary Beth | Yassin, Yosuf | Gschwantler-Kaulich, Daphne | Staudigl, Christine | Hansen, Thomas v. O. | Barkardottir, Rosa Bjork | Kirchhoff, Tomas | Pal, Prodipto | Kosarin, Kristi | Offit, Kenneth | Piedmonte, Marion | Rodriguez, Gustavo C. | Wakeley, Katie | Boggess, John F. | Basil, Jack | Schwartz, Peter E. | Blank, Stephanie V. | Toland, Amanda E. | Montagna, Marco | Casella, Cinzia | Imyanitov, Evgeny N. | Allavena, Anna | Schmutzler, Rita K. | Versmold, Beatrix | Engel, Christoph | Meindl, Alfons | Ditsch, Nina | Arnold, Norbert | Niederacher, Dieter | Deißler, Helmut | Fiebig, Britta | Suttner, Christian | Schönbuchner, Ines | Gadzicki, Dorothea | Caldes, Trinidad | de la Hoya, Miguel | Pooley, Karen A. | Easton, Douglas F. | Chenevix-Trench, Georgia
Human Molecular Genetics  2009;18(22):4442-4456.
Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07–1.25, P-trend = 2.8 × 10−4]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04–1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04–1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98–1.14) was consistent with odds ratio estimates derived from population-based case–control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.
PMCID: PMC2782243  PMID: 19656774
16.  Glomus tumors in neurofibromatosis type 1: genetic, functional and clinical evidence of a novel association 
Cancer research  2009;69(18):7393-7401.
Neurofibromatosis type 1 (NF1) is a common disorder that arises secondary to mutations in the tumor suppressor gene NF1. Glomus tumors are small, benign but painful tumors that originate from the glomus body, a thermoregulatory shunt concentrated in the fingers and toes. We report eleven individuals with NF1 who harbored 20 glomus tumors of the fingers and one in the toe; five individuals had multiple glomus tumors. We hypothesized that bi-allelic inactivation of NF1 underlies the pathogenesis of these tumors. In twelve NF1-associated glomus tumors, we used cell culture and laser capture micro-dissection to isolate DNA. We also analyzed two sporadic (not-NF1-associated) glomus tumors. Genetic analysis showed germline and somatic NF1 mutations in seven tumors. RAS-MAPK hyper-activation was observed in cultured NF1-/- glomus cells, reflecting a lack of inhibition of the pathway by functional neurofibromin, the protein product of NF1. No abnormalities in NF1 or RAS-MAPK activation were found in sporadic glomus tumors. By comparative genomic hybridization, we observed amplification of the 3′-end of CRTAC1 and a deletion of the 5′-end of WASF1 in two NF1-associated glomus tumors. For the first time, we show that loss of neurofibromin function is crucial in the pathogenesis of glomus tumors in NF1. Glomus tumors of the fingers or toes should be considered as part of the tumor spectrum of NF1.
PMCID: PMC2747722  PMID: 19738042
Neurofibromatosis type 1; Glomus tumor; Comparative genomic hybridization; RAS-MAPK hyper-activation; Bi-allelic inactivation
17.  Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer 
BMC Cancer  2008;8:140.
The incidence of breast cancer has doubled over the past 20 years in the Czech Republic. Hereditary factors may be a cause of young onset, bilateral breast or ovarian cancer, and familial accumulation of the disease. BRCA1 and BRCA2 mutations account for an important fraction of hereditary breast and ovarian cancer cases. One thousand and ten unrelated high-risk probands with breast and/or ovarian cancer were analysed for the presence of a BRCA1 or BRCA2 gene mutation at the Masaryk Memorial Cancer Institute (Czech Republic) during 1999–2006.
The complete coding sequences and splice sites of both genes were screened, and the presence of large intragenic rearrangements in BRCA1 was verified. Putative splice-site variants were analysed at the cDNA level for their potential to alter mRNA splicing.
In 294 unrelated families (29.1% of the 1,010 probands) pathogenic mutations were identified, with 44 different BRCA1 mutations and 41 different BRCA2 mutations being detected in 204 and 90 unrelated families, respectively. In total, three BRCA1 founder mutations (c.5266dupC; c.3700_3704del5; p.Cys61Gly) and two BRCA2 founder mutations (c.7913_7917del5; c.8537_8538del2) represent 52% of all detected mutations in Czech high-risk probands. Nine putative splice-site variants were evaluated at the cDNA level. Three splice-site variants in BRCA1 (c.302-3C>G; c.4185G>A and c.4675+1G>A) and six splice-site variants in BRCA2 (c.475G>A; c.476-2>G; c.7007G>A; c.8755-1G>A; c.9117+2T>A and c.9118-2A>G) were demonstrated to result in aberrant transcripts and are considered as deleterious mutations.
This study represents an evaluation of deleterious genetic variants in the BRCA1 and 2 genes in the Czech population. The classification of several splice-site variants as true pathogenic mutations may prove useful for genetic counselling of families with high risk of breast and ovarian cancer.
PMCID: PMC2413254  PMID: 18489799
18.  Benign retroperitoneal schwannoma presenting as colitis: A case report 
We report a case of a patient presenting with clinical, radiological and endoscopic features of colitis due to a compressive left para-aortic mass. Total open surgical excision was performed, which resulted in complete resolution of colitis. Histopathology and immunohistochemistry revealed benign retroperitoneal schwannoma. These neural sheath tumors rarely occur in the retroperitoneum. They are usually asymptomatic but as they enlarge they may compress adjacent structures, which leads to a wide spectrum of non-specific symptoms, including lumbar pain, headache, secondary hypertension, abdominal pain and renal colicky pain. CT and MR findings show characteristic features, but none are specific. Schwannoma can be isolated sporadic lesions, or associated with schwannomatosis or neurofibromatosis type II (NF2). Although they vary in biological and clinical behavior, their presence is, in nearly every case, due to alterations or absence of the NF2 gene, which is involved in the growth regulation of Schwann cells. Both conditions were excluded by thorough mutation analysis. Diagnosis is based on histopathological examination and immunohistochemistry. Total excision is therapeutic and has a good prognosis. Schwannomatosis and NF2 should be excluded through clinical diagnostic criteria. Genetic testing of NF2 is probably not justified in the presence of a solitary retroperitoneal schwannoma.
PMCID: PMC4171291  PMID: 17907300
Colitis; Neurofibromatosis; Retroperitoneum; Schwannoma
19.  Mutation Analysis of the BRCA1 and BRCA2 Genes in the Belgian Patient Population and Identification of a Belgian Founder Mutation BRCA1 IVS5+3A>G 
Disease Markers  2002;15(1-3):69-73.
Since the identification of the BRCA1 and BRCA2 genes, several hundred different germline mutations in both genes have been reported. Recurrent mutations are rare and mainly due to founder effects. As the mutational spectrum of the BRCA1 and BRCA2 genes in the Belgian patient population is largely unknown, we initiated mutation analysis for the complete coding sequence of both genes in Belgian families with multiple breast and/or ovarian cancer patients and in “sporadic” patients with early onset disease. We completed the analysis in 49 families and in 19 “sporadic” female patients with early onset breast and/or ovarian cancer. In 15 families we identified a mutation (12 mutations in BRCA1 and 3 mutations in BRCA2). In 5 apparently unrelated families the same splice site mutation was identified (BRCA1 IVS5+3A>G). Haplotype analysis revealed a common haplotype immediately flanking the mutation in all families suggesting that disease alleles are identical by descent. In none of the 19 sporadic patients was a mutation found.
PMCID: PMC3851655  PMID: 10595255

Results 1-19 (19)