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23 results on '"Ekaterina, Kuchinskaya"'

1. Extended genetic analysis and tumor characteristics in over 4600 women with suspected hereditary breast and ovarian cancer

Author

Anna Öfverholm, Therese Törngren, Anna Rosén, Brita Arver, Zakaria Einbeigi, Karin Haraldsson, Anne Kinhult Ståhlbom, Ekaterina Kuchinskaya, Annika Lindblom, Beatrice Melin, Ylva Paulsson-Karlsson, Marie Stenmark-Askmalm, Emma Tham, Anna von Wachenfeldt, Anders Kvist, Åke Borg, and Hans Ehrencrona

Subjects
BRCA1, BRCA2, Genetic testing, Cancer, Breast cancer, Ovarian cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Genetic screening for pathogenic variants (PVs) in cancer predisposition genes can affect treatment strategies, risk prediction and preventive measures for patients and families. For decades, hereditary breast and ovarian cancer (HBOC) has been attributed to PVs in the genes BRCA1 and BRCA2, and more recently other rare alleles have been firmly established as associated with a high or moderate increased risk of developing breast and/or ovarian cancer. Here, we assess the genetic variation and tumor characteristics in a large cohort of women with suspected HBOC in a clinical oncogenetic setting. Methods Women with suspected HBOC referred from all oncogenetic clinics in Sweden over a six-year inclusion period were screened for PVs in 13 clinically relevant genes. The genetic outcome was compared with tumor characteristics and other clinical data collected from national cancer registries and hospital records. Results In 4622 women with breast and/or ovarian cancer the overall diagnostic yield (the proportion of women carrying at least one PV) was 16.6%. BRCA1/2 PVs were found in 8.9% of women (BRCA1 5.95% and BRCA2 2.94%) and PVs in the other breast and ovarian cancer predisposition genes in 8.2%: ATM (1.58%), BARD1 (0.45%), BRIP1 (0.43%), CDH1 (0.11%), CHEK2 (3.46%), PALB2 (0.84%), PTEN (0.02%), RAD51C (0.54%), RAD51D (0.15%), STK11 (0) and TP53 (0.56%). Thus, inclusion of the 11 genes in addition to BRCA1/2 increased diagnostic yield by 7.7%. The yield was, as expected, significantly higher in certain subgroups such as younger patients, medullary breast cancer, higher Nottingham Histologic Grade, ER-negative breast cancer, triple-negative breast cancer and high grade serous ovarian cancer. Age and tumor subtype distributions differed substantially depending on genetic finding. Conclusions This study contributes to understanding the clinical and genetic landscape of breast and ovarian cancer susceptibility. Extending clinical genetic screening from BRCA1 and BRCA2 to 13 established cancer predisposition genes almost doubles the diagnostic yield, which has implications for genetic counseling and clinical guidelines. The very low yield in the syndrome genes CDH1, PTEN and STK11 questions the usefulness of including these genes on routine gene panels.

Published
2023
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2. P506: CLINICAL VALIDATION OF THE NORDIC GUIDELINES FOR GERMLINE TESTING IN MYELOID NEOPLASMS: RESULTS FROM A MULTI-CENTER PROSPECTIVE COHORT STUDY

Author

Bianca Tesi, Anna Eriksson, Berivan Baskin, Vladimir Lazarevic, Stefan Deneberg, Martin Höglund, Linda Fogelstrand, Johanna Ungerstedt, Tatjana Pandzic, Magnus Tobiasson, Hege Gravdahl Garelius, Ekaterina Kuchinskaya, Fredrik Persson, Helena Ågerstam, Bertil Uggla, Helene Hallböök, Thoas Fioretos, Ann-Charlotte Thuresson, Sören Lehmann, Claes Ladenvall, Gisela Barbany, Lovisa Vennström, Elisabeth Ejerblad, Lucia Cavelier, Jörg Cammenga, Martin Jädersten, Eva Hellström Lindberg, and Panagiotis Baliakas

Subjects
Diseases of the blood and blood-forming organs, RC633-647.5
Published
2023
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3. Register-based and genetic studies of Prader-Willi syndrome show a high frequency of gonadal tumors and a possible mechanism for tumorigenesis through imprinting relaxation

Author

Carolina Maya-González, Sandra Wessman, Kristina Lagerstedt-Robinson, Fulya Taylan, Bianca Tesi, Ekaterina Kuchinskaya, W. Glenn McCluggage, Anna Poluha, Stefan Holm, Ricard Nergårdh, Teresita Díaz De Ståhl, Charlotte Höybye, Giorgio Tettamanti, Angelica Maria Delgado-Vega, Anna Skarin Nordenvall, and Ann Nordgren

Subjects
Prader-Willi syndrome, ovarian tumor, germ-cell tumor, cancer predisposition, loss-of-imprinting, imprinting relaxation, Medicine (General), R5-920
Abstract

Prader-Willi syndrome (PWS) is a rare disease caused by a lack of expression of inherited imprinted genes in the paternally derived Prader-Willi critical region on chromosome 15q11.2-q13. It is characterized by poor feeding and hypotonia in infancy, intellectual disability, behavioral abnormalities, dysmorphic features, short stature, obesity, and hypogonadism. PWS is not a known cancer predisposition syndrome, but previous investigations regarding the prevalence of cancer in these patients suggest an increased risk of developing specific cancer types such as myeloid leukemia and testicular cancer. We present the results from a Swedish national population-based cohort study of 360 individuals with PWS and 18,000 matched comparisons. The overall frequency of cancer was not increased in our PWS cohort, but we found a high frequency of pediatric cancers. We also performed whole-genome sequencing of blood- and tumor-derived DNAs from a unilateral dysgerminoma in a 13-year-old girl with PWS who also developed bilateral ovarian sex cord tumors with annular tubules. In germline analysis, there were no additional findings apart from the 15q11.2-q13 deletion of the paternal allele, while a pathogenic activating KIT mutation was identified in the tumor. Additionally, methylation-specific multiplex ligation-dependent probe amplification revealed reduced methylation at the PWS locus in the dysgerminoma but not in the blood. In conclusion, our register-based study suggests an increased risk of cancer at a young age, especially testicular and ovarian tumors. We found no evidence of a general increase in cancer risk in patients with PWS. However, given our limited observational time, further studies with longer follow-up times are needed to clarify the lifetime cancer risk in PWS. We have also described the second case of locus-specific loss-of-imprinting in a germ cell tumor in PWS, suggesting a possible mechanism of carcinogenesis.

Published
2023
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4. Expanding the mutation and phenotype spectrum of MYH3-associated skeletal disorders

Author

Sen Zhao, Yuanqiang Zhang, Sigrun Hallgrimsdottir, Yuzhi Zuo, Xiaoxin Li, Dominyka Batkovskyte, Sen Liu, Hillevi Lindelöf, Shengru Wang, Anna Hammarsjö, Yang Yang, Yongyu Ye, Lianlei Wang, Zihui Yan, Jiachen Lin, Chenxi Yu, Zefu Chen, Yuchen Niu, Huizi Wang, Zhi Zhao, Pengfei Liu, Guixing Qiu, Jennifer E. Posey, Zhihong Wu, James R. Lupski, Ieva Micule, Britt-Marie Anderlid, Ulrika Voss, Dennis Sulander, Ekaterina Kuchinskaya, Ann Nordgren, Ola Nilsson, Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study, Terry Jianguo Zhang, Giedre Grigelioniene, and Nan Wu

Subjects
Medicine, Genetics, QH426-470
Abstract

Abstract Pathogenic variants in MYH3 cause distal arthrogryposis type 2A and type 2B3 as well as contractures, pterygia and spondylocarpotarsal fusion syndromes types 1A and 1B. These disorders are ultra-rare and their natural course and phenotypic variability are not well described. In this study, we summarize the clinical features and genetic findings of 17 patients from 10 unrelated families with vertebral malformations caused by dominant or recessive pathogenic variants in MYH3. Twelve novel pathogenic variants in MYH3 (NM_002470.4) were identified: three of them were de novo or inherited in autosomal dominant way and nine were inherited in autosomal recessive way. The patients had vertebral segmentation anomalies accompanied with variable joint contractures, short stature and dysmorphic facial features. There was a significant phenotypic overlap between dominant and recessive MYH3-associated conditions regarding the degree of short stature as well as the number of vertebral fusions. All monoallelic variants caused significantly decreased SMAD3 phosphorylation, which is consistent with the previously proposed pathogenic mechanism of impaired canonical TGF-β signaling. Most of the biallelic variants were predicted to be protein-truncating, while one missense variant c.4244T>G,p.(Leu1415Arg), which was inherited in an autosomal recessive way, was found to alter the phosphorylation level of p38, suggesting an inhibition of the non-canonical pathway of TGF-β signaling. In conclusion, the identification of 12 novel pathogenic variants and overlapping phenotypes in 17 affected individuals from 10 unrelated families expands the mutation and phenotype spectrum of MYH3-associated skeletal disorders. We show that disturbances of canonical or non-canonical TGF-β signaling pathways are involved in pathogenesis of MYH3-associated skeletal fusion (MASF) syndrome.

Published
2022
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5. A search for modifying genetic factors in CHEK2:c.1100delC breast cancer patients

Author

Camilla Wendt, Taru A. Muranen, Lotta Mielikäinen, Jessada Thutkawkorapin, Carl Blomqvist, Xiang Jiao, Hans Ehrencrona, Emma Tham, Brita Arver, Beatrice Melin, Ekaterina Kuchinskaya, Marie Stenmark Askmalm, Ylva Paulsson-Karlsson, Zakaria Einbeigi, Anna von Wachenfeldt Väppling, Eija Kalso, Tiina Tasmuth, Anne Kallioniemi, Kristiina Aittomäki, Heli Nevanlinna, Åke Borg, and Annika Lindblom

Subjects
Medicine, Science
Abstract

Abstract The risk of breast cancer associated with CHEK2:c.1100delC is 2–threefold but higher in carriers with a family history of breast cancer than without, suggesting that other genetic loci in combination with CHEK2:c.1100delC confer an increased risk in a polygenic model. Part of the excess familial risk has been associated with common low-penetrance variants. This study aimed to identify genetic loci that modify CHEK2:c.1100delC-associated breast cancer risk by searching for candidate risk alleles that are overrepresented in CHEK2:c.1100delC carriers with breast cancer compared with controls. We performed whole-exome sequencing in 28 breast cancer cases with germline CHEK2:c.1100delC, 28 familial breast cancer cases and 70 controls. Candidate alleles were selected for validation in larger cohorts. One recessive synonymous variant, rs16897117, was suggested, but no overrepresentation of homozygous CHEK2:c.1100delC carriers was found in the following validation. Furthermore, 11 non-synonymous candidate alleles were suggested for further testing, but no significant difference in allele frequency could be detected in the validation in CHEK2:c.1100delC cases compared with familial breast cancer, sporadic breast cancer and controls. With this method, we found no support for a CHEK2:c.1100delC-specific genetic modifier. Further studies of CHEK2:c.1100delC genetic modifiers are warranted to improve risk assessment in clinical practice.

Published
2021
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6. OA03 Are there any differences in the outcomes of treatment of a 12-month course of rituximab BCD020 biosimilar in systemic lupus erythematosus in children with early and late administration of the drug

Author

Kalashnikova, Elvira, primary, Rinat, Raupov, additional, Lubimova, Natalia, additional, Ekaterina, Kuchinskaya, additional, Isupova, Eugeniya, additional, Gaidar, Ekaterina, additional, Masalova, Vera, additional, Snegireva, Lyudmila, additional, Kornishina, Tatyana, additional, Sorokina, Lyuobov, additional, Kaneva, Mariya, additional, Kalashnikova, Olga, additional, Burtseva, Tatiana, additional, Argunova, Vera, additional, Sleptsova, Polina, additional, Chasnyk, Vyacheslav, additional, and Kostik, Mikhail, additional

Published
2023
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7. Whole-Body MRI Surveillance—Baseline Findings in the Swedish Multicentre Hereditary TP53-Related Cancer Syndrome Study (SWEP53)

Author

Meis Omran, Emma Tham, Yvonne Brandberg, Håkan Ahlström, Claudia Lundgren, Ylva Paulsson-Karlsson, Ekaterina Kuchinskaya, Gustav Silander, Anna Rosén, Fredrik Persson, Henrik Leonhardt, Marie Stenmark-Askmalm, Johanna Berg, Danielle van Westen, Svetlana Bajalica-Lagercrantz, Lennart Blomqvist, and on behalf of the Swedish Clinical TP53 Study Group (SweClinTP53)

Subjects
cancer, cancer prevention, clinically actionable TP53 variant, germline TP53, hTP53rc syndrome, Li–Fraumeni, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

A surveillance strategy of the heritable TP53-related cancer syndrome (hTP53rc), commonly referred to as the Li–Fraumeni syndrome (LFS), is studied in a prospective observational nationwide multi-centre study in Sweden (SWEP53). The aim of this sub-study is to evaluate whole-body MRI (WB-MRI) regarding the rate of malignant, indeterminate, and benign imaging findings and the associated further workup generated by the baseline examination. Individuals with hTP53rc were enrolled in a surveillance program including annual whole-body MRI (WB-MRI), brain-MRI, and in female carriers, dedicated breast MRI. A total of 68 adults ≥18 years old have been enrolled to date. Of these, 61 fulfilled the inclusion criteria for the baseline MRI scan. In total, 42 showed a normal scan, while 19 (31%) needed further workup, of whom three individuals (3/19 = 16%) were diagnosed with asymptomatic malignant tumours (thyroid cancer, disseminated upper GI cancer, and liver metastasis from a previous breast cancer). Forty-three participants were women, of whom 21 had performed risk-reducing mastectomy prior to inclusion. The remaining were monitored with breast MRI, and no breast tumours were detected on baseline MRI. WB-MRI has the potential to identify asymptomatic tumours in individuals with hTP53rc syndrome. The challenge is to adequately and efficiently investigate all indeterminate findings. Thus, a multidisciplinary team should be considered in surveillance programs for individuals with hTP53rc syndrome.

Published
2022
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8. Proceedings of the 23rd Paediatric Rheumatology European Society Congress: part two

Author

Olga Lomakina, Ekaterina Alekseeva, Sania Valieva, Tatiana Bzarova, Irina Nikishina, Elena Zholobova, Svetlana Rodionovskaya, Maria Kaleda, Yasuo Nakagishi, Masaki Shimizu, Mao Mizuta, Akihiro Yachie, Yuko Sugita, Nami Okamoto, Kousuke Shabana, Takuji Murata, Hiroshi Tamai, Eve M. Smith, Peng Yin, Andrea L. Jorgensen, Michael W. Beresford, on behalf of On behalf of the UK JSLE Cohort Study, Antonio Eleuteri, Beatrice Goilav, Laura Lewandowski, Angel Phuti, Dawn Wahezi, Tamar Rubinstein, Caroline Jones, Paul Newland, Stephen Marks, Rachel Corkhill, Diana Ekdawy, Clarissa Pilkington, Kjell Tullus, Chaim Putterman, Chris Scott, Antony C. Fisher, Andrea Jorgensen, Ezgi Deniz Batu, Can Kosukcu, Ekim Taskiran, Sema Akman, Kubra Ozturk, Betul Sozeri, Erbil Unsal, Zelal Ekinci, Yelda Bilginer, Mehmet Alikasifoglu, Seza Ozen, Hanna Lythgoe, Hermine I. Brunner, Gaurav Gulati, Jordan T. Jones, Mekibib Altaye, Jamie Eaton, Mark Difrancesco, Joo Guan Yeo, Jingyao Leong, Loshinidevi D/O Thana Bathi, Thaschawee Arkachaisri, Salvatore Albani, Nagla Abdelrahman, Michael W Beresford, Valentina Leone, UK JSLE study group supported by the National Institute of Health Research Clinical Research Network, Noortje Groot, D. Shaikhani, I. E. M. Bultink, M. Bijl, R. J. E. M. Dolhain, Y. K. O. Teng, E. Zirkzee, K. de Leeuw, R. Fritsch-Stork, S. S. M. Kamphuis, Rachael D. Wright, Reem Abdawani, Laila Al Shaqshi, Ibrahim Al Zakwani, Natali W. Gormezano, David Kern, Oriany L. Pereira, Gladys C. C. Esteves, Adriana M. Sallum, Nadia E. Aikawa, Rosa M. Pereira, Clovis A. Silva, Eloisa Bonfa, Jessica Beckmann, Nora Bartholomä, Nils Venhoff, Philipp Henneke, Ulrich Salzer, Ales Janda, Alina Lucica Boteanu, Sandra Garrote Corral, Alberto Sifuentes Giraldo, Mariluz Gámir Gámir, Antonio Zea Mendoza, Amra Adrovic, Reyhan Dedeoglu, Sezgin Sahin, Kenan Barut, Aida Koka, Funda Oztunc, Ozgur Kasapcopur, Ana Luisa Rodriguez-Lozano, Francisco Rivas-Larrauri, Silvestre García de la Puente, Andressa G. F. Alves, Maria F. D. A. Giacomin, Juliana Farhat, Alfésio L. F. Braga, Adriana M. E. Sallum, Lúcia M. D. A. Campos, Luiz A. A. Pereira, Ana J. D. F. C. Lichtenfels, Clóvis A. Silva, Sylvia C. L. Farhat, Banu Acar, Z. Birsin Ozcakar, Nilgün Çakar, Nermin Uncu, Gökçe Gür, Semanur Özdel, Fatoş Yalçınkaya, Christiaan Scott, Nicky Brice, Peter Nourse, Christine Arango, Angela C. Mosquera, Clara Malagon, Ana P. Sakamoto, Marco F. C. D. Silva, Ananadreia S. Lopes, Gleice C. S. Russo, Adriana E. M. Sallum, Katia Kozu, Eloisa Bonfá, Claudia Saad-Magalhães, Rosa M. R. Pereira, Claudio A. Len, Maria T. Terreri, Deepti Suri, Siyaram Didel, Amit Rawat, Surjit Singh, Despoina Maritsi, MArgarita Onoufriou, Olga Vougiouka, Maria Tsolia, Edi Paleka Bosak, Mandica Vidović, Mirta Lamot, Lovro Lamot, Miroslav Harjaček, Erika Van Nieuwenhove, Adrian Liston, Carine Wouters, Fatemeh Tahghighi, Vahid Ziaee, Seid-Reza Raeeskarami, Francisca Aguiar, Sandra Pereira, Mariana Rodrigues, Cláudia Moura, Gustavo Rocha, Hercília Guimarães, Iva Brito, Rita Fonseca, Gerd Horneff, Ariane Klein, Kirsten Minden, Hans-Iko Huppertz, Frank Weller-Heinemann, Jasmin Kuemmerle-Deschner, J-Peter Haas, Anton Hospach, BIKER collaborative group, Ricardo Menendez-Castro, Boris Huegle, Johannes-Peter Haas, Joost Swart, Gabriella Giancane, Francesca Bovis, Elio Castagnola, Andreas Groll, Daniel J. Lovell, Tom Wolfs, Michael Hofer, Violeta Panaviene, Susan Nielsen, Jordi Anton, Florence Uettwiller, Valda Stanevicha, Maria Trachana, Denise Pires Marafon, Constantin Ailioaie, Elena Tsitsami, Sylvia Kamphuis, Troels Herlin, Pavla Doležalová, Gordana Susic, Berit Flatø, Flavio Sztajnbok, Angela Pistorio, Alberto Martini, Nico Wulffraat, Nicolino Ruperto, Marco Gattorno, Antonio Brucato, Martina Finetti, George Lazaros, Silvia Maestroni, Mara Carraro, Davide Cumetti, Alessandra Carobbio, Monia Lorini, Alessandro Rimini, Renzo Marcolongo, Anna Valenti, Gian Luca Erre, Riccardo Belli, Fiorenzo Gaita, Maria Pia Sormani, Massimo Imazio, Mario Abinun, Nicola Smith, Tim Rapley, Flora McErlane, Lianne Kearsley-Fleet, Kimme L. Hyrich, Helen Foster, Nikolay Tzaribachev, Andrew Zeft, Rolando Cimaz, John Bohnsack, Thomas Griffin, Ruy Carrasco, Jason Dare, Ivan Foeldvari, Richard Vehe, Teresa Simon, Hermine Brunner, S. Verazza, S. Davì, A. Consolaro, A. Insalaco, V. Gerloni, R. Cimaz, F. Zulian, S. Pastore, F. Corona, G. Conti, P. Barone, M. Cattalini, E. Cortis, L. Breda, A. N. Olivieri, A. Civino, R. Podda, D. Rigante, F. La Torre, G. D’Angelo, M. Jorini, R. Gallizzi, M. C. Maggio, R. Consolini, A. De Fanti, M. G. Alpigiani, A. Martini, A. Ravelli, on behalf of Italian Pediatric Rheumatology Study Group, Aysenur Pac Kısaarslan, Zubeyde Gunduz, Ruhan Dusunsel, Ismail Dursun, Hakan Poyrazoglu, Ekaterina Kuchinskaya, Farida Abduragimova, Mikhail Kostik, Erik Sundberg, Soley Omarsdottir, Lena Klevenvall, Helena Erlandsson-Harris, Gokalp Basbozkurt, Ozge Erdemli, Dogan Simsek, Fatih Yazici, Yildirim Karsioglu, Aysen Tezcaner, Dilek Keskin, Huseyin Ozkan, Cengizhan Acikel, Erkan Demirkaya, Ilonka Orbán, Krisztina Sevcic, Valentin Brodszky, Emese Kiss, Ismaiel A. Tekko, Madeleine Rooney, James McElnay, Cliff Taggart, Helen McCarthy, Ryan F. Donnelly, Drug Delivery Group, Mary Slatter, Zohreh Nademi, Mark Friswell, Sharmila Jandial, Terence Flood, Sophie Hambleton, Andrew Gennery, Andrew Cant, Phoi-Ngoc Duong, Isabelle Koné-Paut, Giovanni Filocamo, María Luz Gamir, Helga Sanner, Laura Carenini, Mesut Topdemir, Yildirim Karslioglu, Faysal Gok, Nadezhda Tsurikova, Elena Ligostaeva, Navdha R. Ramchurn, O. Kostareva, I. Nikishina, S. Arsenyeva, S. Rodionovskaya, M. Kaleda, D. Alexeev, Ismail Dursun Dursun, Sara Murias, Estefania Barral, Rosa Alcobendas, Eugenia Enriquez, Agustin Remesal, Jaime de Inocencio, Tania M. Castro, Simone A. Lotufo, Tatjana Freye, Raffaella Carlomagno, Thomas Zumbrunn, Jan Bonhoeffer, Elvira Cannizzaro Schneider, Daniela Kaiser, Michaël Hofer, Véronique Hentgen, Andreas Woerner, Juvenile Inflammatory Rheumatism (JIR) Cohort, Tobias Schwarz, Jens Klotsche, Martina Niewerth, Gerd Ganser, ICON study group, Jerold Jeyaratnam, Nienke ter Haar, Donato Rigante, Fatma Dedeoglu, Ezgi Baris, Sebastiaan Vastert, Joost Frenkel, Jonathan S. Hausmann, Kathleen G. Lomax, Ari Shapiro, Karen L. Durrant, P. A. Brogan, M. Hofer, J. B. Kuemmerle-Deschner, B. Lauwerys, A. Speziale, K. Leon, X. Wei, R. M. Laxer, Sara Signa, Marta Rusmini, Elena Campione, Sabrina Chiesa, Alice Grossi, Alessia Omenetti, Roberta Caorsi, Gianmaria Viglizzo, Isabella Ceccherini, Silvia Federici, Helen Lachmann, Nicola Ruperto, on behalf of PRINTO and Eurofever Registry, Federica Vanoni, on behalf of PRINTO and Eurofever Project, Sonia Melo Gomes, Ebun Omoyinmi, Juan I. Arostegui, Eva Gonzalez-Roca, Despina Eleftheriou, Nigel Klein, Paul Brogan, Stefano Volpi, Elettra Santori, Paolo Picco, Claudia Pastorino, Gillian Rice, Alessandra Tesser, Yanick Crow, Fabio Candotti, Ada B. Sinoplu, Gozde Yucel, Gizem Pamuk, Laura O. Damian, Cecilia Lazea, Mihaela Sparchez, Paulina Vele, Laura Muntean, Adriana Albu, Simona Rednic, Calin Lazar, Leonardo O. Mendonça, Alessandra Pontillo, Jorge Kalil, Fabio M. Castro, Myrthes T. Barros, Manuela Pardeo, Virginia Messia, Fabrizio De Benedetti, Antonella Insalaco, Giorgia Malighetti, Chiara Gorio, Francesca Ricci, Ilaria Parissenti, Paola Montesano, Barbara Bonafini, Veronica Medeghini, Marco Cattalini, Lucio Giordano, Giulia Zani, Rosalba Ferraro, Donatella Vairo, Silvia Giliani, Maria Cristina Maggio, Girolamo Luppino, Giovanni Corsello, Maria Isabel Gonzalez Fernandez, Berta Lopez Montesinos, Adriana Rodriguez Vidal, Juan I. Arostegui Gorospe, Inmaculada Calvo Penades, Nadia K. Rafiq, Karen Wynne, Khalid Hussain, Paul A. Brogan, Elizabeth Ang, Nicholas Ng, Ayla Kacar, Ozge Altug Gucenmez, Balahan Makay, Sevket Erbil Unsal, Yasin Sahin, Tufan Kutlu, Fugen Cullu-Cokugras, Hasret Ayyildiz-Civan, Tulay Erkan, Sana Al Zuhbi, Eiman Abdalla, Ricardo A. Russo, María M. Katsicas, Francesca Minoia, Angelo Ravelli, Sagar Bhattad, Anju Gupta, Vignesh Pandiarajan, Ritambhra Nada, Kaara Tiewsoh, Philip Hawkins, Dorota Rowczenio, Sarka Fingerhutova, Jana Franova, Leona Prochazkova, Eva Hlavackova, Pavla Dolezalova, Havva Evrengül, Selçuk Yüksel, Mustafa Doğan, Dolunay Gürses, Harun Evrengül, Silvia De Pauli, Serena Pastore, Anna Monica Bianco, Giovanni Maria Severini, Andrea Taddio, Alberto Tommasini, Svetlana O. Salugina, Evgeny Fedorov, Elena Kamenets, Ekaterina Zaharova, Tatiana Sleptsova, Ekaterina Alexeeva, Kirill Savostyanov, Alexander Pushkov, Tatyana Bzarova, Saniya Valieva, Rina Denisova, Kseniya Isayeva, Evgeniya Chistyakova, Margarita Soloshenko, Elena Kaschenko, Utako Kaneko, Chihaya Imai, Akihiko Saitoh, Vitor A. Teixeira, Filipa O. Ramos, Manuela Costa, Yonatan Butbul Aviel, Shafe Fahoum, Riva Brik, Zeynep Birsin Özçakar, Banu Acar Celikel, Fatos Yalcinkaya, Benedetta Schiappapietra, Sergio Davi’, Federica Mongini, Luisa Giannone, Cecilia Bava, Maria Giannina Alpigiani, Alessandro Consolaro, Dragana S. Lazarevic, Jelena Vojinovic, Jelena Basic, Valentina Muratore, Valentina Marzetti, Neus Quilis, Belen Serrano Benavente, Alessandra Alongi, Adele Civino, Lorenzo Quartulli, Giedre Januskeviciute, Pieter van Dijkhuizen, N. Groot, W. van Dijk, A. Kardolus, Raul Gutiérrez Suárez, Ellen B. Nordal, Veronika G. Rypdal, Lillemor Berntson, Maria Ekelund, Kristiina Aalto, Suvi Peltoniemi, Marek Zak, Mia Glerup, Ellen D. Arnstad, Anders Fasth, Marite Rygg, the Nordic Study Group of Pediatric Rheumatology (NoSPeR), Ana Catarina Duarte, Sandra Sousa, Lídia Teixeira, Ana Cordeiro, Mª José Santos, Ana Filipa Mourão, Maria José Santos, Mónica Eusébio, Ana Lopes, Filipa Oliveira-Ramos, Manuel Salgado, Paula Estanqueiro, José Melo-Gomes, Fernando Martins, José Costa, Carolina Furtado, Ricardo Figueira, Jaime C. Branco, João E. Fonseca, Helena Canhão, Ana F. Mourão, Maria Jose Santos, Andrea Coda, Samuel Cassidy, Kerry West, Gordon Hendry, Debra Grech, Julie Jones, Fiona Hawke, Davinder Singh Grewal, Charlene Foley, Orla Killeen, Emma MacDermott, Douglas Veale, Ursula Fearon, Dilek Konukbay, Ela Tarakci, Nilay Arman, Sezgin Şahin, Jane Munro, Esi Morgan, Meredith Riebschleger, Jennifer Horonjeff, Vibeke Strand, Clifton Bingham, Ma. Theresa M. Collante, Margarita Ganeva, Stefan Stefanov, Albena Telcharova, Dimitrina Mihaylova, Radoslava Saraeva, Reni Tzveova, Radka Kaneva, Adelina Tsakova, Katya Temelkova, GRANT Medical University, Sofia 68/, Maria Mercedes C. Picarelli, Luiz C. Danzmann, Florencia Barbé-Tuana, Lucas K. Grun, Marcus H. Jones, Marijan Frković, Karla Ištuk, Ika Birkić, Saša Sršen, Marija Jelušić, Alan Easton, Rachael Quarmby, Raju Khubchandani, Mercedes Chan, Radoslav Srp, Katerina Kobrova, Dana Nemcova, Jozef Hoza, Michal Uher, Melania Saifridova, Lenka Linkova, Sirirat Charuvanij, Isree Leelayuwattanakul, Thita Pacharapakornpong, Sakda A.-O. Vallipakorn, Butsabong Lerkvaleekul, Soamarat Vilaiyuk, Stefano Lanni, Sergio Davì, Randy Q. Cron, Chiara Passarelli, Elisa Pisaneschi, Antonio Novelli, Claudia Bracaglia, Ivan Caiello, Kathy de Graaf, Florence Guilhot, Walter Ferlin, Grant Schulert, Alexi A. Grom, Robert Nelson, Cristina de Min, Dirk Holzinger, Christoph Kessel, Ndate Fall, Alexei Grom, Wilco de Jager, Raffaele Strippoli, Anna Horne, Stephan Ehl, Sandra Ammann, Kai Lehmberg, Karin Beutel, Dirk Foell, AnnaCarin Horne, Laura Pagani, Graciela Espada, Yi-jin Gao, Susan Shenoi, Sheila Weitzman, Giusi Prencipe, Antonia Pascarella, Walter G. Ferlin, Laurence Chatel, Philippe Jacqmin, Kathy De Graaf, Maria Ballabio, Zoë Johnson, Geneviève Lapeyre, Fabrizio de Benedetti, de Min Cristina, Hiroyuki Wakiguchi, Shunji Hasegawa, Reiji Hirano, Fumiko Okazaki, Tamaki Nakamura, Hidenobu Kaneyasu, Shouichi Ohga, Kazuko Yamazaki, Tomo Nozawa, Taichi Kanetaka, Shuichi Ito, Shumpei Yokota, Kirsty McLellan, Ishbel MacGregor, Neil Martin, Joyce Davidson, Sandra Hansmann, Andreas Eikelberg, Iris Haug, Sabrina Schuller, Susanne M. Benseler, Single Hub and Access point for paediatric Rheumatology in Europe (SHARE), Liliia S. Nazarova, Kseniia V. Danilko, Viktor A. Malievsky, Tatiana V. Viktorova, Angela Mauro, Angela Barnicoat, Jane Hurst, Nathalie Canham, Sandrine Lacassagne, Anastasia Wiener, Boris Hügle, Bernd Denecke, Ivan Costa-Filho, Johannes Peter Haas, Klaus Tenbrock, David Popp, Arjan Boltjes, Frank Rühle, Stefanie Herresthal, Femke van Wijk, Joachim Schultze, Monika Stoll, Luisa Klotz, Thomas Vogl, Johannes Roth, Estefania Quesada-Masachs, Daniel Álvarez de la Sierra, Marina Garcia Prat, Ana M. Marín Sánchez, Ricardo Pujol Borrell, Sara Marsal Barril, Mónica Martínez Gallo, Consuelo Modesto Caballero, Iryna Chyzheuskaya, Lyudmyla M. Byelyaeva, Rostislav M. Filonovich, Helena K. Khrustaleva, Larisa I. Zajtseva, Tamara M. Yuraga, Thomas Giner, Lukas Hackl, Julia Albrecht, Reinhard Würzner, Juergen Brunner, Marta Minute, Fulvio Parentin, Agostino Nocerino, Mette Nørgaard, Mikel Alberdi-Saugstrup, Marek S. Zak, Susan M. Nielsen, Ellen Nordal, Klaus G. Müller, Nordic Study Group of Pediatric Rheumatology (NoSPeR), Mojca Zajc Avramovič, Vita Dolžan, Nataša Toplak, Tadej Avčin, N. Ruperto, D. J. Lovell, C. Wallace, M. Toth, I. Foeldvari, J. Bohnsack, D. Milojevic, C. Rabinovich, D. Kingsbury, K. Marzan, P. Quartier, K. Minden, E. Chalom, G. Horneff, R. M. Kuester, J. Dare, M. Heinrich, H. Kupper, J. Kalabic, H. I. Brunner, on behalf of PRINTO and PRCSG, Ruben Burgos-Vargas, Tamas Constantin, Joke Dehoorne, Valda Stanevica, Katarzyna Kobusinska, Zbigniew Zuber, Richard Mouy, Ingrida Rumba-Rozenfelde, Chantal Job-Deslandre, Ronald Pederson, Jack Bukowski, Tina Hinnershitz, Bonnie Vlahos, Paula Keskitalo, Salla Kangas, Paula Vähäsalo, Raul A. Chavez Valencia, David Martino, Anne-Louise Ponsonby, Rachel Chiaroni-Clarke, Braydon Meyer, Roger C. Allen, Jonathan D. Akikusa, Jeffrey M. Craig, Richard Saffrey, Justine A. Ellis, Carol Wallace, Yosef Uziel, Gary Sterba, Rayfel Schneider, Ricardo Russo, Athimalaipet V. Ramanan, Jana Pachlopnik Schmid, Kim E Nichols, Paivi Miettunen, Toshiyuki Kitoh, Norman T. Ilowite, Jan-Inge Henter, Alexei A Grom, Edward M. Behrens, Tadej Avcin, Maurizio Aricò, Sriharsha Grevich, Peggy Lee, Sarah Ringold, Brian Leroux, Hannah Leahey, Megan Yuasa, Jessica Foster, Jeremy Sokolove, Lauren Lahey, William Robinson, Joshua Newson, Anne Stevens, Stephanie J. W. Shoop, Suzanne M. M. Verstappen, Wendy Thomson, Janet E. McDonagh, CAPS, Timothy Beukelman, Yuki Kimura, Marc Natter, Norm Ilowite, Kelly Mieszkalski, Grendel Burrell, Brian Best, Helen Bristow, Shannon Carr, Anne Dennos, Rachel Kaufmann, Laura Schanberg, for the CARRA Registry Investigators, Gabriele Simonini, Francesca Lancini, Margaux Gerbaux, Phu-Quoc Lê, Laurence Goffin, Valérie Badot, Céline La, Laure Caspers, François Willermain, Alina Ferster, Maria Ceci, Francesco Licciardi, Marco Turco, Francesca Santarelli, Davide Montin, Claudia Toppino, Clotilde Alizzi, Bruno Papia, Beatrice Vergara, Umberto Corpora, Luca Messina, Maria Tsinti, Vasiliko Dermentzoglou, Panagiotis Tziavas, Marija Perica, Lana Tambić Bukovac, Mustafa Çakan, Nuray Aktay Ayaz, Gonca Keskindemirci, Michael Lang, Catherine Laing, Susanne Benseler, Tommy Gerschman, Nadia Luca, Heinrike Schmeling, Anastasia Dropol, Jaymi Taiani, Nicole Johnson, Brian Rusted, Panagiota Nalbanti, Polyxeni Pratsidou, Grigoris Pardalos, Vasiliki Tzimouli, Anna Taparkou, Maria Stavrakidou, Fotios Papachristou, Florence Kanakoudi-Tsakalidou, Peter Bale, Emily Robinson, Jason Palman, Elizabeth Ralph, Kimberly Gilmour, Clare Heard, Lucy R. Wedderburn, Yara Barrense-Dias, Antonarakis Gregory, Dhouib Amira, Scolozzi Paolo, Hanquinet Sylviane, Hofer Michaël, Nataliya Panko, Salah Shokry, Liudmila Rakovska, Sally Pino, Adriana Diaz-Maldonado, Pilar Guarnizo, Sofia Torreggiani, Paolo Cressoni, Umberto Garagiola, Giancarla Di Landro, Giampietro Farronato, Fabrizia Corona, Samantha Bell, Parveen Bhatti, Lee Nelson, Beth A. Mueller, T. A. Simon, A. Baheti, N. Ray, Z. Guo, Anasuya Hazra, Thomas Stock, Ronnie Wang, Charles Mebus, Christine Alvey, Manisha Lamba, Sriram Krishnaswami, Umberto Conte, Min Wang, Daniel Kingsbury, Elena Koskova, Elzbieta Smolewska, Richard K. Vehe, Daniel Lovell, Tomohiro Kubota, Junko Yasumura, Toshitaka Kizawa, Masato Yashiro, Tsuyoshi Yamatou, Yuichi Yamasaki, Syuji Takei, Yoshifumi Kawano, Ulrika Järpemo Nykvist, Bo Magnusson, Rikard Wicksell, Karin Palmblad, Gunnar L. Olsson, Mohammadreza Modaressi, Mohammad-Hassan Moradinejad, Valentina Seraya, Alisa Vitebskaya, Veronica Moshe, Gil Amarilyo, Liora Harel, Phillip J Hashkes, Amir Mendelson, Noa Rabinowicz, Yonit Reis, Zane Dāvidsone, Arina Lazareva, Ruta Šantere, Dace Bērziņa, Valda Staņēviča, Giulia Camilla Varnier, Susan Maillard, Cristina Ferrari, Silvia Zaffarano, Juvenile Dermatomyositis Research Group and European Federation of Immunological Societies, Judith Wienke, Felicitas Bellutti Enders, Lucas L. van den Hoogen, Jorre S. Mertens, Timothy R. Radstake, Henny G. Hotten, Ruth Fritsch, Lucy Wedderburn, Kiran Nistala, Berent Prakken, Annet van Royen-Kerkhof, Mohammad Alhemairi, Mohammed Muzaffer, Pieter Van Dijkhuizen, Claire T. Deakin, Stefania Simou, Maria De Iorio, Qiong Wu, Tania Amin, Lee Dossetter, Juvenile Dermatomyositis Research Group (JDRG), Raquel Campanilho-Marques, Claire Deakin, Clarissa A. Pilkington, on behalf of Juvenile Dermatomyositis Research Group (JDRG), Silvia Rosina, Sirisucha Soponkanaporn, on behalf of the UK Juvenile Dermatomyositis Research Group (JDRG), Zehra S. Arıcı, Gökçen D. Tuğcu, Ezgi D. Batu, Hafize E. Sönmez, Deniz Doğru-Ersöz, Beril Talim, Nural Kiper, Seza Özen, Alexander Solyom, Ezgi Batu, John Mitchell, Ariana Kariminejad, Fatemeh Hadipour, Zahra Hadipour, Marta Torcoletti, Carlo Agostoni, Maja Di Rocco, Pranoot Tanpaiboon, Andrea Superti-Furga, Luisa Bonafé, Nur Arslan, Norberto Guelbert, Karoline Ehlert, Giedre Grigelioniene, Ratna Puri, Edward Schuchman, Pilar Gomez, Tatiana Gonzalez, Ricardo Yepez, Camilo Vargas, GRIP study group, Falcini Fernanda, Gemma Lepri, Alessandra Ferrari, Marco Matucci-Cerinic, Antonella Meini, Gian Marco Moneta, Emiliano Marasco, Rebecca Nicolai, Luisa Bracci-Laudiero, Olga Kopchak, Alexander Mushkin, Alexey Maletin, Catalina Mosquera, Rita A. Amorim, Juliana Molina, Gustavo Moreira, Flávia H. Santos, Melissa Fraga, Livia Keppeke, Vanessa M. Silva, Camila Hirotsu, Sergio Tufik, Maria Teresa Terreri, Vinícius L. Braga, Maria Beatriz Fonseca, Vania Schinzel, Maria Teresa R. Terreri, Liliana Jorge, Liana Guerra, Edson Amaro Junior, Maria Cristina Castiglione, Alessandra Tricarico, Emily Boulter, Andre Schultz, Kevin Murray, Fernanda Falcini, Stefano Stagi, Eleonora Bellucci, Ingrid H. R. Grein, Gecilmara Pileggi, Natália B. F. Pinto, Aline L. de Oliveira, Lyudmila Belyaeva, Rostislav Filonovich, Helena Khrustaleva, Larisa Zajtseva, Jaanika Ilisson, Chris Pruunsild, Olivier Gilliaux, Francis Corazza, Christophe Lelubre, on behalf of PANLAR Pediatric Rheumatology Study Group, Zoilo Morel, Claudia Saad-Magalhães C, Luis Lira, Mabel Ladino, Ruth Eraso, Ivonne Arroyo, Clovis Silva, Carlos Rose, and PANLAR Pediatric Rheumatology Study Group

Subjects
Pediatrics, RJ1-570, Diseases of the musculoskeletal system, RC925-935
Published
2017
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10. Whole-body MRI surveillance in TP53 carriers is perceived as beneficial with no increase in cancer worry regardless of previous cancer: Data from the Swedish TP53 Study

Author

Meis, Omran, Hemming, Johansson, Claudia, Lundgren, Gustav, Silander, Marie, Stenmark-Askmalm, Niklas, Loman, Annika, Baan, Jamila, Adra, Ekaterina, Kuchinskaya, Lennart, Blomqvist, Emma, Tham, Svetlana, Bajalica-Lagercrantz, and Yvonne, Brandberg

Subjects
Cancer och onkologi, Cancer Research, cancer worry scale, health-related quality-of-life, hereditary cancer, heritable TP53-related cancer syndromes, Li-Fraumeni syndrome, surveillance, Oncology, Cancer and Oncology
Abstract

BackgroundTo evaluate the psychosocial consequences of surveillance with whole-body MRI (WB-MRI) in individuals with the heritable TP53-related cancer (hTP53rc) syndrome, also known as the Li-Fraumeni syndrome, with regard to cancer worry, perceived benefits and risks to surveillance and overall health. Patients and methodsSince 2016, the national Swedish TP53 Study (SWEP53) has offered surveillance with WB-MRI to all individuals with hTP53rc syndrome. Seventy-five individuals have been included in the study. Sixty consecutive participants fulfilled a base-line evaluation as well as an evaluation after 1 year with structured questionnaires including the Cancer Worry Scale (CWS), perceived benefits and risks of surveillance, and the 36-item Short Form Survey (SF-36). Individuals with or without previous personal cancer diagnosis were enrolled and results at baseline and after 1 year of surveillance were compared. For SF-36, a comparison with the normal population was also made. ResultsParticipants with previous cancer tend to worry more about cancer, but both individuals with and without cancer had a positive attitude toward surveillance with no differences regarding perceived benefits and barriers to surveillance. Participants with a previous cancer scored significantly lower on some of the SF-36 subscales, but between-group differences were found only for social functioning after 1 year. ConclusionsSurveillance with WB-MRI is feasible from a psychosocial point of view both among TP53 carriers with as well as without a previous history of cancer and does not increase cancer worry in any of the groups. Plain language summary Individuals with heritable TP53-related cancer syndrome (also known as the Li-Fraumeni syndrome) have a high lifetime risk of developing cancer.These TP53 carriers are offered surveillance with whole-body MRI to detect cancer early. There are few reports of the psychosocial impact of surveillance.In this study, we wanted to evaluate cancer worry, benefits and barriers to participation, and perceived overall health.Our study shows no increase in cancer worry after 1 year of surveillance, regardless of previous cancer. Funding Agencies|Cancer Research Funds of Radiumhemmet [201052]; Swedish Childhood Cancer Fund [TJ2018-0054, TJ2021-0125]; Cancer Research KI; Stockholm County Council [SLL20180046, SLL500306]; Rare Disease Research Foundation; Swedish Cancer Society [CAN 2016/775]

Published
2022

11. Familial platelet disorder due to germline exonic deletions in

Author

Marie, Engvall, Ylva, Karlsson, Ekaterina, Kuchinskaya, Åsa, Jörnegren, Lucy, Mathot, Tatjana, Pandzic, Josefine, Palle, Viktor, Ljungström, Lucia, Cavelier, Eva, Hellström Lindberg, Jörg, Cammenga, and Panagiotis, Baliakas

Subjects
Leukemia, Myeloid, Acute, Germ Cells, Core Binding Factor Alpha 2 Subunit, Humans, Protein Isoforms, Blood Platelet Disorders, Exons
Abstract

Germline pathogenic variants in

Published
2022

12. Genome sequencing is a sensitive first-line test to diagnose individuals with intellectual disability

Author

Anna Lindstrand, Marlene Ek, Malin Kvarnung, Britt-Marie Anderlid, Erik Björck, Jonas Carlsten, Jesper Eisfeldt, Giedre Grigelioniene, Peter Gustavsson, Anna Hammarsjö, Hafdís T. Helgadóttir, Maritta Hellström-Pigg, Ekaterina Kuchinskaya, Kristina Lagerstedt-Robinson, Lars-Åke Levin, Agne Lieden, Hillevi Lindelöf, Helena Malmgren, Daniel Nilsson, Eva Svensson, Martin Paucar, Ellika Sahlin, Bianca Tesi, Emma Tham, Johanna Winberg, Max Winerdal, Josephine Wincent, Maria Johansson Soller, Maria Pettersson, and Ann Nordgren

Subjects
Fragile X Mental Retardation Protein, Neurodevelopmental Disorders, Chromosomal microarray, Clinical diagnostics, FMR1 analysis, Genome sequencing, Intellectual disability, Intellectual Disability, Developmental Disabilities, Humans, Genetic Testing, Child, Microarray Analysis, Medical Genetics, Genetics (clinical), Medicinsk genetik, Pathology and Forensic Medicine
Abstract

Purpose: Individuals with intellectual disability (ID) and/or neurodevelopment disorders (NDDs) are currently investigated with several different approaches in clinical genetic diagnostics. Methods: We compared the results from 3 diagnostic pipelines in patients with ID/NDD: genome sequencing (GS) first (N = 100), GS as a secondary test (N = 129), or chromosomal microarray (CMA) with or without FMR1 analysis (N = 421). Results: The diagnostic yield was 35% (GS -first), 26% (GS as a secondary test), and 11% (CMA/FMR1). Notably, the age of diagnosis was delayed by 1 year when GS was performed as a secondary test and the cost per diagnosed individual was 36% lower with GS first than with CMA/FMR1. Furthermore, 91% of those with a negative result after CMA/FMR1 analysis (338 individuals) have not yet been referred for additional genetic testing and remain undiagnosed. Conclusion: Our findings strongly suggest that genome analysis outperforms other testing strategies and should replace traditional CMA and FMR1 analysis as a first-line genetic test in individuals with ID/NDD. GS is a sensitive, time-and cost-effective method that results in a confirmed molecular diagnosis in 35% of all referred patients. (c) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Published
2022

13. Familial platelet disorder due to germline exonic deletions in RUNX1 : a diagnostic challenge with distinct alterations of the transcript isoform equilibrium

Author

Marie Engvall, Ylva Karlsson, Ekaterina Kuchinskaya, Åsa Jörnegren, Lucy Mathot, Tatjana Pandzic, Josefine Palle, Viktor Ljungström, Lucia Cavelier, Eva Hellström Lindberg, Jörg Cammenga, and Panagiotis Baliakas

Subjects
Cancer Research, Oncology, FPD, hemic and lymphatic diseases, leukemia, RUNX1 deletions, thrombocytopenia, MM, Hematology, Hematologi
Abstract

Germline pathogenic variants in RUNX1 are associated with familial platelet disorder with predisposition to myeloid malignancies (FPD/MM) with intragenic deletions in RUNX1 accounting for almost 7% of all reported variants. We present two new pedigrees with FPD/MM carrying two different germline RUNX1 intragenic deletions. The aforementioned deletions encompass exons 1-2 and 9-10 respectively, with the exon 9-10 deletion being previously unreported. RNA sequencing of patients carrying the exon 9-10 deletion revealed a fusion with LINC00160 resulting in a change in the 3 sequence of RUNX1. Expression analysis of the transcript isoform demonstrated altered RUNX1a/b/c ratios in carriers from both families compared to controls. Our data provide evidence on the impact of intragenic RUNX1 deletions on transcript isoform expression and highlight the importance of routinely performing copy number variant analysis in patients with suspected MM with germline predisposition. Funding Agencies|Lions Cancer Research Foundation, Uppsala

Published
2022

14. Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition

Author

Alisa Olkinuora, Taina T. Nieminen, Emma Mårtensson, Anna Rohlin, Ari Ristimäki, Laura Koskenvuo, Anna Lepistö, Samuel Gebre-Medhin, Margareta Nordling, Päivi Peltomäki, Gustav Silander, Ekaterina Kuchinskaya, Christos Aravidis, Theofanis Zagoras, Mef Nilbert, Åke Borg, Department of Medical and Clinical Genetics, Medicum, Department of Pathology, HUSLAB, Genome-Scale Biology (GSB) Research Program, Research Programs Unit, HUS Abdominal Center, II kirurgian klinikka, Clinicum, and Department of Surgery

Subjects
0301 basic medicine, polyposis, MLH3, HEREDITARY, 030105 genetics & heredity, Biology, Familial adenomatous polyposis, Loss of heterozygosity, 03 medical and health sciences, Chromosome instability, medicine, Genetics (clinical), Exome sequencing, Genetics, HMLH3, MUTATIONS, Haplotype, 1184 Genetics, developmental biology, physiology, DNA MISMATCH REPAIR, MSH3, medicine.disease, CANCER, 3. Good health, 030104 developmental biology, biallelic germline variant, DNA mismatch repair, 3111 Biomedicine
Abstract

Purpose: Some 10% of familial adenomatous polyposis (FAP) and 80% of attenuated polyposis (AFAP) cases remain molecularly unexplained. We scrutinized such cases by exome-wide and targeted methods to search for novel susceptibility genes. Methods: Exome sequencing was conducted on 40 unexplained (mainly sporadic) cases with FAP or AFAP from Finland. The DNA mismatch repair (MMR) gene MLH3 (MutL Homolog 3) was pinpointed and prompted a subsequent screen of similar to 1000 Swedish patients referred to clinical panel sequencing for colon tumor susceptibility. Results: Three homozygous carriers of a truncating variant in MLH3, c.3563C>G, p.Ser1188Ter, were identified among the index cases from the Finnish series. An additional biallelic carrier of the same variant was present in the Swedish series. All four patients shared a 0.8-Mb core haplotype around MLH3, suggesting a founder variant. Colorectal polyps from variant carriers showed no instability at mono-, di-, tri-, or tetranucleotide repeats, in agreement with previous findings of a minor role of MLH3 in MMR. Multiple loci were affected by loss of heterozygosity, suggesting chromosomal instability. Conclusion: Our results show that a biallelic nonsense variant of MLH3 underlies a novel syndrome with susceptibility to classical or attenuated adenomatous polyposis and possibly extracolonic tumors, including breast cancer.

Published
2019

15. Hereditary evaluation and genetic counselling in young individuals with colorectal cancer in a population-based cohort

Author

Erik Lundqvist, Ekaterina Kuchinskaya, Kalle Landerholm, Jeanette Assarsson, Anna Benckert, Pär Myrelid, and Staffan Haapaniemi

Subjects
Cohort Studies, Adenomatous Polyposis Coli, Oncology, Kirurgi, Mutation, Humans, Genetic Counseling, Surgery, Colorectal Neoplasms, Colorectal Neoplasms, Hereditary Nonpolyposis, digestive system diseases
Abstract

Aim: Early-onset colorectal cancer should raise suspicions of a hereditary colorectal cancer (CRC) syndrome, including Lynch syndrome (LS) and Familial Adenomatous Polyposis (FAP). Collection of family history and genetic counselling (GC) is mandatory but previous studies have revealed low awareness of hereditary CRC among clinicians why there has been an incentive to implement universal LS screening. In this population-based cohort study, we aimed to observe the uptake of GC in the Swedish South-Eastern medical care region for young CRC patients and to investigate the frequency of patients diagnosed with LS.& nbsp;Methods: Patients below 50 years of age diagnosed with CRC between 2008 and 2017 were identified from the national Swedish Colorectal Cancer Registry. Medical records were reviewed regarding family history, co-morbidity and referral for GC, with a follow-up time of at least three years.& nbsp;Results: The analysis included 278 patients with 287 tumours, 108 (38%) located in rectum and 179 (62%) in colon. One hundred sixteen (42%) individuals were referred to the Regional Clinical Genetics service, whereof 74 (27%) underwent complete investigation. Thirteen (18%) patients were identified with a mutation, eleven (15%) had LS and two (3%) FAP. The remaining 61 (82%), without proven mutation, were considered as familial CRC. Younger age correlated with a higher chance of referral for GC.& nbsp;Conclusion: The study found that only a minority of young CRC patients underwent genetic counselling, contrary to clinical guidelines. Hereditary CRC is therefore probably underdiagnosed even among young individuals.

Published
2022

16. Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors

Author

Stefan Zschiedrich, Nicole Reisch, Ursula Ploeckinger, Joanne Ngeow, Raymond H. Kim, William F. Young, Dmitry Beltsevich, Francesca Schiavi, Umit Ugurlu, Madson Q. Almeida, Taweesak Wannachalee, Gabriela Sanso, Mònica Recasens, Angelica Malinoc, Roman Petrov, Luis Robles Diaz, Andrzej Januszewicz, Jochen Seufert, Holger Amthauer, Svetlana Yaremchuk, Karl-Heinrich Link, Ulrich F. Wellner, Timm Denecke, Jens Aberle, Nalini S. Shah, Xiao-Ping Qi, Marina Y. Yukina, Zheiwei Zhang, Ernst von Dobschuetz, Marta Barontini, Maria Candida Barisson Villares Fragoso, Andrey Kvachenyuk, Laura von Duecker, Giuseppe Opocher, Swati S Jadhav, Roland Därr, Birke Bausch, Merav Fraenkel, Viacheslav I. Egorov, Staffan Welin, Özer Makay, Sirinart Sirinvaravong, Rene Eduardo Diaz, Garrett Bullivant, Matthias Schott, Ana Rosa Pinto Quidute, Ekaterina Kuchinskaya, Camilla Schalin-Jäntti, Charis Eng, Martin K. Walz, Ana O. Hoff, Barbara Jarzab, Tobias B. Huber, Thera P. Links, Nikolaus Tiling, Kornelia Hasse-Lazar, Eric Jonasch, Gianmaria Pennelli, Per Hellman, Maria Adelaide Albergaria Pereira, Nelson Wohllk, Tada Kunavisarut, Attila Patócs, Dirk Bausch, Juri Ruf, Hartmut P. H. Neumann, Alice Helena Dutra Violante, Simona Grozinsky-Glasberg, Stefania Zovato, Oliver Gimm, Alfonso Massimiliano Ferrara, Delmar Munir Lourenço, Mariola Pęczkowska, Marija Pfeifer, Irina Bancos, Tobias Krauss, Karina Villar Gómez de las Heras, Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
Oncology, INVOLVEMENT, Cancer Research, Endocrinology, Diabetes and Metabolism, Medizin, Disease, Neuroendocrine tumors, PanNET, 0302 clinical medicine, Endocrinology, management recommendations, CRITERIA, Registries, Child, Islet cell tumors, Middle Aged, GA-68-DOTATOC, 3. Good health, Tumor Burden, Neuroendocrine Tumors, 030220 oncology & carcinogenesis, survival, von Hippel–Lindau disease, GROWTH, Adult, medicine.medical_specialty, Adolescent, PET/CT, 030209 endocrinology & metabolism, 03 medical and health sciences, Young Adult, Internal medicine, SURVEILLANCE, medicine, Humans, Von Hippel–Lindau disease, Preventive healthcare, Aged, PET-CT, business.industry, JAPANESE PATIENTS, CLINICAL-FEATURES, von Hippel-Lindau disease, medicine.disease, Pancreatic Neoplasms, ISLET-CELL TUMORS, Mutation, business
Abstract

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel–Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10–75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

Published
2018

17. Identification and rescue of a tRNA wobble inosine deficiency causing intellectual disability disorder

Author

Stefanie Kellner, Lars Feuk, Ekaterina Kuchinskaya, Benjamin Phelan, Ryan Bell, Felix Hagelskamp, Dragony Fu, Melissa Proven, Jonatan Halvardson, Ann-Charlotte Thuresson, and Jillian Ramos

Subjects
Male, TRNA modification, Adenosine, Adolescent, Adenosine Deaminase, Protein subunit, Active Transport, Cell Nucleus, Mutation, Missense, inosine, Wobble base pair, Article, 03 medical and health sciences, Adenosine deaminase, Protein Domains, RNA, Transfer, Intellectual Disability, ADAT3, Exome Sequencing, medicine, Missense mutation, Humans, Genetic Predisposition to Disease, Inosine, Child, Molecular Biology, Cells, Cultured, 030304 developmental biology, Genetics, 0303 health sciences, Binding Sites, biology, 030302 biochemistry & molecular biology, Biochemistry and Molecular Biology, RNA-Binding Proteins, adenosine deaminase, Pedigree, intellectual disability, Child, Preschool, Transfer RNA, biology.protein, Codon, Terminator, Female, tRNA modification, Biokemi och molekylärbiologi, medicine.drug
Abstract

The deamination of adenosine to inosine at the wobble position of tRNA is an essential post-transcriptional RNA modification required for wobble decoding in bacteria and eukaryotes. In humans, the wobble inosine modification is catalyzed by the heterodimeric ADAT2/3 complex. Here, we describe novel pathogenic ADAT3 variants impairing adenosine deaminase activity through a distinct mechanism that can be corrected through expression of the heterodimeric ADAT2 subunit. The variants were identified in a family in which all three siblings exhibit intellectual disability linked to biallelic variants in the ADAT3 locus. The biallelic ADAT3 variants result in a missense variant converting alanine to valine at a conserved residue or the introduction of a premature stop codon in the deaminase domain. Fibroblast cells derived from two ID-affected individuals exhibit a reduction in tRNA wobble inosine levels and severely diminished adenosine tRNA deaminase activity. Notably, the ADAT3 variants exhibit impaired interaction with the ADAT2 subunit and alterations in ADAT2-dependent nuclear localization. Based upon these findings, we find that tRNA adenosine deaminase activity and wobble inosine modification can be rescued in patient cells by overexpression of the ADAT2 catalytic subunit. These results uncover a key role for the inactive ADAT3 deaminase domain in proper assembly with ADAT2 and demonstrate that ADAT2/3 nuclear import is required for maintaining proper levels of the wobble inosine modification in tRNA.

Published
2020

18. Interphase fluorescent in situ hybridization deletion analysis of the 9p21 region and prognosis in childhood acute lymphoblastic leukaemia (ALL): results from a prospective analysis of 519 Nordic patients treated according to the NOPHO-ALL 2000 protocol

Author

Erik Forestier, Peder Skov Wehner, Sigrid Sahlén, Mats Heyman, Stefan Söderhäll, Finn Wesenberg, Ekaterina Kuchinskaya, Kim Vettenranta, Magnus Nordenskjöld, Olafur G. Jonsson, Elisabeth Blennow, and Ann Nordgren

Subjects
Male, medicine.medical_specialty, Pathology, Adolescent, In situ hybridization, Biology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Gastroenterology, Prospective analysis, Internal medicine, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Prospective Studies, Child, Childhood all, In Situ Hybridization, Fluorescence, Incidence (epidemiology), Significant difference, Infant, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, Cytogenetic Aberrations, Survival Analysis, Treatment Outcome, Child, Preschool, Lymphoblastic leukaemia, Interphase, Female, Chromosome Deletion, Chromosomes, Human, Pair 9
Abstract

Summary Interphase fluorescent in situ hybridization (FISH) was applied on diagnostic BM smears from 519 children with acute lymphoblastic leukaemia (ALL) in order to establish the frequency and prognostic importance of 9p21 deletion in children enrolled in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ‐ 2000 treatment protocol. Among the patients, 452 were diagnosed with B-cell precursor (BCP)-ALL and 66 with T-ALL. A higher incidence of 9p21 deletions was found in T-ALL (38%) compared to BCP-ALL (15AE7%). Homozygous deletions were found in 19AE7% of T-ALL and 4AE0% of BCP-ALL; hemizygous deletions were found in 18AE2% and 11AE7% respectively. In our series, 9p21 deletions were detected in all age groups with a steady rise in the frequency with age. There was no significant difference in outcome between cases with or without 9p21 deletion or between cases with hemi- or homozygous deletions of 9p21. In conclusion, in this large series of childhood ALL deletion of 9p21 was not associated with worse prognosis. However, interphase FISH deletion analysis of 9p21 could be used as a first step to detect unfavourable subtle cytogenetic aberrations such as the dic(9;20) rearrangement.

Published
2011

19. The frequency and prognostic impact of dic(9;20)(p13.2;q11.2) in childhood B-cell precursor acute lymphoblastic leukemia: results from the NOPHO ALL-2000 trial

Author

Vasilios Zachariadis, Lucia Cavelier, Fredrika Gauffin, Magnus Nordenskjöld, Elisabeth Blennow, Jacqueline Schoumans, Mats Heyman, Irina Golovleva, Linda Palmqvist, Agneta Nordgren, Bertil Johansson, Gisela Barbany, Hans Ehrencrona, Ekaterina Kuchinskaya, Erik Forestier, Britt Gustafsson, and Gudmar Lönnerholm

Subjects
Male, Cancer Research, medicine.medical_specialty, Pathology, Adolescent, Chromosomes, Human, Pair 20, Biology, Gastroenterology, Translocation, Genetic, Dicentric chromosome, CDKN2A, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Child, B cell, In Situ Hybridization, Fluorescence, Chromosome Aberrations, Hematology, medicine.diagnostic_test, Cytogenetics, Cancer, Infant, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, Prognosis, Chromosome Banding, Survival Rate, medicine.anatomical_structure, Oncology, Child, Preschool, Karyotyping, Female, Hyperdiploidy, Chromosomes, Human, Pair 9, Fluorescence in situ hybridization
Abstract

The dic(9;20)(p13.2;q11.2) is reported to be present in ∼2% of childhood B-cell precursor acute lymphoblastic leukemia (BCP ALL). However, it easily escapes detection by G-banding analysis and its true prevalence is hence unknown. We performed interphase fluorescence in situ hybridization analyses—in a three-step manner—using probes for: (i) CDKN2A at 9p21, (ii) 20p and 20q subtelomeres and (iii) cen9 and cen20. Out of 1033 BCP ALLs diagnosed from 2001 to 2006, 533 were analyzed; 16% (84/533) displayed 9p21 deletions, of which 30% (25/84) had dic(9;20). Thus, dic(9;20)-positivity was found in 4.7% (25/533), making it the third most common genetic subgroup after high hyperdiploidy and t(12;21)(p13;q22). The dic(9;20) was associated with a female predominance and an age peak at 3 years; 18/25 (72%) were allocated to non-standard risk treatment at diagnosis. Including cases detected by G-banding alone, 29 dic(9;20)-positive cases were treated according to the NOPHO ALL 2000 protocol. Relapses occurred in 24% (7/29) resulting in a 5-year event-free survival of 0.69, which was significantly worse than for t(12;21) (0.87; P=0.002) and high hyperdiploidy (0.82; P=0.04). We conclude that dic(9;20) is twice as common as previously surmised, with many cases going undetected by G-banding analysis, and that dic(9;20) should be considered a non-standard risk abnormality.

Published
2011

20. Array-CGH reveals hidden gene dose changes in children with acute lymphoblastic leukaemia and a normal or failed karyotype by G-banding

Author

Stefan Söderhäll, Magnus Nordenskjöld, Ann Nordgren, Dan Grandér, Elisabeth Blennow, Jacqueline Schoumans, Ekaterina Kuchinskaya, Johan Staaf, Åke Borg, and Mats Heyman

Subjects
Chromosome Aberrations, medicine.medical_specialty, Pathology, Hematology, G banding, Cytogenetics, Gene Dosage, Nucleic Acid Hybridization, Karyotype, Biology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, Molecular biology, Chromosome Banding, ETV6, Acute lymphocytic leukemia, Internal medicine, Karyotyping, medicine, Humans, Hyperdiploidy, Child, In Situ Hybridization, Fluorescence, Comparative genomic hybridization
Abstract

A tiling path 33K BAC array was used to study 28 children with acute lymphoblastic leukaemia (ALL) who had normal or failed G-banded karyotypes. Twenty-two patients (79%) had a total of 135 copy number alterations (CNA) (69 gains and 66 losses); most of these patients showed CNA that were below the resolution of G-banding. Molecular cytogenetic and array comparative genomic hybridization results enabled the division of B-precursor ALL patients into five groups: high hyperdiploidy, intrachromosomal amplification of 21q, ETV6/RUNX1 rearrangement, others and no CNA. Apart from a shared deletion of 9p21.3, T-ALL patients had additional small CNA, with no region in common.

Published
2008

21. Tiling-resolution array-CGH reveals the pattern of DNA copy number alterations in acute lymphoblastic leukemia with 21q amplification: the result of telomere dysfunction and breakage/fusion/breakage cycles?

Author

Magnus Nordenskjöld, Mats Heyman, Jacqueline Schoumans, Åke Borg, Dan Grandér, Stefan Söderhäll, Martin Corcoran, Ann Nordgren, Johan Staaf, Ekaterina Kuchinskaya, and Elisabeth Blennow

Subjects
Cancer Research, medicine.medical_specialty, Adolescent, Chromosomes, Human, Pair 21, Lymphoblastic Leukemia, Gene Dosage, Biology, chemistry.chemical_compound, Breakage, hemic and lymphatic diseases, Internal medicine, Acute lymphocytic leukemia, medicine, Humans, Child, Fusion, Acute leukemia, Hematology, Gene Amplification, Nucleic Acid Hybridization, Chromosome Breakage, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Telomere, medicine.disease, Oncology, chemistry, Cytogenetic Analysis, Cancer research, DNA
Abstract

Tiling-resolution array-CGH reveals the pattern of DNA copy number alterations in acute lymphoblastic leukemia with 21q amplification: the result of telomere dysfunction and breakage/fusion/breakage cycles?

Published
2007

22. Children and adults with acute lymphoblastic leukaemia have similar gene expression profiles

Author

A Zaritskey, Magnus Nordenskjöld, Mats Heyman, Yudi Pawitan, A Porwit-Macdonald, Elisabeth Blennow, Ann Nordgren, Mats Linderholm, Stefan Söderhäll, Ekaterina Kuchinskaya, Dan Grandér, E Zueva, and Martin Corcoran

Subjects
Adult, Male, medicine.medical_specialty, Fusion Proteins, bcr-abl, Disease, hemic and lymphatic diseases, Internal medicine, Gene expression, medicine, Humans, Philadelphia Chromosome, Child, Oligonucleotide Array Sequence Analysis, Hematology, business.industry, Gene Expression Regulation, Leukemic, Gene Expression Profiling, Genes, p16, hemic and immune systems, General Medicine, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Gene expression profiling, Child, Preschool, Immunology, Lymphoblastic leukaemia, Female, business, Gene Deletion
Abstract

To compare the gene expression pattern in children and adults with acute lymphoblastic leukaemia (ALL) in order to improve our understanding of the difference in disease biology and prognosis.The gene expression profiles in diagnostic samples from 29 children and 15 adults with ALL were analysed using the oligonucleotide chip Hu95ver2a, produced by Affymetrix.Unsupervised hierarchical cluster analysis revealed that, in spite of differences in outcome, patients clustered irrespective of age, first by T-cell or B-precursor immunophenotype, and second by cytogenetic changes within the B-precursor group. The expression pattern analysis allowed the reclassification of some samples into the proper cytogenetic group. We also showed that separate clustering of samples with the BCR/ABL translocation could be explained by different breakpoint regions in the BCR. No significant difference in gene expression was observed between samples with and without CDKN2A deletion within the B-precursor group. Analysis of different age groups revealed a similarity in expression profiles when infants with the MLL translocation and adults over 40 yr of age were compared irrespective of karyotype.In spite of the difference in clinical outcome, the gene expression pattern in children and adults with ALL is very similar and is primarily dependent on immunophenotype and cytogenetic aberrations. However, when age groups are compared, the expression patterns of infants and adults over 40 show a remarkable similarity.

Published
2005

23. Extending the phenotype of BMPER-related skeletal dysplasias to ischiospinal dysostosis

Author

Ok Hwa Kim, Ekaterina Kuchinskaya, Giedre Grigelioniene, Tae Joon Cho, Gintautas Grigelionis, Hye Ran Lee, Lotta Högberg, Gen Nishimura, and Anna Hammarsjö

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Craniofacial abnormality, Biology, medicine.disease_cause, Compound heterozygosity, Ischiospinal dysostosis, Diaphanospondylodysostosis, BMPER, Vertebral anomaly, Ischial hypoplasia, 03 medical and health sciences, medicine, Genetics(clinical), Pharmacology (medical), Nephroblastomatosis, Genetics (clinical), Genetics, Medicine(all), Mutation, Klinisk medicin, Dysostosis, General Medicine, medicine.disease, Dysostoses, Phenotype, Hypoplasia, 3. Good health, 030104 developmental biology, Clinical Medicine
Abstract

Ischiospinal dysostosis (ISD) is a polytopic dysostosis characterized by ischial hypoplasia, multiple segmental anomalies of the cervicothoracic spine, hypoplasia of the lumbrosacral spine and occasionally associated with nephroblastomatosis. ISD is similar to, but milder than the lethal/semilethal condition termed diaphanospondylodysostosis (DSD), which is associated with homozygous or compound heterozygous mutations of bone morphogenetic protein-binding endothelial regulator protein (BMPER) gene. Here we report for the first time biallelic BMPER mutations in two patients with ISD, neither of whom had renal abnormalities. Our data supports and further extends the phenotypic variability of BMPER-related skeletal disorders. Funding Agencies|Stockholm County Council; Karolinska Institutet; Kronprinsessan Lovisas; Axel Tiellmans Minnesfond Foundation; Samariten Foundation; Sallskapet Barnavard Foundation; Promobilia Foundations; Genome Technology to Business Translation Program of the National Research Foundation (NRF) - Ministry of Science, ICT & Future Planning of the government of Republic of Korea [NRF-2014M3C9A2064684]

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