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1. Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes

Author

Loviglio, M. N, Leleu, M., Männik, K., Passeggeri, M., Giannuzzi, G., van der Werf, I., Waszak, S. M., Zazhytska, M., Roberts Caldeira, I., Gheldof, N., Migliavacca, E., Alfaiz, A. A., Hippolyte, L., Maillard, A. M., van Dijck, A., Kooy, R. F., Sanlaville, D., Rosenfeld, J. A., Shaffer, L. G., Andrieux, J., Marshall, C., Scherer, S. W., Shen, Y., Gusella, J. F., Thorsteinsdottir, U., Thorleifsson, G., Dermitzakis, E. T., Deplancke, B., Beckmann, J. S., Rougemont, J., Jacquemont, S., Reymond, A., Collaborators: Loviglio MN, Männik, K, van der Werf, I, Giannuzzi, G, Zazhytska, M, Gheldof, N, Migliavacca, E, Alfaiz, Aa, Roberts Caldeira, I, Hippolyte, L, Maillard, Am, Ferrarini, A, Butschi, Fn, Conrad, B, Addor, Mc, Belfiore, M, Roetzer, K, Dijck, Av, Blaumeiser, B, Kooy, F, Roelens, F, Dheedene, A, Chiaie, Bd, Menten, B, Oostra, A, Caberg, Jh, Carter, M, Kellam, B, Stavropoulos, Dj, Marshall, C, Scherer, Sw, Weksberg, R, Cytrynbaum, C, Bassett, A, Lowther, C, Gillis, J, Mackay, S, Bache, I, Ousager, Lb, Smerdel, Mp, Graakjaer, J, Kjaergaard, S, Metspalu, A, Mathieu, M, Bonneau, D, Guichet, A, Parent, P, Férec, C, Gerard, M, Plessis, G, Lespinasse, J, Masurel, A, Marle, N, Faivre, L, Callier, P, Layet, V, Meur, Nl, Le Goff, C, Duban Bedu, B, Sukno, S, Boute, O, Andrieux, J, Blanchet, P, Geneviève, D, Puechberty, J, Schneider, A, Leheup, B, Jonveaux, P, Mercier, S, David, A, Le Caignec, C, de Pontual, L, Pipiras, E, Jacquette, A, Keren, B, Gilbert Dussardier, B, Bilan, F, Goldenberg, A, Chambon, P, Toutain, A, Till, M, Sanlaville, D, Leube, B, Royer Pokora, B, Grabe, Hj, Schmidt, Co, Schurmann, C, Homuth, G, Thorleifsson, G, Thorsteinsdottir, U, Bernardini, L, Novelli, A, Micale, L, Merla, G, Zollino, M, Mari, Francesca, Rizzo, Cl, Renieri, Alessandra, Silengo, M, Vulto van Silfhout AT, Schouten, M, Pfundt, R, de Leeuw, N, Vansenne, F, Maas, Sm, Barge Schaapveld DQ, Knegt, Ac, Stadheim, B, Rodningen, O, Houge, G, Price, S, Hawkes, L, Campbell, C, Kini, U, Vogt, J, Walters, R, Blakemore, A, Gusella, Jf, Shen, Y, Scott, D, Bacino, Ca, Tsuchiya, K, Ladda, R, Sell, S, Asamoah, A, Hamati, Ai, Rosenfeld, Ja, Shaffer, Lg, Mitchell, E, Hodge, Jc, Beckmann, Js, Jacquemont, S, Reymond, A, Ewans, Lj, Mowat, D, Walker, J, Amor, Dj, Esch, Hv, Leroy, P, Bamforth, Js, Babu, D, Isidor, B, Didonato, N, Hackmann, K, Passeggeri, M, Haeringen, Av, Smith, R, Ellingwood, S, Farber, Dm, Puri, V, Zadeh, N, Weaver, Dd, Miller, M, Wilks, T, Jorgez, Cj, Lafayette, D, Blaumeiser, Bettina, 2p15 Consortium, 16p11.2 Consortium, Loviglio, M.N., Männik, K., van der Werf, I., Giannuzzi, G., Zazhytska, M., Gheldof, N., Migliavacca, E., Alfaiz, A.A., Roberts-Caldeira, I., Hippolyte, L., Maillard, A.M., Ferrarini, A., Butschi, F.N., Conrad, B., Addor, M.C., Belfiore, M., Roetzer, K., Dijck, A.V., Blaumeiser, B., Kooy, F., Roelens, F., Dheedene, A., Chiaie, B.D., Menten, B., Oostra, A., Caberg, J.H., Carter, M., Kellam, B., Stavropoulos, D.J., Marshall, C., Scherer, S.W., Weksberg, R., Cytrynbaum, C., Bassett, A., Lowther, C., Gillis, J., MacKay, S., Bache, I., Ousager, L.B., Smerdel, M.P., Graakjaer, J., Kjaergaard, S., Metspalu, A., Mathieu, M., Bonneau, D., Guichet, A., Parent, P., Férec, C., Gerard, M., Plessis, G., Lespinasse, J., Masurel, A., Marle, N., Faivre, L., Callier, P., Layet, V., Meur, N.L., Le Goff, C., Duban-Bedu, B., Sukno, S., Boute, O., Andrieux, J., Blanchet, P., Geneviève, D., Puechberty, J., Schneider, A., Leheup, B., Jonveaux, P., Mercier, S., David, A., Le Caignec, C., de Pontual, L., Pipiras, E., Jacquette, A., Keren, B., Gilbert-Dussardier, B., Bilan, F., Goldenberg, A., Chambon, P., Toutain, A., Till, M., Sanlaville, D., Leube, B., Royer-Pokora, B., Grabe, H.J., Schmidt, C.O., Schurmann, C., Homuth, G., Thorleifsson, G., Thorsteinsdottir, U., Bernardini, L., Novelli, A., Micale, L., Merla, G., Zollino, M., Mari, F., Rizzo, C.L., Renieri, A., Silengo, M., Vulto-van Silfhout, A.T., Schouten, M., Pfundt, R., de Leeuw, N., Vansenne, F., Maas, S.M., Barge-Schaapveld, D.Q., Knegt, A.C., Stadheim, B., Rodningen, O., Houge, G., Price, S., Hawkes, L., Campbell, C., Kini, U., Vogt, J., Walters, R., Blakemore, A., Gusella, J.F., Shen, Y., Scott, D., Bacino, C.A., Tsuchiya, K., Ladda, R., Sell, S., Asamoah, A., Hamati, A.I., Rosenfeld, J.A., Shaffer, L.G., Mitchell, E., Hodge, J.C., Beckmann, J.S., Jacquemont, S., Reymond, A., Ewans, L.J., Mowat, D., Walker, J., Amor, D.J., Esch, H.V., Leroy, P., Bamforth, J.S., Babu, D., Isidor, B., DiDonato, N., Hackmann, K., Passeggeri, M., Haeringen, A.V., Smith, R., Ellingwood, S., Farber, D.M., Puri, V., Zadeh, N., Weaver, D.D., Miller, M., Wilks, T., Jorgez, C.J., Lafayette, D., Other departments, and Human Genetics

Subjects
0301 basic medicine, Male, Microcephaly, Autism Spectrum Disorder, Obesity/genetics, Settore MED/03 - GENETICA MEDICA, Body Mass Index, Microcephaly/genetics, Gene duplication, Chromosome Duplication, ddc:576.5, Copy-number variation, Child, In Situ Hybridization, In Situ Hybridization, Fluorescence, Genetics, medicine.diagnostic_test, Chromosome Mapping, Middle Aged, Phenotype, Chromatin, Chemistry, Psychiatry and Mental Health, Child, Preschool, Female, Original Article, Chromosomes, Human, Pair 16/genetics, Megalencephaly/genetics, Chromosome Deletion, Autistic Disorder/genetics, Molecular Biology, Cellular and Molecular Neuroscience, Human, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, Adolescent, DNA Copy Number Variations, Locus (genetics), DNA Copy Number Variations/genetics, Biology, Aged, Autistic Disorder, Chromosomes, Human, Pair 16, Humans, Infant, Intellectual Disability, Megalencephaly, Obesity, Chromosomes, Fluorescence, Chromatin/metabolism, 03 medical and health sciences, medicine, Preschool, Gene, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Pair 16, medicine.disease, Intellectual Disability/genetics, Autism Spectrum Disorder/genetics, 030104 developmental biology, Human medicine, Chromosome Mapping/methods, Fluorescence in situ hybridization
Abstract

Contains fulltext : 174530.pdf (Publisher’s version ) (Open Access) Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts' maps could uncover functionally and clinically related genes.

Published
2015
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2. Sertoli-Leydig cell tumor: a clinicopathological analysis in a comprehensive, national cohort.

Author

Bekker P, Miland-Samuelsen AR, Smerdel MP, Schnack TH, Lauszus FF, and Karstensen SH

Subjects
Male, Humans, Female, Child, Adolescent, Young Adult, Adult, Middle Aged, Aged, Prognosis, Ribonuclease III, DEAD-box RNA Helicases, Sertoli-Leydig Cell Tumor genetics, Sertoli-Leydig Cell Tumor therapy, Sertoli-Leydig Cell Tumor pathology, Ovarian Neoplasms genetics, Ovarian Neoplasms therapy, Ovarian Neoplasms pathology, Sex Cord-Gonadal Stromal Tumors pathology
Abstract

Introduction: Sertoli-Leydig cell tumors are rare tumors of the ovary. Moderate and poorly differentiated tumors can metastasize and have a poor outcome. A pathogenic variant in DICER1 is associated with an increased risk of developing these tumors along with other clinical phenotypes. We aimed to describe a national cohort of all Sertoli-Leydig cell tumors with regard to clinicopathological characteristics and frequency of DICER1 pathogenic variants., Methods: In May 2018, all patients registered from January 1997 to December 2017 with the Systematized Nomenclature of Medicine code M86310 (Sertoli-Leydig cell tumor) were obtained from the Danish National Pathology Registry. Validation of the diagnosis depended on comments in the reports that two pathologists validated the initial diagnosis or revision of the pathology at another facility. We performed descriptive statistics to describe baseline characteristics, and cancer related survival was calculated using Kaplan-Meier analysis followed by a log rank test for differences between variables RESULTS: 41 women with Sertoli-Leydig cell tumors were identified. Median age was 41 years (range 6-79). The stages according to the International Federation of Gynecology and Obstetrics (FIGO) were: stage I, 85% (n=35), stage II, 2% (n=1), stage III, 5% (n=2), and stage IV, 7% (n=3). The 5 year cancer related survival was 100% for patients with localized disease (stages I-II) and 0% in advanced tumor stages (stages III-IV). Histological differentiation grade of the tumors was well differentiated in 29% (n=12), moderately differentiated in 56% (n=23), and poorly differentiated in 15% (n=6), and the 5 year cancer related survival was 100%, 96%, and 33%, respectively, according to grade. All patients underwent surgery. Twenty-two patients had fertility sparing surgery and four of these had given birth at the time of follow-up. Analysis of DICER1 was performed in eight women. Four carried a pathogenic variant. Four patients received adjuvant chemotherapy, three because of advanced tumor stage, and one because of a poorly differentiated Sertoli-Leydig cell tumor., Conclusion: The prognosis for women with Sertoli-Leydig cell tumors with localized disease is excellent. Women with advanced stages (III-IV) have a poor prognosis, regardless of adjuvant chemotherapy. Fertility sparing surgery seems to be a viable option for localized Sertoli-Leydig cell tumors. DICER1 screening was rarely performed in previous cohorts and concomitant organ screening programs are topics for discussion., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2023
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3. Carboplatin re-treatment in platinum-resistant epithelial ovarian cancer patients.

Author

Hansen MKG, Smerdel MP, Waldstrøm M, Andersen RF, Adimi P, Jakobsen A, and Steffensen KD

Subjects
Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bevacizumab administration & dosage, Bevacizumab adverse effects, Biomarkers, Tumor blood, Carboplatin adverse effects, Carcinoma, Ovarian Epithelial blood, Carcinoma, Ovarian Epithelial mortality, Carcinoma, Ovarian Epithelial pathology, Cell-Free Nucleic Acids blood, Chemotherapy, Adjuvant methods, Chemotherapy, Adjuvant statistics & numerical data, Cytoreduction Surgical Procedures, Drug Monitoring methods, Drug Resistance, Neoplasm, Feasibility Studies, Female, Humans, Middle Aged, Ovarian Neoplasms blood, Ovarian Neoplasms mortality, Ovarian Neoplasms pathology, Prognosis, Progression-Free Survival, Prospective Studies, Response Evaluation Criteria in Solid Tumors, Retreatment methods, Retreatment statistics & numerical data, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Carboplatin administration & dosage, Carcinoma, Ovarian Epithelial therapy, Ovarian Neoplasms therapy
Abstract

Purpose: Treatment of multi-resistant epithelial ovarian cancer represents a clinical challenge with limited choices. Anti-angiogenic therapy has shown great potential in combination with frontline-therapy. Studies investigating heavily pre-treated patients are few. This study investigated the effect of re-treating patients with carboplatin combined with bevacizumab and cell-free DNA (cfDNA) as a potential predictor of outcome., Methods: This single-center study enrolled 73 multi-resistant ovarian cancer patients from 2008 to 2015. Patients were treated with a combination of bevacizumab (10 mg/kg) and carboplatin (AUC5) every 3 weeks. Baseline plasma samples were analyzed for cfDNA levels. Treatment response was evaluated based on the Response Evaluation Criteria in Solid Tumors (RECIST) criteria and CA125 blood values., Results: The response rate according to RECIST and/or CA125 was 57%. Median number of cycles was 6. The median progression-free survival and overall survival was 5.0 and 11.2 months, respectively. Eighteen patients developed allergic reactions to carboplatin. Patients were grouped into two cfDNA-groups according to median value. The cfDNA value was correlated to progression-free survival (PFS, p = 0.015), but not to overall survival (OS, p = 0.067) in the univariate analysis. In the multivariate analysis both PFS and OS were highly correlated to the levels of cfDNA (PFS, hazard ratio = 1.87, p = 0.012; OS, hazard ratio = 1.67, p = 0.037) with patients with high levels of cfDNA having poorest outcome., Conclusion: Our results might provide guidance in cases with heavily pre-treated patients, where alternatives are limited. Carboplatin and bevacizumab treatment should be weighed against best supportive care, current non-platinum therapies and experimental treatment. cfDNA seems to offer prognostic insight.

Published
2020
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4. Revised Danish guidelines for the cancer surveillance of patients with Cowden Syndrome.

Author

Smerdel MP, Skytte AB, Jelsig AM, Ebbehøj E, and Stochholm K

Subjects
Denmark, Early Detection of Cancer methods, Genetic Testing methods, Genetic Testing standards, Hamartoma Syndrome, Multiple genetics, Humans, Neoplasms, Second Primary genetics, PTEN Phosphohydrolase genetics, Early Detection of Cancer standards, Hamartoma Syndrome, Multiple diagnosis, Neoplasms, Second Primary diagnosis, Practice Guidelines as Topic
Abstract

Introduction: Cowden syndrome is a cancer predisposition syndrome caused by pathogenic variants in PTEN. The affected patients possess an increased risk of breast, thyroid, renal, colorectal, endometrial cancers as well as malignant melanoma. Thus prophylactic surveillance and follow up is crucial for these patients., Methods: A review of the literature including existing guidelines from the years 1996 until 2017 was carried out. In total, 2078 scientific papers were identified through database searches on Cowden syndrome. Among these, 11 manuscripts were included based on scientific relevance and quality. Expert consensus was reached to define management guidelines., Results: The literature revealed a high risk of cancer in specific organs for patients diagnosed with Cowden Syndrome. Alternative management guidelines were proposed and discussed., Conclusions: Here we propose a revised set of management guidelines for patients with Cowden syndrome in Denmark to address the increased risk of various cancer types., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Published
2020
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5. The predictive value of serum VEGF in multiresistant ovarian cancer patients treated with bevacizumab.

Author

Smerdel MP, Steffensen KD, Waldstrøm M, Brandslund I, and Jakobsen A

Subjects
Adult, Aged, Angiogenesis Inhibitors therapeutic use, Antibodies, Monoclonal, Humanized, Bevacizumab, Drug Resistance, Neoplasm, Female, Humans, Middle Aged, Ovarian Neoplasms genetics, Polymorphism, Genetic, Predictive Value of Tests, Vascular Endothelial Growth Factor A genetics, Vascular Endothelial Growth Factor Receptor-1 blood, Vascular Endothelial Growth Factor Receptor-2 blood, Antibodies, Monoclonal therapeutic use, Ovarian Neoplasms blood, Ovarian Neoplasms drug therapy, Vascular Endothelial Growth Factor A blood
Abstract

Objective: Bevacizumab, a humanized monoclonal antibody against VEGF (vascular endothelial growth factor), has shown antitumor activity, but so far no biomarkers have been identified to predict outcome. The purpose of the present study was to investigate the efficacy of bevacizumab in patients with multiresistant ovarian cancer and, furthermore, to investigate the possible predictive value of serum VEGF, VEGFR1-2 and VEGF gene polymorphisms., Methods: Patients received single-agent bevacizumab 10 mg/kg every 3 weeks. All patients were followed with CA 125 measurements and serum VEGF/VEGFR1-2 levels prior to each cycle. Endpoints were response rate (RR), progression-free survival (PFS) and overall survival (OS)., Results: Thirty-eight patients were included. All patients were heavily pre-treated with a median of five prior regimens. The median number of bevacizumab treatments was 4. Overall response rate was 30% according to CA 125 (GCIG criteria). Median PFS was 5.9 months (95% CI, 3.5-9.4) and median OS was 8.6 months (95% CI, 6.6-12.8). The VEGF serum level decreased during treatment in all patients. A low pre-treatment VEGF level was predictive to response. The median value was 540 pg/ml and divided the patients into two groups with a response rate of 60% and 0%, respectively (p=0.0007). The difference translated to a significant difference in PFS (p=0.047) and OS (p=0.01). VEGF gene polymorphisms -2578, -1154, -460, +405, +936 did not reveal any association with response or survival and the same applied to serum VEGFR1-2., Conclusions: Single agent bevacizumab has activity in ovarian cancer patients. Pre-treatment serum VEGF seems to have predictive value., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Published
2010
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6. Prognostic importance of vascular endothelial growth factor-A expression and vascular endothelial growth factor polymorphisms in epithelial ovarian cancer.

Author

Smerdel MP, Waldstrøm M, Brandslund I, Steffensen KD, Andersen RF, and Jakobsen A

Subjects
Adult, Aged, Epithelial Cells pathology, Female, Humans, Immunohistochemistry, Middle Aged, Multivariate Analysis, Ovarian Neoplasms metabolism, Ovarian Neoplasms pathology, Polymorphism, Single Nucleotide, Prognosis, Proportional Hazards Models, Ovarian Neoplasms genetics, Vascular Endothelial Growth Factor A biosynthesis, Vascular Endothelial Growth Factor A genetics
Abstract

Introduction: Vascular endothelial growth factors (VEGFs) play a central role in angiogenesis and consequently, in various steps of ovarian carcinogenesis. Gene polymorphisms within the VEGF system have revealed a correlation with prognosis in some malignancies. The aim of the present study was to examine the possible importance of 2 VEGF polymorphisms and VEGF-A expression in ovarian cancer., Methods: We investigated 2 single nucleotide polymorphisms VEGF +405G/C and VEGF -460C/T by polymerase chain reaction and also analyzed VEGF-A expression by immunohistochemistry in 159 women with ovarian cancer., Results: Vascular endothelial growth factor-A expression revealed a significant correlation with survival in a Cox proportional hazards regression model (P = 0.012). Germline polymorphisms were not correlated with clinicopathological parameters such as stage, type, and histology. Heterozygous genotype in VEGF +405G/C predicted a better survival compared with homozygous genotypes (P = 0.034), and the heterozygous genotype in VEGF -460C/T pointed to the same direction. A multivariate analysis also indicated that heterozygosity of either of the 2 polymorphisms held independent prognostic significance (P = 0.001)., Conclusions: Vascular endothelial growth factor polymorphisms +405G/C and VEGF expression seem to have independent prognostic importance.

Published
2009
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