Author: "Marie Stenmark Askmalm" / Topic: humans - Searchworks@Jio Institute Digital Library Search Results

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23 results on '"Marie Stenmark Askmalm"'

1. Prevalence of germline pathogenic variants in 22 cancer susceptibility genes in Swedish pediatric cancer patients

Author: Marie Stenmark-Askmalm, Cecilia Wahlström, Håkan Olsson, Anders Kvist, Ingrid Øra, Jan Koster, Lars Hjorth, Ulf Kristoffersson, Karl Johan Stjernfelt, Thomas Wiebe, Kristoffer von Stedingk, Oncogenomics, and CCA - Cancer biology and immunology
Subjects: Science, Population, Article, Germline, Cohort Studies, Cancer screening, Paediatric cancer, Neoplasms, Biomarkers, Tumor, Prevalence, Humans, Medicine, Genetic Predisposition to Disease, Family history, Child, education, Cancer genetics, Gene, Germ-Line Mutation, Cancer, Sweden, Genetics, education.field_of_study, Multidisciplinary, business.industry, Incidence (epidemiology), Cancer susceptibility, Pediatric cancer, Cohort, business
Abstract: Up to 10% of pediatric cancer patients harbor pathogenic germline variants in one or more cancer susceptibility genes. A recent study from the US reported pathogenic variants in 22 out of 60 analyzed autosomal dominant cancer susceptibility genes, implicating 8.5% of pediatric cancer patients. Here we aimed to assess the prevalence of germline pathogenic variants in these 22 genes in a population-based Swedish cohort and to compare the results to those described in other populations. We found pathogenic variants in 10 of the 22 genes covering 3.8% of these patients. The prevalence of TP53 mutations was significantly lower than described in previous studies, which can largely be attributed to differences in tumor diagnosis distributions across the three cohorts. Matched family history for relatives allowed assessment of familial cancer incidence, however, no significant difference in cancer incidence was found in families of children carrying pathogenic variants compared to those who did not.
Published: 2021
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2. Increased Cancer Risk in Families with Pediatric Cancer Is Associated with Gender, Age, Diagnosis, and Degree of Relation to the Child

Author: Karl-Johan Stjernfelt, Håkan Olsson, Marie Stenmark-Askmalm, Ulf Kristoffersson, Ingrid Øra, Lars Hjorth, Kristoffer von Stedingk, and Thomas Wiebe
Subjects: 0301 basic medicine, Male, Epidemiology, Population, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Neoplasms, Medicine, Humans, Genetic Predisposition to Disease, Registries, education, education.field_of_study, business.industry, Incidence (epidemiology), Incidence, Age Factors, Cancer, Gender Identity, Middle Aged, medicine.disease, Pediatric cancer, 030104 developmental biology, Increased risk, Oncology, 030220 oncology & carcinogenesis, Cohort, Female, Cancer risk, business, Population Register, Demography
Abstract: Background: Studies of cancer risk among relatives of children with cancer beyond parents and siblings are limited. We have investigated the cancer risk up to the third degree of relation in families with pediatric cancer to reveal patterns of inheritance. Methods: A single-center cohort of 757 patients with pediatric cancer was linked to the Swedish National Population Register, resulting in 16,137 relatives up to the third degree of relation. All relatives were matched to the Swedish Cancer Register, and standard incidence ratios (SIR) were calculated to define relatives at risk. Results: Children and adults up to the third degree of relation had increased cancer risk, with SIRs of 1.48 (P = 0.01) and 1.07 (P < 0.01), respectively. The SIRs for first- and third-degree adult relatives were 1.22 and 1.10, respectively, but no increased risk was observed in second-degree relatives. Male relatives had a higher risk than females, especially when related to a girl and when the child had leukemia. The risk was mainly increased for lung, prostate, and gastrointestinal cancer. When excluding 29 families of children with known pathogenic germline variants, the increased risk remained. Conclusions: Relatives to children with cancer up to third degree of relation have an increased cancer risk. Known pathogenic germline variants do not explain this increased risk. Impact: The overall increased cancer risk among relatives of children with cancer in this population-based cohort strengthens the importance of surveillance programs for families with pediatric cancer.
Published: 2020

3. ABCB1 single-nucleotide variants and survival in patients with glioblastoma treated with radiotherapy concomitant with temozolomide

Author: Charlotte Bratthäll, Hans Skovgaard Poulsen, M Mudaisi, Annika Malmström, Ingrid Jakobsen, Lisa Åkesson, Peter Milos, Victoria Fomichov, Michael Strandeus, Martin Hallbeck, Kirsten Grunnet, Peter Söderkvist, Angeliki Papagiannopoulou, Marie Stenmark-Askmalm, Małgorzata Łysiak, Henrik Gréen, and Helle Broholm
Subjects: 0301 basic medicine, Oncology, Adult, Male, medicine.medical_specialty, ATP Binding Cassette Transporter, Subfamily B, viruses, medicine.medical_treatment, Pilot Projects, 030226 pharmacology & pharmacy, Polymorphism, Single Nucleotide, law.invention, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Polymorphism (computer science), law, Internal medicine, Genetics, medicine, Temozolomide, Humans, Antineoplastic Agents, Alkylating, Aged, Pharmacology, Sweden, business.industry, Brain Neoplasms, Standard treatment, Genetic Variation, Chemoradiotherapy, Middle Aged, Radiation therapy, Survival Rate, 030104 developmental biology, Treatment Outcome, Concomitant, Cohort, Molecular Medicine, Female, business, Glioblastoma, Cohort study, medicine.drug
Abstract: Standard treatment for glioblastoma (GBM) patients is surgery and radiochemotherapy (RCT) with temozolomide (TMZ). TMZ is a substrate for ABCB1, a transmembrane drug transporter. It has been suggested that survival for GBM patients receiving TMZ is influenced by different single-nucleotide variants (SNV) of ABCB1. We therefore examined SNV:s of ABCB1, namely 1199G>A, 1236C>T, 2677G>T/A, and 3435C>T and correlated to survival for GBM patients receiving RCT. In a pilot cohort (97 patients) a significant correlation to survival was found for SNV 1199G>A, with median OS for variant G/G patients being 18.2 months versus 11.5 months for A/G (p = 0.012). We found no correlation to survival for the other SNV:s. We then expanded the cohort to 179 patients (expanded cohort) and also included a confirmatory cohort (49 patients) focusing on SNV 1199G>A. Median OS for G/G versus A/G plus A/A was 15.7 and 11.5 months, respectively (p = 0.085) for the expanded cohort and 13.8 versus 16.8 months (p = 0.19) for the confirmatory. In conclusion, in patients with GBM receiving RCT with TMZ, no correlation with survival was found for the SNV:s 1236C>T, 2677G>T/A, and 3435C>T of ABCB1. Although the SNV 1199G>A might have some impact, a clinically significant role could not be confirmed.
Published: 2019

4. Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population

Author: Christos Aravidis, Margareta Nordling, Kristina Lagerstedt-Robinson, Anna Rohlin, Mef Nilbert, Beatrice Melin, Annika Lindblom, and Marie Stenmark-Askmalm
Subjects: Male, 0301 basic medicine, Oncology, Cancer Research, DNA Mutational Analysis, Gene mutation, DNA Mismatch Repair, 0302 clinical medicine, Mismatch Repair Endonuclease PMS2, Sequence Deletion, education.field_of_study, General Medicine, Middle Aged, Lynch syndrome, DNA-Binding Proteins, MutS Homolog 2 Protein, 030220 oncology & carcinogenesis, Female, Microsatellite Instability, DNA mismatch repair, Colorectal Neoplasms, MutL Protein Homolog 1, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Population, Biology, HNPCC, MLH1, MSH2, MSH6, EPCAM, hereditary colorectal cancer, 03 medical and health sciences, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, education, neoplasms, Sweden, Cancer och onkologi, nutritional and metabolic diseases, Cancer, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, digestive system diseases, 030104 developmental biology, Cancer and Oncology, Mutation, Cancer research
Abstract: Lynch syndrome caused by constitutional mismatch-repair defects is one of the most common hereditary cancer syndromes with a high risk for colorectal, endometrial, ovarian and urothelial cancer. Lynch syndrome is caused by mutations in the mismatch repair (MMR) genes i.e., MLH1, MSH2, MSH6 and PMS2. After 20 years of genetic counseling and genetic testing for Lynch syndrome, we have compiled the mutation spectrum in Sweden with the aim to provide a population-based perspective on the contribution from the different MMR genes, the various types of mutations and the influence from founder mutations. Mutation data were collected on a national basis from all laboratories involved in genetic testing. Mutation analyses were performed using mainly Sanger sequencing and multiplex ligation-dependent probe amplification. A total of 201 unique disease-predisposing MMR gene mutations were identified in 369 Lynch syndrome families. These mutations affected MLH1 in 40%, MSH2 in 36%, MSH6 in 18% and PMS2 in 6% of the families. A large variety of mutations were identified with splice site mutations being the most common mutation type in MLH1 and frameshift mutations predominating in MSH2 and MSH6. Large deletions of one or several exons accounted for 21% of the mutations in MLH1 and MSH2 and 22% in PMS2, but were rare (4%) in MSH6. In 66% of the Lynch syndrome families the variants identified were private and the effect from founder mutations was limited and predominantly related to a Finnish founder mutation that accounted for 15% of the families with mutations in MLH1. In conclusion, the Swedish Lynch syndrome mutation spectrum is diverse with private MMR gene mutations in two-thirds of the families, has a significant contribution from internationally recognized mutations and a limited effect from founder mutations. Funding Agencies|Swedish Cancer Society
Published: 2016
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5. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

Author: Javier Benitez, Marie Stenmark-Askmalm, Susan L. Neuhausen, Pascal Guénel, Jane Carpenter, Christine B. Ambrosone, Dominique Stoppa-Lyonnet, Nadine Tung, Gad Rennert, Stephen J. Chanock, Andrew K. Godwin, Regina M. Santella, Brita Arver, Karoline Kuchenbaecker, Kamila Czene, Vessela N. Kristensen, Natalia Bogdanova, Nazneen Rahman, Jianjun Liu, Federico Canzian, Hoda Anton-Culver, Maya Ghoussaini, Mark E. Robson, Sue K. Park, Manjeet K. Bolla, Roger L. Milne, Veli-Matti Kosma, Siranoush Manoukian, Angela Cox, Daniel F. Schmidt, Kay-Tee Khaw, Rosario Tumino, Melissa C. Southey, Ramunas Janavicius, Irene Konstantopoulou, Carl Blomqvist, John L. Hopper, Sue Healey, Christine Rappaport, Marco Montagna, SA Gayther, Heather Eliassen, Carolien H.M. van Deurzen, Jacques Simard, Emiel J. Rutgers, Jonine Figueroa, Maria A. Caligo, Volker Arndt, Sylvie Mazoyer, Diana Eccles, M.J. Hooning, Antoinette Hollestelle, Mary B. Daly, Robert Winqvist, Antonis C. Antoniou, Patricia A. Ganz, Orland Diez, Priyanka Sharma, Ana Osorio, Daniel Barrowdale, Loic Le Marchand, Drakoulis Yannoukakos, Elinor J. Sawyer, Conxi Lázaro, Soo-Hwang Teo, Penny Soucy, Paolo Radice, John W. M. Martens, Steve Ellis, David E. Goldgar, Anna Jakubowska, Maria Kabisch, Raymonda Varon-Mateeva, Diether Lambrechts, Paul D.P. Pharoah, Leigha Senter, Anna González-Neira, Cecilia M. Dorfling, Brian E. Henderson, Rulla M. Tamimi, Sara Margolin, Susan M. Gapstur, Ian Tomlinson, Thérèse Truong, Robert A.E.M. Tollenaar, Amanda E. Toland, Anna Marie Mulligan, Irene L. Andrulis, Isabelle Romieu, Monica Barile, Florentia Fostira, Johanna Rantala, Enes Makalic, Eitan Friedman, Zhaoming Wang, Mark H. Greene, Noralane M. Lindor, Julie M. Cunningham, Riccardo Dolcetti, Steven N. Hart, Mary Beth Terry, Jenny Chang-Claude, Austin Miller, Georgia Chenevix-Trench, Asta Försti, Kathleen E. Malone, Paolo Peterlongo, Lothar Haeberle, Celine M. Vachon, Elizabeth J. van Rensburg, Michael Jones, Laima Tihomirova, Penelope Miron, Eunjung Lee, María José Sánchez, Hatef Darabi, Frans B. L. Hogervorst, Matthias W. Beckmann, Edith Olah, Annika Lindblom, Phuong L. Mai, Emily Hallberg, Alison M. Dunning, Kathleen Claes, Esther M. John, Sofia Khan, David J. Hunter, Kristiina Aittomäki, Katherine L. Nathanson, Lars Beckmann, Stephanie V. Blank, Wei Zheng, Olufunmilayo I. Olopade, Heli Nevanlinna, Miguel de la Hoya, Olga M. Sinilnikova, Bruce Poppe, Catherine M. Phelan, S. Lindstrom, Stig E. Bojesen, Curtis Olswold, Fredrick R. Schumacher, Janet E. Olson, Tuomas Heikkinen, Judy Garber, Fergus J. Couch, Tara M. Friebel, Isabel dos-Santos-Silva, Douglas F. Easton, Song Yao, Dieter Flesch-Janys, Hans Ehrencrona, Simon S. Cross, Rodney J. Scott, Kenneth Offit, Petra H.M. Peeters, Clare Turnbull, Taru A. Muranen, William J. Tapper, Trinidad Caldés, Jenny Lester, Robert L. Nussbaum, Paul A. James, Marike Gabrielson, Susan M. Domchek, Mads Thomassen, Marilie D. Gammon, Susan L. Slager, Graham G. Giles, Silje Nord, Hans Wildiers, Hiltrud Brauch, Gustavo Mendoza-Fandiño, Christopher A. Haiman, Martine Dumont, Mark S. Goldberg, Bernardo Bonanni, Jirong Long, Kyriaki Michailidou, Ute Hamann, Wendy K. Chung, Marc J. Gunter, Mia M. Gaudet, Keith Humphreys, Per Hall, Yuan C. Ding, Simona Agata, Julia A. Knight, Robert Pilarski, Claudine Isaacs, Alvaro A.N. Monteiro, Montserrat Garcia-Closas, Rosa B. Barkardottir, Beth Y. Karlan, Uffe Birk Jensen, Arif B. Ekici, Evgeny N. Imyanitov, Alex Teulé, Anne-Marie Gerdes, Frederik Marme, Debra Frost, Anthony J. Swerdlow, Yon Ko, Xiaohong R. Yang, Jan Lubinski, Peter A. Fasching, Lesley McGuffog, Jacek Gronwald, Katri Pylkäs, Banu Arun, Josef Herzog, Gord Glendon, Doris Steinemann, Tomasz Huzarski, Peter Kraft, Anja Rudolph, Arto Mannermaa, Habibul Ahsan, Christian F. Singer, Rita K. Schmutzler, Julian Peto, Giski Ursin, Shan Wang-Gohrke, Andrea L. Richardson, Jeffrey N. Weitzel, Børge G. Nordestgaard, Marjanka K. Schmidt, Alice S. Whittemore, Hermann Brenner, Barbara Burwinkel, D Thompson, Csilla I. Szabo, M. Pilar Zamora, Janna Lilyquist, Muhammad G. Kibriya, Yael Laitman, Helen Tsimiklis, W. D. Foulkes, Thomas Hansen, Francesca Damiola, Robert N. Hoover, Ava Kwong, Alfons Meindl, Siddhartha Kar, Manuel R. Teixeira, Elisabete Weiderpass, Bernard Peissel, Saundra S. Buys, Peter Devilee, Unión Europea. Comisión Europea. 7 Programa Marco, Cancer Research UK (Reino Unido), National Institutes of Health (Estados Unidos), Canadian Institutes of Health Research, Florida Breast Cancer Foundation (Estados Unidos), Dunning, Alison [0000-0001-6651-7166], Ghoussaini, Maya [0000-0002-2415-2143], Khaw, Kay-Tee [0000-0002-8802-2903], Thompson, Deborah [0000-0003-1465-5799], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Apollo - University of Cambridge Repository, Medical Oncology, Obstetrics & Gynecology, Pathology, Cell biology, Medicum, Kristiina Aittomäki / Principal Investigator, Department of Medical and Clinical Genetics, Clinicum, Department of Oncology, Department of Obstetrics and Gynecology, HUS Gynecology and Obstetrics, and [ 1 ] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA [ 2 ] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA [ 3 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England [ 4 ] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Canc Epidemiol Program, Tampa, FL 33612 USA [ 5 ] Radiumhosp, Oslo Univ Hosp, Inst Canc Res, Dept Genet, N-0310 Oslo, Norway [ 6 ] IRCCS, IOV, Immunol & Mol Oncol Unit, I-20133 Padua, Italy [ 7 ] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA [ 8 ] Univ Chicago, Ctr Comprehens Canc, Chicago, IL 60637 USA [ 9 ] Univ Chicago, Dept Med & Human Genet, Chicago, IL 60637 USA [ 10 ] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki 00029, Finland [ 11 ] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA [ 12 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada [ 13 ] Univ Toronto, Dept Mol Genet, Toronto, ON M5B 1W8, Canada [ 14 ] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5B 1W8, Canada [ 15 ] Univ Calif Irvine, Dept Epidemiol, Irvine, CA 92697 USA [ 16 ] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, D-69120 Heidelberg, Germany [ 17 ] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA [ 18 ] Karolinska Univ Hosp, Dept Oncol, SE-17176 Stockholm, Sweden [ 19 ] Ist Europeo Oncol, Div Canc Prevent & Genet, I-20141 Milan, Italy [ 20 ] Landspitali Univ Hosp, Dept Pathol, IS-101 Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital [ 21 ] Univ Iceland, Sch Med, IS-101 Reykjavik, Iceland [ 22 ] Inst Qual & Efficiency Hlth Care IQWiG, D-50670 Cologne, Germany [ 23 ] Univ Erlangen Nurnberg, Comprehens Canc Ctr Erlangen EMN, Univ Breast Ctr Franconia, Dept Gynecol & Obstet,Univ Hosp Erlangen, D-91054 Erlangen, Germany [ 24 ] Spanish Natl Canc Ctr CNIO, Human Genet Grp, Human Canc Genet Program, Madrid 28029, Spain [ 25 ] Spanish Natl Canc Ctr CNIO, Human Canc Genet Program, Genotyping Unit CeGen, Madrid 28029, Spain [ 26 ] Biomed Network Rare Dis CIBERER, Madrid 28029, Spain [ 27 ] NYU, Sch Med, NYU Womens Canc Program, New York, NY 10016 USA [ 28 ] Univ Helsinki, Dept Oncol, FI-00029 Helsinki, Finland [ 29 ] Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland [ 30 ] Hannover Med Sch, Dept Radiat Oncol, D-30625 Hannover, Germany [ 31 ] Copenhagen Univ Hosp, Herlev Hosp, Copenhagen Gen Populat Study, DK-2730 Herlev, Denmark [ 32 ] Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, Germany [ 33 ] Univ Tubingen, D-72074 Tubingen, Germany [ 34 ] German Canc Res Ctr, Div Prevent Oncol, D-69120 Heidelberg, Germany [ 35 ] Natl Ctr Tumor Dis NCT, D-69120 Heidelberg, Germany [ 36 ] Heidelberg Univ, Dept Obstet & Gynecol, D-69120 Heidelberg, Germany [ 37 ] Univ Utah, Sch Med, Dept Med, Huntsman Canc Inst, Salt Lake City, UT 84112 USA [ 38 ] IdISSC, Hosp Clin San Carlos, Mol Oncol Lab, Madrid 28040, Spain [ 39 ] Univ Pisa, Dept Lab Med, Sect Genet Oncol, I-56126 Pisa, Italy [ 40 ] Univ Hosp Pisa, I-56126 Pisa, Italy [ 41 ] German Canc Res Ctr, Genom Epidemiol Grp, D-69120 Heidelberg, Germany [ 42 ] Univ Sydney, Westmead Millennium Inst, Australian Breast Canc Tissue Bank, Sydney, NSW 2145, Australia [ 43 ] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany [ 44 ] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA [ 45 ] Columbia Univ, Dept Pediat, New York, NY 10032 USA [ 46 ] Columbia Univ, Dept Med, New York, NY 10032 USA [ 47 ] Univ Ghent, Ctr Med Genet, B-9000 Ghent, Belgium [ 48 ] Univ Sheffield, Dept Oncol, Sheffield Canc Res Ctr, Sheffield S10 2RX, S Yorkshire, England [ 49 ] Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Sheffield S10 2HQ, S Yorkshire, England [ 50 ] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden [ 51 ] Fox Chase Canc Ctr, Dept Clin Genet, Philadelphia, PA 19111 USA [ 52 ] Univ Lyon, CNRS, UMR5286, Ctr Rech Cancerol Lyon,INSERM,U1052, F-69373 Lyon, France [ 53 ] Leiden Univ, Med Ctr, Dept Human Genet, NL-2333 ZC Leiden, Netherlands [ 54 ] Leiden Univ, Med Ctr, Dept Pathol, NL-2333 ZC Leiden, Netherlands [ 55 ] Univ Hosp Vall dHebron, VHIO, Oncogenet Grp, Barcelona 08035, Spain [ 56 ] Univ Autonoma Barcelona, Barcelona 08035, Spain [ 57 ] City Hope Natl Med Ctr, Beckman Res Inst, Dept Populat Sci, Duarte, CA 91010 USA [ 58 ] CRO Aviano Natl Canc Inst, Canc Bioimmunotherapy Unit, I-33081 Aviano, Italy [ 59 ] Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA [ 60 ] Univ Pretoria, Dept Genet, ZA-0007 Pretoria, South Africa [ 61 ] Univ London London Sch Hyg & Trop Med, Dept Non Communicable Dis Epidemiol, Keppel St, London WC1E 7HT, England [ 62 ] Ctr Hosp Univ Quebec, Canc Genom Lab, Quebec City, PQ G1V 4G2, Canada [ 63 ] Univ Laval, Quebec City, PQ G1V 4G2, Canada [ 64 ] Univ Cambridge, Dept Oncol, Ctr Canc Genet Epidemiol, Cambridge CB1 8RN, England [ 65 ] Univ Southampton, Southampton Univ Hosp, Fac Med, Southampton SO16 6YD, Hants, England [ 66 ] Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden [ 67 ] Univ Lund Hosp, Dept Clin Genet, SE-22185 Lund, Sweden [ 68 ] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Inst Human Genet, D-91054 Erlangen, Germany [ 69 ] Comprehens Canc Ctr EMN, D-91054 Erlangen, Germany [ 70 ] Brigham & Womens Hosp, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA [ 71 ] Harvard Univ, Sch Med, Boston, MA 02115 USA [ 72 ] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA [ 73 ] Univ Clin Hamburg Eppendorf, Clin Canc Registry, Dept Canc Epidemiol, D-20246 Hamburg, Germany [ 74 ] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, D-20246 Hamburg, Germany [ 75 ] German Canc Res Ctr, Div Mol Genet Epidemiol, D-69120 Heidelberg, Germany [ 76 ] Lund Univ, Ctr Primary Hlth Care Res, SE-22100 Malmo, Sweden [ 77 ] Natl Ctr Sci Res Demokritos, INRASTES, Mol Diagnost Lab, Athens 15310, Greece [ 78 ] McGill Univ, Program Canc Genet, Montreal, PQ H3A 0G4, Canada [ 79 ] Univ Philadelphia, Philadelphia, PA 19104 USA [ 80 ] Chaim Sheba Med Ctr, Susanne Levy Gertner Oncogenet Unit, IL-52621 Tel Hashomer, Israel [ 81 ] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA [ 82 ] Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, UCLA Sch Med, Los Angeles, CA 90095 USA [ 83 ] Jonsson Comprehens Canc Ctr, Div Canc Prevent & Control Res, UCLA Sch Publ Hlth, Los Angeles, CA 90095 USA [ 84 ] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA [ 85 ] Dana Farber Canc Inst, Canc Risk & Prevent Clin, Boston, MA 02215 USA [ 86 ] Cedars Sinai Med Ctr, Dept Biomed Sci, Los Angeles, CA 90048 USA [ 87 ] Copenhagen Univ Hosp, Rigshosp, Dept Clin Genet, DK-2100 Copenhagen, Denmark [ 88 ] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3010, Australia [ 89 ] Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66205 USA [ 90 ] McGill Univ, Dept Med, Montreal, PQ H3G 2M1, Canada [ 91 ] McGill Univ, Ctr Hlth, Royal Victoria Hosp, Div Clin Epidemiol, Montreal, PQ H4A 3J1, Canada [ 92 ] Univ Utah, Sch Med, Huntsman Canc Inst, Dept Dermatol, Salt Lake City, UT 84132 USA [ 93 ] Spanish Natl Canc Res Ctr CNIO, Human Canc Genet Program, Human Genotyping CEGEN Unit, Madrid 28029, Spain [ 94 ] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA [ 95 ] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland [ 96 ] CESP Ctr Res Epidemiol & Populat Hlth, Inserm Natl Inst Hlth & Med Res, U1018, Environm Epidemiol Canc, F-70115 Villejuif, France [ 97 ] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London SW7 2AZ, England [ 98 ] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA [ 99 ] German Canc Res Ctr, Mol Genet Breast Canc, D-69120 Heidelberg, Germany [ 100 ] Copenhagen Univ Hosp, Rigshosp, Ctr Genom Med, DK-2100 Copenhagen, Denmark [ 101 ] QIMR Berghofer Med Res Inst, Dept Genet, Brisbane, Qld 4029, Australia [ 102 ] Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland [ 103 ] City Hope Clin Canc Genet Community Res Network, Clin Canc Genet, Duarte, CA 91010 USA [ 104 ] Netherlands Canc Inst, Family Canc Clin, NL-1000 BE Amsterdam, Netherlands [ 105 ] Erasmus MC Canc Inst, Dept Med Oncol, NL-3008 AE Rotterdam, Netherlands [ 106 ] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Med Oncol, NL-3008 AE Rotterdam, Netherlands [ 107 ] Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic 3010, Australia [ 108 ] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, 665 Huntington Ave, Boston, MA 02115 USA [ 109 ] NN Petrov Oncol Res Inst, St Petersburg 197758, Russia [ 110 ] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA [ 111 ] Peter MacCallum Canc Ctr, Familial Canc Ctr, Melbourne, Vic 8006, Australia [ 112 ] Univ Melbourne, Dept Oncol, Melbourne, Vic 8006, Australia [ 113 ] State Res Inst, Ctr Innovat Med, LT-08661 Vilnius, Lithuania [ 114 ] Aarhus Univ Hosp, Dept Clin Genet, DK-8200 Aarhus N, Denmark [ 115 ] Canc Prevent Inst Calif, Dept Epidemiol, Fremont, CA 94538 USA [ 116 ] Inst Canc Res, Div Genet & Epidemiol, Sutton SM2 5NG, Surrey, England [ 117 ] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Womens Canc Program, Los Angeles, CA 90048 USA [ 118 ] Univ Helsinki, Dept Obstet & Gynecol, FI-00029 Helsinki, Finland [ 119 ] Univ Helsinki, Cent Hosp, FI-00029 Helsinki, Finland [ 120 ] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England [ 121 ] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Prosserman Ctr Hlth Res, Toronto, ON M5G 1X5, Canada [ 122 ] Evangel Kliniken Bonn gGmbH, Johanniter Krankenhaus, Dept Internal Med, D-53113 Bonn, Germany [ 123 ] Univ Eastern Finland, Inst Clin Med Pathol & Forens Med, Sch Med, FI-70211 Kuopio, Finland [ 124 ] Hong Kong Hereditary Breast Canc Family Registry, Canc Genet Ctr, Hong Kong Sanat & Hosp, Hong Kong, Hong Kong, Peoples R China [ 125 ] Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China [ 126 ] VIB, Vesalius Res Ctr, B-3000 Leuven, Belgium [ 127 ] IDIBELL Catalan Inst Oncol, Hereditary Canc Program, Mol Diagnost Unit, Barcelona 08908, Spain [ 128 ] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90032 USA [ 129 ] Univ Canc Ctr, Canc Epidemiol Program, Honolulu, HI 96813 USA [ 130 ] Karolinska Inst, Dept Mol Med & Surg, SE-17177 Stockholm, Sweden [ 131 ] Mayo Clin, Hlth Sci Res, Scotsdale, AZ 85259 USA [ 132 ] Harvard Univ, Sch Publ Hlth, Program Genet Epidemiol & Stat Genet, Boston, MA 02115 USA [ 133 ] Genome Inst Singapore, Div Human Genet, Singapore 138672, Singapore [ 134 ] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol,Dept Med, Nashville, TN 37203 USA [ 135 ] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Div Epidemiol,Dept Med, Nashville, TN 37203 USA [ 136 ] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA [ 137 ] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA [ 138 ] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Med Genet, I-20133 Milan, Italy [ 139 ] Tech Univ Munich, Dept Obstet & Gynaecol, D-81675 Munich, Germany [ 140 ] Roswell Pk Canc Inst, NRG Oncol Stat & Data Management Ctr, Buffalo, NY 14263 USA [ 141 ] Case Western Reserve Univ, Sch Med, Dept Genom & Genome Sci, Cleveland, OH 44106 USA [ 142 ] Univ Hlth Network, Lab Med Program, Toronto, ON M5B 1W8, Canada [ 143 ] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5B 1W8, Canada [ 144 ] Invitae Corp, San Francisco, CA 94107 USA [ 145 ] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA [ 146 ] Natl Inst Oncol, Dept Mol Genet, H-1122 Budapest, Hungary [ 147 ] Univ Chicago, Med Ctr, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA [ 148 ] Seoul Natl Univ, Coll Med, Dept Prevent Med & Biomed Sci, Seoul 110799, South Korea [ 149 ] Seoul Natl Univ, Canc Res Inst, Seoul 110799, South Korea [ 150 ] Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, Dept Epidemiol, NL-3508 GA Utrecht, Netherlands [ 151 ] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, MRC PHE Ctr Environm & Hlth, London SW7 2AZ, England [ 152 ] Fdn Ist FIRC Oncol Mol, IFOM, I-20133 Milan, Italy [ 153 ] Ohio State Univ, Ctr Comprehens Canc, Dept Internal Med, Div Human Genet, Columbus, OH 43210 USA [ 154 ] Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Dept Clin Chem, FI-90220 Oulu, Finland [ 155 ] Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Dept Clin Chem, FI-90220 Oulu, Finland [ 156 ] Univ Oulu, NordLab Oulu, Oulu Univ Hosp, Lab Canc Genet & Tumor Biol,Bioctr Oulu, FI-90220 Oulu, Finland [ 157 ] Fdn IRCCS Ist Nazl Tumori INT, Dept Prevent & Predict Med, Unit Mol Bases Genet Risk & Genet Testing, I-20133 Milan, Italy [ 158 ] Inst Canc Res, Sect Canc Genet, Sutton SM2 5NG, Surrey, England [ 159 ] Karolinska Univ Hosp, Dept Clin Genet, SE-17176 Stockholm, Sweden [ 160 ] Med Univ Vienna, Ctr Comprehens Canc, Dept Obstet & Gynecol, A-1090 Vienna, Austria [ 161 ] Clalit Natl Israeli Canc Control Ctr, IL-34362 Haifa, Israel [ 162 ] Carmel Hosp, Dept Community Med & Epidemiol, IL-34362 Haifa, Israel [ 163 ] B Rappaport Fac Med, IL-34362 Haifa, Israel [ 164 ] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA [ 165 ] Int Agcy Res Canc, F-69008 Lyon, France [ 166 ] Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, NL-1006 BE Amsterdam, Netherlands [ 167 ] Univ Granada, Hosp Univ Granada, Inst Invest Biosanitaria Ibs GRANADA, Escuela Andaluza Salud Publ, E-18014 Granada, Spain [ 168 ] CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain [ 169 ] Columbia Univ, Dept Environm Hlth Sci, New York, NY 10032 USA [ 170 ] Kings Coll London, Guys Hosp, Div Canc Studies, Res Oncol, London SE1 9RT, England [ 171 ] Univ Hosp Cologne, Fac Med, Ctr Hereditary Breast & Ovarian Canc, D-50931 Cologne, Germany [ 172 ] Univ Hosp Cologne, Fac Med, CIO, D-50931 Cologne, Germany [ 173 ] Univ Cologne, CMMC, D-50931 Cologne, Germany [ 174 ] John Hunter Hosp, Hunter Area Pathol Serv, Div Genet, Newcastle, NSW 2305, Australia [ 175 ] Univ Kansas, Med Ctr, Dept Hematol & Oncol, Kansas City, KS 66205 USA [ 176 ] Univ Laval, Ctr Hosp Univ Quebec, Res Ctr, Quebec City, PQ G1V 4G2, Canada [ 177 ] Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, F-69373 Lyon, France [ 178 ] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia [ 179 ] Hannover Med Sch, D-30625 Hannover, Germany [ 180 ] Linkoping Univ, Dept Clin & Expt Med, Div Clin Genet, SE-58185 Linkoping, Sweden [ 181 ] Inst Curie, Dept Tumour Biol, F-75248 Paris, France [ 182 ] Univ Paris 05, Sorbonne Paris Cite, F-75248 Paris, France [ 183 ] NHGRI, NIH, Bethesda, MD 20892 USA [ 184 ] Portuguese Oncol Inst, Dept Genet, P-4200072 Oporto, Portugal [ 185 ] Univ Porto, Biomed Sci Inst ICBAS, P-4200072 Oporto, Portugal [ 186 ] Canc Res Initiat Fdn, Sime Darby Med Ctr, Subang Jaya 47500, Malaysia [ 187 ] Univ Malaya, Med Ctr, Canc Res Inst, Fac Med, Kuala Lumpur 50603, Malaysia [ 188 ] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA [ 189 ] Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark [ 190 ] Latvian Biomed Res & Study Ctr, LV-1067 Riga, Latvia [ 191 ] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA [ 192 ] Leiden Univ, Med Ctr, Dept Surg Oncol, NL-2333 ZC Leiden, Netherlands [ 193 ] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England [ 194 ] Univ Oxford, Oxford Biomed Res Ctr, Oxford OX3 7BN, England [ 195 ] IDIBELL Catalan Inst Oncol, Hereditary Canc Program, Genet Counseling Unit, Barcelona 08908, Spain [ 196 ] Civ MP Arezzo Hosp, Canc Registry, I-97100 Asp Ragusa, Italy [ 197 ] Civ MP Arezzo Hosp, Histopathol Unit, I-97100 Asp Ragusa, Italy [ 198 ] Beth Israel Deaconess Med Ctr, Dept Med Oncol, Boston, MA 02215 USA [ 199 ] Inst Populat Based Canc Res, Canc Registry Norway, N-0304 Oslo, Norway [ 200 ] Erasmus Univ, Med Ctr, Family Canc Clin, Dept Pathol, NL-3000 CA Rotterdam, Netherlands [ 201 ] Charite, Inst Human Genet, D-13353 Berlin, Germany [ 202 ] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Gaithersburg, MD 20877 USA [ 203 ] Univ Hosp Ulm, D-89075 Ulm, Germany [ 204 ] Univ Tromso, Fac Hlth Sci, Dept Community Med, N-9037 Tromso, Norway [ 205 ] Folkhalsan Res Ctr, Genet Epidemiol Grp, Helsinki 2016, Finland [ 206 ] Stanford Univ, Sch Med, Dept Hlth Res Policy Epidemiol, Stanford, CA 94305 USA [ 207 ] Univ Hosp, Dept Gen Med Oncol, Multidisciplinary Breast Ctr, B-3000 Leuven, Belgium [ 208 ] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA [ 209 ] Hosp Univ La Paz, Med Oncol Serv, Madrid 28046, Spain [ 210 ] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA [ 211 ] QIMR Berghofer Med Res Inst, Canc Div, Brisbane, Qld 4029, Australia [ 212 ] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20850 USA
Subjects: 0301 basic medicine, Oncology, General Physics and Astronomy, Genome-wide association study, Cyclophilins, Breast cancer, 3123 Gynaecology and paediatrics, Risk Factors, Brjóstakrabbamein, Genotype, BRCA2 MUTATION CARRIERS, Medicine and Health Sciences, CONFER SUSCEPTIBILITY, skin and connective tissue diseases, Cancer, GENE-EXPRESSION, Genetics, RISK, tRNA Methyltransferases, Multidisciplinary, Genome, VDP::Medisinske Fag: 700::Helsefag: 800::Samfunnsmedisin, sosialmedisin: 801, Loci, BRCA1 Protein, Chromosome Mapping, COMMON VARIANTS, IDENTIFY, PANCREATIC-CANCER, 3. Good health, Multidisciplinary Sciences, Biological sciences, Receptors, Estrogen, Chromosomes, Human, Pair 2, Science & Technology - Other Topics, Female, NAF12, medicine.medical_specialty, Heterozygote, Science, 3122 Cancers, Locus (genetics), Breast Neoplasms, Biology, Breast Neoplasms/genetics, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, Càncer de mama, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, Pancreatic cancer, MD Multidisciplinary, medicine, Genetic predisposition, Journal Article, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, Cancer och onkologi, Science & Technology, VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Oncology: 762, General Chemistry, Arfgengi, medicine.disease, TRNA Methyltransferases, VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Onkologi: 762, 030104 developmental biology, Cancer and Oncology, Expression quantitative trait loci, Mutation, TELOMERE LENGTH, 3111 Biomedicine, Gene expression, VDP::Medical disciplines: 700::Health sciences: 800::Community medicine, Social medicine: 801, Genome-Wide Association Study
Abstract: Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P, B.C.A.C. was funded through a European Community Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS); Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692); the National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), R01 grants (CA128978, CA176785, CA192393), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative); the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Breast Cancer Res. Foundation, and the Ovarian Cancer Research Fund. CIMBA genotyping was supported by National Institutes of Health grant (CA128978); the Department of Defence (W81XWH-10-1-0341); and the Breast Cancer Res. Foundation. CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. This study made use of data generated by the Wellcome Trust Case Control consortium. Functional studies were supported by the Florida Breast Cancer Foundation. A full description of funding and acknowledgments is provided in Supplementary Note 1.
Published: 2018
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6. The gynecological surveillance of women with Lynch syndrome in Sweden

Author: Miriam Mints, Emil Andersson, Theofanis Zagoras, Maria Soller, Gerasimos Tzortzatos, Marie Stenmark Askmalm, Emma Tham, Annika Lindblom, and Patrik Georgii-Hemming
Subjects: Adult, medicine.medical_specialty, medicine.medical_treatment, medicine, Atypia, Humans, Genetic Predisposition to Disease, Early Detection of Cancer, Aged, Retrospective Studies, Ovarian Neoplasms, Sweden, Gynecology, Hysterectomy, medicine.diagnostic_test, business.industry, Endometrial cancer, Obstetrics and Gynecology, Cancer, Middle Aged, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, Prophylactic Surgery, Lynch syndrome, Endometrial Neoplasms, Oncology, Female, business, Ovarian cancer, Endometrial biopsy
Abstract: Objective. Women with Lynch syndrome (LS) have up to a 60% lifetime risk of endometrial cancer (EC) and up to a 24% risk of ovarian cancer (OC). Gynecological surveillance is recommended, but the benefit and how it should be performed remain unclear. The purpose of this study was to assess diagnostic modalities for gynecological screening of LS patients in Sweden and clinical outcome. Methods. A retrospective nationwide study of 170 women with molecularly confirmed LS. Data including gynecological LS screening history, biopsy results (if any), genetic records, number of screening visits, results from screening including transvaginal ultrasound (TVUS), endometrial biopsy (EB), blood test for tumor marker cancer antigen (CA) 125, prophylactic surgery including age at procedure, and setting from which screening data were obtained from medical records. Results. A total of 117 women were eligible for gynecological screening and of these, 86 patients attended screening visits. Of these, 41 underwent prophylactic hysterectomy and/or bilateral salpingo-oophorectomy. Two patients (4.9%) were diagnosed with EC and two (4.9%) with precancerous lesions in conjunction with prophylactic surgery. Total incidence of gynecological cancer in the surveillance group (45 women) was 20% EC, 4% OC. Five patients had endometrial cancer or complex hyperplasia with atypia (n = 2) detected by endometrial biopsy. Four additional cases were detected due to interval bleeding. Both cases of ovarian cancer were detected by transvaginal ultrasound in patients with ovarian cysts under surveillance. The youngest woman with endometrial cancer was diagnosed at 35 years of age, before she was aware of her diagnosis of Lynch syndrome. Conclusions. Gynecological surveillance of women with Lynch syndrome may lead to earlier detection of precancerous lesions, which might have some impact on the morbidity from endometrial cancer although further studies are needed to prove this. Prophylactic hysterectomy with or without bilateral salpingo-oophorectomy reduces the cancer incidence. A practical approach to surveillance in Lynch syndrome women would be to offer annual surveillance beginning at age 30 years including probably both TVUS and EB in order to increase diagnostic yield with prospective data registry for follow-up studies. Prophylactic surgery could be performed at a suitable age after childbearing to obtain a balance between reducing the risk of cancer and minimizing long-term complications from premature menopause. (C) 2015 Elsevier Inc. All rights reserved.
Published: 2015
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7. Association of Type and Location of BRCA1 and BRCA2 Mutations With Risk of Breast and Ovarian Cancer

Author: Caroline Seynaeve, Katja Harbst, Eric A. Ross, Nandita Mitra, Elisa Alducci, Marco Montagna, Janusz Menkiszak, Marion Gauthier-Villars, Javier Benitez, Carole Brewer, Etienne Rouleau, Inge Søkilde Pedersen, Orland Diez, Anya Kushnir, Antonis C. Antoniou, Christine Rappaport, Florentia Fostira, Maurizio Genuardi, Simona Agata, Mark H. Greene, Mary Beth Terry, Nicola Dikow, David E. Goldgar, Anna Jakubowska, Min Hyuk Lee, Sylvie Mazoyer, Diana Eccles, Shirley Hodgson, Anne-Marie Gerdes, Alexander Miron, Laima Tihomirova, Alan Donaldson, Adalgeir Arason, Rosalind A. Eeles, Fergus J. Couch, Hans Jörg Plendl, Francesca Vignolo-Lutati, Ute Hamann, Jackie Cook, Torben A Kruse, Shani Paluch-Shimon, Lisa Walker, Doris Steinemann, Dorothea Gadzicki, Juul T. Wijnen, Markus C. Fleisch, Kenneth Offit, Mary B. Daly, Jamal Zidan, Georgia Chenevix-Trench, Stephanie V. Blank, Marc Tischkowitz, Esther Darder, Annette Fontaine, Louise Izatt, Elżbieta Złowocka-Perłowska, Nadia Boutry-Kryza, Frans B. L. Hogervorst, Stefanie Engert, Danièle Muller, Susan M. Domchek, Phuong L. Mai, Senno Verhoef, Bernhard H. F. Weber, Cecilia M. Dorfling, Kathleen Claes, Kristiina Aittomäki, Annemarie H. van der Hout, Sharon Sand, Olufunmilayo I. Olopade, Margreet G. E. M. Ausems, Aleksandra Tołoczko-Grabarek, Trevor Cole, Giulietta Scuvera, Ana Osorio, Niklas Loman, Timothy R. Rebbeck, Riccardo Dolcetti, Marit Beer, Harsh B. Pathak, Douglas F. Easton, Lone Sunde, Conxi Lázaro, Raanan Berger, Paolo Radice, Mads Thomassen, Ignacio Blanco, Joseph Vijai, Kristie Bobolis, János Papp, Jean-Pierre Fricker, Christine Walsh, Patricia A. Ganz, Marie Stenmark-Askmalm, Andrea Gehrig, Vernon S. Pankratz, Atocha Romero, Xianshu Wang, Loris Bernard, Viviana Gismondi, Mary Porteous, Muy-Kheng Tea, Karen H. Lu, Gustavo C. Rodriguez, Bernardo Bonanni, Christoph Mundhenke, Julian Adlard, Bent Ejlertsen, Dominique Stoppa-Lyonnet, Nadine Tung, Patrick J. Morrison, Dezheng Huo, Cezary Cybulski, Jack Basil, Georg Pfeiler, Daphne Gschwantler-Kaulich, Heli Nevanlinna, Anders Bojesen, Marion Piedmonte, Katherine L. Nathanson, Amanda E. Toland, Sung-Won Kim, Judy Garber, Amanda B. Spurdle, Noralane M. Lindor, Sanne Traasdahl Moeller, Hans Ehrencrona, Trinidad Caldés, Rosemarie Davidson, Karin Kast, Jenny Lester, Shan Wang-Gohrke, Norbert Arnold, Ana Peixoto, Christine Lasset, Andreas Berger, Olga M. Sinilnikova, Katie Wakely, Claude Houdayer, Mercedes Durán, Robert L. Nussbaum, Ramūnas Janavičius, Christina G. Selkirk, Paolo Aretini, Nina Ditsch, J. Margriet Collée, Rosa B. Barkardottir, Sue Healey, Tomasz Huzarski, Cora M. Aalfs, Gillian Mitchell, Peter J. Hulick, Encarna B. Gomez Garcia, Zakaria Einbeigi, Christian F. Singer, Leigha Senter, Yuan Chun Ding, Dieter Niederacher, Yael Laitman, Siranoush Manoukian, Christoph Engel, Anne De Paepe, Anneliese Fink-Retter, Irene L. Andrulis, Rachel Laframboise, Maria A. Caligo, Priyanka Sharma, Miguel de la Hoya, Teresa Ramón y Cajal, Bruce Poppe, Thomas Hansen, Francesca Damiola, Anne-Bine Skytte, Susan L. Neuhausen, Christian Sutter, Marie-Agnès Collonge-Rame, Johannes J. P. Gille, Barbara Pasini, Wendy K. Chung, Noah D. Kauff, M. John Kennedy, Diana Torres, Salina B. Chan, Mark E. Robson, Elizabeth J. van Rensburg, Eric Hahnen, Barbara Wappenschmidt, Grzegorz Sukiennicki, Esther M. John, Rohini Rau-Murthy, Alice S. Whittemore, Kunle Odunsi, Masoud Azodi, John F. Boggess, Sue K. Park, Rita K. Schmutzler, Muriel Belotti, Jeffrey N. Weitzel, Simon A. Gayther, Fei Wan, Andrew K. Godwin, Arjen R. Mensenkamp, Daniela Zaffaroni, Jacques Simard, Susan Peock, Soo Hwang Teo, Claus R. Bartram, Evgeny N. Imyanitov, Maria-Isabel Tejada, Giuseppe Giannini, Mónica Salinas, Banu Arun, Jan C. Oosterwijk, Jacek Gronwald, Alexandra Becker, Tara M. Friebel, Lenka Foretova, Catherine Noguès, Muhammad Usman Rashid, Valeria Pensotti, Antonella Savarese, Debra Frost, Beatrice Melin, Drakoulis Yannoukakos, Steve Ellis, Jean-Philippe Peyrat, Hagay Sobol, Kim De Leeneer, Radka Platte, Jan Lubinski, Javier Godino, Lesley McGuffog, Tomasz Byrski, Claudine Isaacs, Johanna Rantala, Kelly-Anne Phillips, Carolien M. Kets, Uffe Birk Jensen, Katarzyna Durda, Linda Steele, Beth Y. Karlan, Ava Kwong, Alfons Meindl, Lucia Guidugli, Raymonda Varon-Mateeva, D. Gareth Evans, Edith Olah, Isabelle Mortemousque, Manuel R. Teixeira, Joyce Seldon, Katarzyna Jaworska-Bieniek, Bernard Peissel, Saundra S. Buys, Peter Devilee, Kerstin Rhiem, Eitan Friedman, RS: GROW - Oncology, RS: GROW - R4 - Reproductive and Perinatal Medicine, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Targeted Gynaecologic Oncology (TARGON), Cancer Research UK, National Institutes of Health (US), University of Pennsylvania, Breast Cancer Research Foundation, Human Genetics, Human genetics, and Epidemiology and Data Science
Subjects: endocrine system diseases, Genes, BRCA2, MathematicsofComputing_GENERAL, Genes, BRCA1, cancer risk, Settore MED/03 - GENETICA MEDICA, medicine.disease_cause, MOUSE MODELS, Risk Factors, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Age of Onset, POSITION, skin and connective tissue diseases, Adult, Breast Neoplasms, Female, Heterozygote, Humans, Middle Aged, Nucleotides, Ovarian Neoplasms, Genetic Predisposition to Disease, Mutation, Medicine (all), MESSENGER-RNA DECAY, UNKNOWN CLINICAL-SIGNIFICANCE, BRCA1 and BRCA2 genes, mutation type and position, cancer risk, TheoryofComputation_GENERAL, General Medicine, GERMLINE MUTATIONS, CARRIERS, 3. Good health, SUSCEPTIBILITY GENE, Medical genetics, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], medicine.medical_specialty, PROTEINS, mutation type and position, BRCA1 and BRCA2 genes, DNA-SEQUENCE VARIANTS, Article, REGION, Breast cancer, Germline mutation, medicine, BRCA1 or BRCA2, business.industry, Cancer, Heterozygote advantage, medicine.disease, Cancer research, Age of onset, Ovarian cancer, business
Abstract: CIMBA Consortium et al., PMID: 25849179, [Importance]: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. [Objective]: To identify mutation-specific cancer risks for carriers of BRCA1/2. [Design, Setting, and Participants]: Observational study ofwomen whowere ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents.We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position.We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. [Exposures]: Mutations of BRCA1 or BRCA2. [Main Outcomes and Measures]: Breast and ovarian cancer risks. [Results]: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95%CI, 1.22-1.74; P = 2 × 10-6), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95%CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95%CI, 1.22-1.55; P = 6 × 10-9).We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95%CI, 0.56-0.70; P = 9 × 10-17). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95%CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95%CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95%CI, 1.69-3.16; P = .00002).We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95%CI, 0.44-0.60; P = 6 × 10-17). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95%CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. [Conclusions and Relevance]: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations., Dr Antoniou and the CIMBA data management are funded by Cancer Research UK. Dr Easton is a Principal Research Fellow of Cancer Research UK. Dr Rebbeck is supported by R01-CA083855, R01-CA102776, and P50-CA083638 from the National Institutes of Health (NIH). Dr Rebbeck, Dr Nathanson, Ms Friebel, and Dr Domchek are supported by the Basser Research Center at the University of Pennsylvania. Dr Nathanson is supported by the Breast Cancer Research Foundation. Drs Domchek and Nathanson are supported by the Rooney Family Foundation. Dr Poppe is supported by R01-CA112520 from NIH. Cancer Research UK provided financial support for this work. Dr Antoniou is a Senior Cancer Research UK Cancer Research Fellow. Dr Phillips is a National Breast Cancer Foundation (Australia) Practitioner Fellow.
Published: 2015
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8. Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment

Author: Koki Aihara, Hiroyuki Aburatani, Peter Söderkvist, Joseph F. Costello, Jaap C. Reijneveld, Mitchell S. Berger, Martine L.M. Lamfers, Pieter Wesseling, Shaun D. Fouse, Tali Mazor, Marie Stenmark-Askmalm, Annette M. Molinaro, Barry S. Taylor, Annika Malmström, Martin Hallbeck, Nobuhito Saito, Brett E. Johnson, Jan J. Heimans, Hinke F. van Thuijl, Akitake Mukasa, Chibo Hong, Bauke Ylstra, Susan M. Chang, Jenneke Kloezeman, Neurosurgery, Pathology, Neurology, and CCA - Innovative therapy
Subjects: Male, Methyltransferase, medicine.disease_cause, Cohort Studies, Immunologic, Receptors, Hypermutator, Receptors, Immunologic, DNA Modification Methylases, Cancer, Mutation, Brain Neoplasms, Statistics, Glioma, Alkylating, Dacarbazine, DNA methylation, Disease Progression, DNA mismatch repair, Female, MGMT, medicine.drug, DNA repair, Clinical Sciences, Low-grade glioma, Clinical Neurology, Antineoplastic Agents, Context (language use), Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], Biology, Statistics, Nonparametric, Article, Mismatch repair, Pathology and Forensic Medicine, Cellular and Molecular Neuroscience, Rare Diseases, Genetics, medicine, Temozolomide, Humans, Nonparametric, neoplasms, Antineoplastic Agents, Alkylating, Neurology & Neurosurgery, Tumor Suppressor Proteins, Neurosciences, DNA Methylation, medicine.disease, DNA Repair-Deficiency Disorders, digestive system diseases, Brain Disorders, Brain Cancer, DNA Repair Enzymes, Immunology, Cancer research, Neurology (clinical)
Abstract: Contains fulltext : 155226.pdf (Publisher’s version ) (Closed access) Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O (6) -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-naive LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.
Published: 2015
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9. What Information Do Cancer Genetic Counselees Prioritize?

Author: Chathrine Bjorvatn, Richard Rosenquist, Charlotta Ingvoldstad, Afsaneh Hayat Roshanai, Claudia Lampic, Karin Nordin, and Marie Stenmark Askmalm
Subjects: Sweden, medicine.medical_specialty, Norway, Two-alternative forced choice, Genetic counseling, Public health, Alternative medicine, Genetic Counseling, Session (web analytics), Patient Education as Topic, Neoplasms, Surveys and Questionnaires, Family medicine, Screening method, medicine, Humans, Hereditary Cancer, Decision-making, Psychology, Social psychology, Genetics (clinical)
Abstract: This study explored the informational needs of individuals attending genetic counseling for hereditary cancer, using a free-choice and a forced choice method. Prior to the consultation the informational needs of 334 counselees from Sweden and Norway were assessed by the QUOTE-gene (ca) questionnaire and by a study specific forced choice method, using Q-methodology. Questionnaire responses indicated that counselees' major concerns pertained to the need to be taken seriously, to be provided with sufficient risk estimation and medical/genetic information and to be involved in the decision making process. Furthermore, prior to counseling, counselees noted that the counselors' consideration and skillfulness were also extremely important. Analysis of the Q-sorting results revealed that counselees' needs could be assigned to one of five groups: the "need for facts; caring communication and medical information; information and support in communicating the genetic information to others; practical care and practical/medical information". Particularly noteworthy, counselees with varying backgrounds characteristics prioritized different needs. Cancer genetic counselees probably have different needs due to their medical and demographic background when attending genetic counseling. Addressing counselees' specific concerns more sufficiently and thereby increasing the overall effectiveness of the counseling session requires increased insight into individual needs, by for instance, utilizing screening methods such as QUOTE-gene (ca) prior to the counseling session.
Published: 2011
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10. Bilateral Prophylactic Mastectomy in Swedish Women at High Risk of Breast Cancer

Author: Marie Stenmark Askmalm, Jonas Lundberg, Monica Emanuelsson, Anita Ringberg, Yvonne Brandberg, Niklas Loman, Hans Atterhem, Karin Isaksson, Kerstin Sandelin, Brita Arver, Henrik Hellborg, Karin M. Henriksson, Hans Ehrencrona, Annika Baan, Marie Wickman, Per Karlsson, and Leif Bergkvist
Subjects: Adult, Reoperation, medicine.medical_specialty, medicine.medical_treatment, Breast surgery, Genes, BRCA2, Genes, BRCA1, Breast Neoplasms, Risk Assessment, Breast cancer, Risk Factors, medicine, Humans, Genetic Predisposition to Disease, Bilateral Prophylactic Mastectomy, Mastectomy, Aged, Sweden, business.industry, Incidence, Cancer, Middle Aged, medicine.disease, Surgery, Health Care Surveys, Adenocarcinoma, Female, Breast disease, business, Breast reconstruction
Abstract: BACKGROUND/OBJECTIVE:: This study attempted a national inventory of all bilateral prophylactic mastectomies performed in Sweden between 1995 and 2005 in high-risk women without a previous breast malignancy. The primary aim was to investigate the breast cancer incidence after surgery. Secondary aims were to describe the preoperative risk assessment, operation techniques, complications, histopathological findings, and regional differences. METHODS:: Geneticists, oncologists and surgeons performing prophylactic breast surgery were asked to identify all women eligible for inclusion in their region. The medical records were reviewed in each region and the data were analyzed centrally. The BOADICEA risk assessment model was used to calculate the number of expected/prevented breast cancers during the follow-up period. RESULTS:: A total of 223 women operated on in 8 hospitals were identified. During a mean follow-up of 6.6 years, no primary breast cancer was observed compared with 12 expected cases. However, 1 woman succumbed 9 years post mastectomy to widespread adenocarcinoma of uncertain origin. Median age at operation was 40 years. A total of 58% were BRCA1/2 mutation carriers. All but 3 women underwent breast reconstruction, 208 with implants and 12 with autologous tissue. Four small, unifocal, invasive cancers and 4 ductal carcinoma in situ were found in the mastectomy specimens. The incidence of nonbreast related complications was low (3%). Implant loss due to infection/necrosis occurred in 21 women (10%) but a majority received a new implant later. In total, 64% of the women underwent at least 1unanticipated secondary operation. CONCLUSIONS:: Bilateral prophylactic mastectomy is safe and efficacious in reducing future breast cancer in asymptomatic women at high risk. Unanticipated reoperations are common. Given the small number of patients centralization seems justified.
Published: 2011
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11. Intact Mre11/Rad50/Nbs1 Complex Predicts Good Response to Radiotherapy in Early Breast Cancer

Author: Marie Stenmark Askmalm, Bo Nordenskjöld, Karin Söderlund, Lars Erik Rutqvist, Lambert Skoog, and Olle Stål
Subjects: Oncology, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Estrogen receptor, Breast Neoplasms, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, Protein Serine-Threonine Kinases, Breast cancer, MRE11 Homologue Protein, Internal medicine, medicine, Humans, Radiology, Nuclear Medicine and imaging, Chemotherapy, Radiation, business.industry, Tumor Suppressor Proteins, Nuclear Proteins, medicine.disease, Acid Anhydride Hydrolases, Neoplasm Proteins, DNA-Binding Proteins, Radiation therapy, DNA Repair Enzymes, Treatment Outcome, MRN complex, Rad50, Cancer research, Immunohistochemistry, Female, business
Abstract: Purpose To investigate the expression and predictive role of the Mre11/Rad50/Nbs1 (MRN) complex and the ataxia-telangiectasia mutated protein (ATM) for the outcome of radiotherapy in breast cancer patients. Methods and Materials The protein expression of ATM and the DNA repair proteins in the MRN complex were investigated using immunohistochemistry in tumors from 224 women with early breast cancer, who were randomized to receive postoperative radiotherapy or adjuvant chemotherapy. Results Compared with normal breast tissue, the staining intensity of Mre11, Rad50, Nbs1, and ATM was reduced in a majority of the tumors. Weak expression of the MRN complex was correlated with high histologic grade and estrogen receptor negativity (p = 0.01 and p = 0.0001, respectively). Radiotherapy significantly reduced the risk of local recurrence as compared with chemotherapy (p = 0.04). The greatest benefit of radiotherapy was seen in patients with moderate/strong expression of the MRN complex (relative risk = 0.27, 95% confidence interval = 0.098–0.72, p = 0.009), whereas patients with negative/weak MRN expression had no benefit of radiotherapy compared with adjuvant chemotherapy. These results suggest that an intact MRN complex is important for the tumor cell eradicating effect of radiotherapy. Conclusions Reduced expression of the MRN complex predicts a poor effect of radiotherapy in patients with early breast cancer.
Published: 2007
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12. Mutation and accumulation of p53 related to results of adjuvant therapy of postmenopausal breast cancer patients

Author: Lars Erik Rutqvist, Birgit Olsson, Olle Stål, John Carstensen, Marie Stenmark Askmalm, Bo Nordenskjöld, and Lambert Skoog
Subjects: Oncology, medicine.medical_specialty, Antineoplastic Agents, Hormonal, Cyclophosphamide, medicine.medical_treatment, Breast Neoplasms, Gene mutation, Breast cancer, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Adjuvant therapy, Humans, Radiology, Nuclear Medicine and imaging, Neoplasm Metastasis, Chemotherapy, business.industry, Hematology, General Medicine, Genes, p53, medicine.disease, Combined Modality Therapy, Postmenopause, Radiation therapy, Tamoxifen, Methotrexate, Treatment Outcome, Chemotherapy, Adjuvant, Mutation, Female, Radiotherapy, Adjuvant, Fluorouracil, Neoplasm Recurrence, Local, Tumor Suppressor Protein p53, business, Adjuvant, medicine.drug
Abstract: p53 protein accumulation and gene mutation have been implicated in resistance to cytotoxic treatment. This study was performed to further assess the predictive value of p53 in breast cancer. Postmenopausal patients were randomized to adjuvant chemotherapy with cyclophosphamide, metothrexate, or 5-fluorouracil (CMF) vs. postoperative radiotherapy. The patients were also randomized to adjuvant tamoxifen vs. no endocrine treatment. Immunohistochemistry (IHC) and single-strand conformation polymorphism (SSCP), followed by direct sequencing, was performed. The p53 altered group, regarded as positive for p53 gene mutation and/or p53 protein accumulation, tended to benefit more from CMF than from radiotherapy as compared with others regarding distant recurrences. In the group lacking p53 alteration there was a significantly decreased local recurrence rate in the radiotherapy group as compared with the CMF group (RR = 0.24, 95% CI = 0.083 0.62), whereas no benefit from radiotherapy was found for patients showing p53 alterations. Tamoxifen significantly decreased the rate of distant recurrence for estrogen receptor-positive patients with no apparent difference in relation to p53 alteration. It is suggested that p53 alteration indicates benefit from CMF compared with radiotherapy regarding distant recurrence-free survival and the best local control with radiotherapy is achieved in the absence of p53 alteration. Finally, altered p53 status is probably not a marker of resistance to tamoxifen.
Published: 2004
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13. Genetic anticipation in Swedish Lynch syndrome families

Author: Jenny von Salomé, Marie Stenmark-Askmalm, Samuel Gebre-Medhin, Gustav Silander, Masoud Karimi, Christos Aravidis, Philip S. Boonstra, Kristina Lagerstedt-Robinson, Annika Lindblom, and Mef Nilbert
Subjects: Male, 0301 basic medicine, Cancer Research, Heredity, Mismatch Repair, DNA Mismatch Repair/genetics, DNA Mismatch Repair, Biochemistry, 0302 clinical medicine, Neoplasms, Sequence Deletion/genetics, Medicine and Health Sciences, PMS2, Genetics (clinical), Sequence Deletion, Genetics, medicine.diagnostic_test, Cancer Risk Factors, Middle Aged, Lynch syndrome, 3. Good health, DNA-Binding Proteins, Nucleic acids, Oncology, Genetic Diseases, 030220 oncology & carcinogenesis, Medical genetics, Female, DNA mismatch repair, Medical Genetics, Genetic Testing/methods, Research Article, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Mutation/genetics, lcsh:QH426-470, Genetic Causes of Cancer, DNA repair, Biology, MLH1, 03 medical and health sciences, Diagnostic Medicine, Colorectal Neoplasms, Hereditary Nonpolyposis/genetics, Cancer Detection and Diagnosis, medicine, Humans, Genetic Testing, neoplasms, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Medicinsk genetik, Genetic testing, Sweden, Colorectal Cancer, Clinical Genetics, Cancer och onkologi, Anticipation, Genetic, Autosomal Dominant Diseases, Biology and Life Sciences, Cancers and Neoplasms, nutritional and metabolic diseases, Hereditary Nonpolyposis Colorectal Cancer, Human Genetics, DNA, medicine.disease, Colorectal Neoplasms, Hereditary Nonpolyposis, digestive system diseases, MSH6, Neoplasms/etiology, lcsh:Genetics, 030104 developmental biology, MSH2, Anticipation, Genetic/genetics, Cancer and Oncology, Mutation, DNA-Binding Proteins/genetics
Abstract: Among hereditary colorectal cancer predisposing syndromes, Lynch syndrome (LS) caused by mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2 is the most common. Patients with LS have an increased risk of early onset colon and endometrial cancer, but also other tumors that generally have an earlier onset compared to the general population. However, age at first primary cancer varies within families and genetic anticipation, i.e. decreasing age at onset in successive generations, has been suggested in LS. Anticipation is a well-known phenomenon in e.g neurodegenerative diseases and several reports have studied anticipation in heritable cancer. The purpose of this study is to determine whether anticipation can be shown in a nationwide cohort of Swedish LS families referred to the regional departments of clinical genetics in Lund, Stockholm, Linköping, Uppsala and Umeå between the years 1990–2013. We analyzed a homogenous group of mutation carriers, utilizing information from both affected and non-affected family members. In total, 239 families with a mismatch repair gene mutation (96 MLH1 families, 90 MSH2 families including one family with an EPCAM–MSH2 deletion, 39 MSH6 families, 12 PMS2 families, and 2 MLH1+PMS2 families) comprising 1028 at-risk carriers were identified among the Swedish LS families, of which 1003 mutation carriers had available follow-up information and could be included in the study. Using a normal random effects model (NREM) we estimate a 2.1 year decrease in age of diagnosis per generation. An alternative analysis using a mixed-effects Cox proportional hazards model (COX-R) estimates a hazard ratio of exp(0.171), or about 1.19, for age of diagnosis between consecutive generations. LS-associated gene-specific anticipation effects are evident for MSH2 (2.6 years/generation for NREM and hazard ratio of 1.33 for COX-R) and PMS2 (7.3 years/generation and hazard ratio of 1.86). The estimated anticipation effects for MLH1 and MSH6 are smaller., Author summary Genetic anticipation is a phenomenon where symptoms of a hereditary disease appear at an earlier age and/or are more severe in successive generations. In genetic disorders such as Fragile X syndrome, Myotonic dystrophy type 1 and Huntington disease, anticipation is caused by the expansion of unstable trinucleotide repeats during meiosis. Anticipation is also reported to occur in some hereditary cancers though the underlying mechanism behind this observation is unknown. Several studies have investigated anticipation in Lynch syndrome, the most common hereditary colorectal cancer syndrome, yet there is a debate concerning whether anticipation occurs and what underlying mechanism there is. The objective of this project is to study if anticipation is part of the clinical picture in Swedish families with LS, with the long term goal to enable better prediction of age at onset in family members. Our results suggest that anticipation occurs in families with mutation in MSH2 and PMS2, while the evidence is equivocal for MLH1 and MSH6.
Published: 2017
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14. P53 Expression and the Result of Adjuvant Therapy of Breast Cancer

Author: Sten Wingren, Marie Stenmark Askmalm, Bo Nordenskjöld, Lambert Skoog, Siw Sullivan, Olle Stål, Lars Erik Rutqvist, John Carstensen, and Lilianne Ferraud
Subjects: Oncology, Antimetabolites, Antineoplastic, medicine.medical_specialty, Cyclophosphamide, medicine.drug_class, medicine.medical_treatment, Mammary gland, Apoptosis, Breast Neoplasms, Antimetabolite, Mastectomy, Modified Radical, Breast cancer, Risk Factors, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Adjuvant therapy, Humans, Radiology, Nuclear Medicine and imaging, Antineoplastic Agents, Alkylating, Postoperative Care, Chemotherapy, business.industry, DNA, Neoplasm, Hematology, General Medicine, Aneuploidy, medicine.disease, Combined Modality Therapy, Immunohistochemistry, Gene Expression Regulation, Neoplastic, Radiation therapy, Methotrexate, medicine.anatomical_structure, Premenopause, Chemotherapy, Adjuvant, Fluorouracil, Cancer research, Female, Neoplasm Recurrence, Local, Tumor Suppressor Protein p53, business, DNA Damage, medicine.drug
Abstract: Functional p53 protein is essential for the cellular response to drug-induced DNA damage. We investigated p53 accumulation in tumour specimens from premenopausal breast cancer patients who were randomised to adjuvant chemotherapy (CMF) or postoperative radiotherapy. Of the tumours from 139 patients, 20 showed abnormal accumulation as judged with immunohistochemistry (>10% positive tumour cells). The risk of distant recurrence was similar in the two treatment groups for patients whose primary tumours lacked p53 accumulation, whereas there was a significant benefit from CMF for patients showing abnormal accumulation (relative risk 0.18, 95% CI, 0.04–0.93). This result suggests that p53–dependent apoptosis is not a general mechanism by which breast cancer cells respond during CMF chemotherapy.
Published: 1995
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15. Evidence of Gene-Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors

Author: Fergus J, Couch, Xianshu, Wang, Lesley, McGuffog, Andrew, Lee, Curtis, Olswold, Karoline B, Kuchenbaecker, Penny, Soucy, Zachary, Fredericksen, Daniel, Barrowdale, Joe, Dennis, Mia M, Gaudet, Ed, Dicks, Matthew, Kosel, Sue, Healey, Olga M, Sinilnikova, Adam, Lee, François, Bacot, Daniel, Vincent, Frans B L, Hogervorst, Susan, Peock, Dominique, Stoppa-Lyonnet, Anna, Jakubowska, Paolo, Radice, Rita Katharina, Schmutzler, Susan M, Domchek, Marion, Piedmonte, Christian F, Singer, Eitan, Friedman, Mads, Thomassen, Thomas V O, Hansen, Susan L, Neuhausen, Csilla I, Szabo, Ignacio, Blanco, Mark H, Greene, Beth Y, Karlan, Judy, Garber, Catherine M, Phelan, Jeffrey N, Weitzel, Marco, Montagna, Edith, Olah, Irene L, Andrulis, Andrew K, Godwin, Drakoulis, Yannoukakos, David E, Goldgar, Trinidad, Caldes, Heli, Nevanlinna, Ana, Osorio, Mary Beth, Terry, Mary B, Daly, Elizabeth J, van Rensburg, Ute, Hamann, Susan J, Ramus, Amanda Ewart, Toland, Maria A, Caligo, Olufunmilayo I, Olopade, Nadine, Tung, Kathleen, Claes, Mary S, Beattie, Melissa C, Southey, Evgeny N, Imyanitov, Marc, Tischkowitz, Ramunas, Janavicius, Esther M, John, Ava, Kwong, Orland, Diez, Judith, Balmaña, Rosa B, Barkardottir, Banu K, Arun, Gad, Rennert, Soo-Hwang, Teo, Patricia A, Ganz, Ian, Campbell, Annemarie H, van der Hout, Carolien H M, van Deurzen, Caroline, Seynaeve, Encarna B, Gómez Garcia, Flora E, van Leeuwen, Hanne E J, Meijers-Heijboer, Johannes J P, Gille, Margreet G E M, Ausems, Marinus J, Blok, Marjolijn J L, Ligtenberg, Matti A, Rookus, Peter, Devilee, Senno, Verhoef, Theo A M, van Os, Juul T, Wijnen, Debra, Frost, Steve, Ellis, Elena, Fineberg, Radka, Platte, D Gareth, Evans, Louise, Izatt, Rosalind A, Eeles, Julian, Adlard, Diana M, Eccles, Jackie, Cook, Carole, Brewer, Fiona, Douglas, Shirley, Hodgson, Patrick J, Morrison, Lucy E, Side, Alan, Donaldson, Catherine, Houghton, Mark T, Rogers, Huw, Dorkins, Jacqueline, Eason, Helen, Gregory, Emma, McCann, Alex, Murray, Alain, Calender, Agnès, Hardouin, Pascaline, Berthet, Capucine, Delnatte, Catherine, Nogues, Christine, Lasset, Claude, Houdayer, Dominique, Leroux, Etienne, Rouleau, Fabienne, Prieur, Francesca, Damiola, Hagay, Sobol, Isabelle, Coupier, Laurence, Venat-Bouvet, Laurent, Castera, Marion, Gauthier-Villars, Mélanie, Léoné, Pascal, Pujol, Sylvie, Mazoyer, Yves-Jean, Bignon, Elżbieta, Złowocka-Perłowska, Jacek, Gronwald, Jan, Lubinski, Katarzyna, Durda, Katarzyna, Jaworska, Tomasz, Huzarski, Amanda B, Spurdle, Alessandra, Viel, Bernard, Peissel, Bernardo, Bonanni, Giulia, Melloni, Laura, Ottini, Laura, Papi, Liliana, Varesco, Maria Grazia, Tibiletti, Paolo, Peterlongo, Sara, Volorio, Siranoush, Manoukian, Valeria, Pensotti, Norbert, Arnold, Christoph, Engel, Helmut, Deissler, Dorothea, Gadzicki, Andrea, Gehrig, Karin, Kast, Kerstin, Rhiem, Alfons, Meindl, Dieter, Niederacher, Nina, Ditsch, Hansjoerg, Plendl, Sabine, Preisler-Adams, Stefanie, Engert, Christian, Sutter, Raymonda, Varon-Mateeva, Barbara, Wappenschmidt, Bernhard H F, Weber, Brita, Arver, Marie, Stenmark-Askmalm, Niklas, Loman, Richard, Rosenquist, Zakaria, Einbeigi, Katherine L, Nathanson, Timothy R, Rebbeck, Stephanie V, Blank, David E, Cohn, Gustavo C, Rodriguez, Laurie, Small, Michael, Friedlander, Victoria L, Bae-Jump, Anneliese, Fink-Retter, Christine, Rappaport, Daphne, Gschwantler-Kaulich, Georg, Pfeiler, Muy-Kheng, Tea, Noralane M, Lindor, Bella, Kaufman, Shani, Shimon Paluch, Yael, Laitman, Anne-Bine, Skytte, Anne-Marie, Gerdes, Inge Sokilde, Pedersen, Sanne Traasdahl, Moeller, Torben A, Kruse, Uffe Birk, Jensen, Joseph, Vijai, Kara, Sarrel, Mark, Robson, Noah, Kauff, Anna Marie, Mulligan, Gord, Glendon, Hilmi, Ozcelik, Bent, Ejlertsen, Finn C, Nielsen, Lars, Jønson, Mette K, Andersen, Yuan Chun, Ding, Linda, Steele, Lenka, Foretova, Alex, Teulé, Conxi, Lazaro, Joan, Brunet, Miquel Angel, Pujana, Phuong L, Mai, Jennifer T, Loud, Christine, Walsh, Jenny, Lester, Sandra, Orsulic, Steven A, Narod, Josef, Herzog, Sharon R, Sand, Silvia, Tognazzo, Simona, Agata, Tibor, Vaszko, Joellen, Weaver, Alexandra V, Stavropoulou, Saundra S, Buys, Atocha, Romero, Miguel, de la Hoya, Kristiina, Aittomäki, Taru A, Muranen, Mercedes, Duran, Wendy K, Chung, Adriana, Lasa, Cecilia M, Dorfling, Alexander, Miron, Javier, Benitez, Leigha, Senter, Dezheng, Huo, Salina B, Chan, Anna P, Sokolenko, Jocelyne, Chiquette, Laima, Tihomirova, Tara M, Friebel, Bjarni A, Agnarsson, Karen H, Lu, Flavio, Lejbkowicz, Paul A, James, Per, Hall, Alison M, Dunning, Daniel, Tessier, Julie, Cunningham, Susan L, Slager, Chen, Wang, Steven, Hart, Kristen, Stevens, Jacques, Simard, Tomi, Pastinen, Vernon S, Pankratz, Kenneth, Offit, Douglas F, Easton, Georgia, Chenevix-Trench, and Antonis C, Antoniou
Subjects: BRCA2 Protein, Ovarian Neoplasms, Heterozygote, endocrine system diseases, Genotype, BRCA1 Protein, Breast Neoplasms, Middle Aged, Prognosis, Polymorphism, Single Nucleotide, Risk Factors, Mutation, Humans, Medicine, Female, Genetic Predisposition to Disease, skin and connective tissue diseases, Biology, Genome-Wide Association Study, Research Article
Abstract: 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.
Published: 2012

16. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

Author: Ramus, Susan J., Antoniou, Antonis C., Kuchenbaecker, Karoline B., Penny, Soucy, Jonathan, Beesley, Xiaoqing, Chen, Lesley, Mcguffog, Sinilnikova, Olga M., Sue, Healey, Daniel, Barrowdale, Andrew, Lee, Mads, Thomassen, Anne Marie Gerdes, Kruse, Torben A., Uffe Birk Jensen, Anne Bine Skytte, Caligo, Maria A., Annelie, Liljegren, Annika, Lindblom, Hakan, Olsson, Ulf, Kristoffersson, Marie Stenmark Askmalm, Swe Brca Melin, B., Swe, Brca, Domchek, Susan M., Domchek, Sm, Nathanson, Katherine L., Rebbeck, Timothy R., Anna, Jakubowska, Jan, Lubinski, Katarzyna, Jaworska, Katarzyna, Durda, Elzbieta, Złowocka, Jacek, Gronwald, Tomasz, Huzarski, Tomasz, Byrski, Cezary, Cybulski, Aleksandra Toloczko Grabarek, Ana, Osorio, Javier, Benitez, Mercedes, Duran, Maria Isabel Tejada, Ute, Hamann, Matti, Rookus, Van Leeuwen, Flora E., Aalfs, Cora M., Meijers Heijboer, Hanne E. J., Van Asperen, Christi J., Van Roozendaal, K. E. P., Nicoline, Hoogerbrugge, Collee, Margriet J., Margriet Collee, J., Mieke, Kriege, Hebon Van Der Luijt, R. B., Embrace, Embrace, Hebon, Susan, Peock, Debra, Frost, Ellis, Steve D., Radka, Platte, Elena, Fineberg, Gareth Evans, D., Fiona, Lalloo, Chris, Jacobs, Ros, Eeles, Julian, Adlard, Rosemarie, Davidson, Diana, Eccles, Trevor, Cole, Jackie, Cook, Joan, Paterson, Fiona, Douglas, Carole, Brewer, Shirley, Hodgson, Morrison, Patrick J., Lisa, Walker, Porteous, Mary E., John Kennedy, M., Harsh, Pathak, Godwin, Andrew K., Dominique Stoppa Lyonnet, Virginie Caux Moncoutier, Antoine Pauw, D. E., De Pauw, A., Marion Gauthier Villars, Sylvie, Mazoyer, Melanie, Leone, Alain, Calender, Christine, Lasset, Valerie, Bonadona, Agnes, Hardouin, Pascaline, Berthet, Yves Jean Bignon, Nancy, Uhrhammer, Laurence, Faivre, Catherine, Loustalot, Gemo, Saundra, Buys, Mary, Daly, Buys, Daly, S., Alex, Miron, Beth, Terry M., Mary Beth Terry, Terry, M. B., Chung, Wendy K., Esther, John M., John, Em, Melissa, Southey, David, Goldgar, Singer, Christian F., Muy Kheng Tea, Georg, Pfeiler, Anneliese Fink Retter, Hansen, Thomas V. O., Hansen, Tv, Bent, Ejlertsen, Oskar Th Johannsson, Kenneth, Offit, Tomas, Kirchhoff, Gaudet, Mia M., Joseph, Vijai, Mark, Robson, Marion, Piedmonte, Kelly Anne Phillips, Linda Van Le, Hoffman, James S., Amanda Ewart Toland, Ewart Toland, A., Marco, Montagna, Silvia, Tognazzo, Evgeny, Imyanitov, Claudine, Isaacs, Issacs, C., Ramunas, Janavicius, Conxi, Lazaro, Ignacio, Blanco, Eva, Tornero, Matilde, Navarro, Moysich, Kirsten B., Karlan, Beth Y., Jenny, Gross, Edith, Olah, Tibor, Vaszko, Soo Hwang Teo, Ganz, Patricia A., Beattie, Mary S., Dorfling, Cecelia M., Van Rensburg, Elizabeth J., Orland, Diez, Ava, Kwong, Schmutzler, Rita K., Barbara, Wappenschmidt, Christoph, Engel, Alfons, Meindl, Nina, Ditsch, Norbert, Arnold, Simone, Heidemann, Dieter, Niederacher, Sabine Preisler Adams, Dorotehea, Gadzicki, Raymonda Varon Mateeva, Helmut, Deissler, Andrea, Gehrig, Christian, Sutter, Karin, Kast, Britta, Fiebig, Dieter, Schafer, Trinidad, Caldes, Miguel De La Hoya, Heli, Nevanlinna, Kristiina, Aittomaki, Marie, Plante, Kconfab Spurdle, A. B., Kconfab, Neuhausen, Susan L., Neuhausen, Sl, Yuan Chun Ding, Xianshu, Wang, Noralane, Lindor, Zachary, Fredericksen, Shane Pankratz, V., Paolo, Peterlongo, Siranoush, Manoukian, Bernard, Peissel, Daniela, Zaffaroni, Bernardo, Bonanni, Loris, Bernard, Riccardo, Dolcetti, Laura, Papi, Ottini, Laura, Paolo, Radice, Greene, Mark H., Mai, Phuong L., Andrulis, Irene L., Gord, Glendon, Ocgn Ozcelik, H., Ocgn, Pharoah, Paul D. P., Pharoah, Pd, Gayther, Simon A., Jacques, Simard, Easton, Douglas F., Couch, Fergus J., Georgia Chenevix Trench, Behalf Of The Consortium Of Investigators Of Modifiers Of Brca1/2, O. N., Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Human Genetics, CCA -Cancer Center Amsterdam, ARD - Amsterdam Reproduction and Development, Universitat de Barcelona, Genetica & Celbiologie, MUMC+: DA KG Lab Centraal Lab (9), RS: CARIM School for Cardiovascular Diseases, RS: GROW - School for Oncology and Reproduction, and Clinical Genetics
Subjects: Oncology, endocrine system diseases, [SDV]Life Sciences [q-bio], Càncer d'ovari, DCN PAC - Perception action and control, Cohort Studies, Breast cancer, 0302 clinical medicine, brca1, brca2, Odds Ratio, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Ovarian Neoplasms, Genetics, 0303 health sciences, education.field_of_study, BRCA1 Protein, Hazard ratio, Middle Aged, 3. Good health, ovarian cancer, 030220 oncology & carcinogenesis, Female, Adult, Heterozygote, medicine.medical_specialty, Hereditary cancer and cancer-related syndromes Genetics and epigenetic pathways of disease [ONCOL 1], Population, Single-nucleotide polymorphism, Biology, Ovarian Neoplasms - genetics, Polymorphism, Single Nucleotide, Article, Càncer de mama, 03 medical and health sciences, Germline mutation, SDG 3 - Good Health and Well-being, Translational research [ONCOL 3], Ovarian cancer, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, ddc:610, Genetics and epigenetic pathways of disease Translational research [NCMLS 6], education, Retrospective Studies, 030304 developmental biology, BRCA2 Protein, Hereditary cancer and cancer-related syndromes [ONCOL 1], association, Retrospective cohort study, snp, Odds ratio, BRCA1 Protein - genetics, medicine.disease, BRCA2 Protein - genetics, Mutation
Abstract: Germline mutations in BRCA1 and BRCA2 are associated with increased risks of breast and ovarian cancer. A genome-wide association study (GWAS) identified six alleles associated with risk of ovarian cancer for women in the general population. We evaluated four of these loci as potential modifiers of ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Four single-nucleotide polymorphisms (SNPs), rs10088218 (at 8q24), rs2665390 (at 3q25), rs717852 (at 2q31), and rs9303542 (at 17q21), were genotyped in 12,599 BRCA1 and 7,132 BRCA2 carriers, including 2,678 ovarian cancer cases. Associations were evaluated within a retrospective cohort approach. All four loci were associated with ovarian cancer risk in BRCA2 carriers; rs10088218 per-allele hazard ratio (HR) = 0.81 (95% CI: 0.67-0.98) P-trend = 0.033, rs2665390 HR = 1.48 (95% CI: 1.21-1.83) P-trend = 1.8 x 10(-4), rs717852 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.6 x 10(-4), rs9303542 HR = 1.16 (95% CI: 1.02-1.33) P-trend = 0.026. Two loci were associated with ovarian cancer risk in BRCA1 carriers; rs10088218 per-allele HR = 0.89 (95% CI: 0.81-0.99) P-trend = 0.029, rs2665390 HR = 1.25 (95% CI: 1.10-1.42) P-trend = 6.1 x 10(-4). The HR estimates for the remaining loci were consistent with odds ratio estimates for the general population. The identification of multiple loci modifying ovarian cancer risk may be useful for counseling women with BRCA1 and BRCA2 mutations regarding their risk of ovarian cancer., link_to_OA_fulltext
Published: 2012
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17. Cellular accumulation of p53 protein: an independent prognostic factor in stage II breast cancer

Author: Olle Stål, Lilianne Ferraud, Marie Stenmark-Askmalm, Xiao-Feng Sun, John Carstensen, Bo Nordenskjöld, and Siw Sullivan
Subjects: Cytoplasm, Cancer Research, Receptor, ErbB-2, medicine.drug_class, Mammary gland, Breast Neoplasms, Biology, Monoclonal antibody, Gene product, Breast cancer, Proto-Oncogene Proteins, Gene expression, medicine, Humans, Lymph node, Cell Nucleus, DNA, Neoplasm, Middle Aged, Prognosis, medicine.disease, Immunohistochemistry, Survival Analysis, ErbB Receptors, medicine.anatomical_structure, Receptors, Estrogen, Oncology, Cancer research, Female, Tumor Suppressor Protein p53
Abstract: The p53 gene product is a tumour suppressor protein, and alterations of the protein are common in human cancer. Previous studies have focused on nuclear accumulation of p53. To investigate if cytoplasmic accumulation of p53 strengthens the relationships to different pathobiological variables and distant recurrence-free survival in breast cancer, tumours from 164 stage II patients were examined with the monoclonal antibody PAb1801. Nine per cent of the tumours were nuclear positive and 21% were cytoplasmic positive. Cellular p53 accumulation, related to the nucleus or the cytoplasm or both, showed stronger associations with pathobiological variables than nuclear accumulation alone. Accumulation of p53 was significantly correlated to tumour size over 20 mm, negative oestrogen receptor (ER) status, DNA aneuploidy, high S-phase fraction and positive erbB-2 status. Cytoplasmic p53 was significantly correlated to distance recurrence-free survival in patients negative for nuclear p53 (P < 0.0001). Cellular p53 accumulation was an independent prognostic factor, in addition to lymph node status and ER content. We conclude that consideration of cytoplasmic staining enhances the clinical importance of p53.
Published: 1994
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18. Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers

Author: Thomas v O Hansen, Amanda B. Spurdle, Anne-Marie Gerdes, Sue Healey, Per Karlsson, Tomasz Huzarski, Mary B. Daly, Mary Porteous, T. Caldes, Ulf Kristoffersson, Ignacio Blanco, A. Miron, Laurence Faivre, Barbara Wappenschmidt, Laurence Venat-Bouvet, Marie Stenmark Askmalm, Olga M. Sinilnikova, Susan Peock, Alessandra Viel, Conxi Lázaro, Katherine L. Nathanson, Laurent Castera, Douglas F. Easton, Susan L. Neuhausen, Jan Lubinski, Phuong L. Mai, Virginie Moncoutier, Paolo Radice, Heli Nevanlinna, Christi J Asperen, Xianshu Wang, Brita Arver, Christian Sutter, Senno Verhoef, Rosette Lidereau, Mary S Beattie, Bjarni A Agnarsson, Ina Ruehl, Monica Barile, Bent Ejlertsen, Laura Ottini, Catherine Noguès, Jennifer A. Przybylo, Cinzia Casella, Trevor Cole, Norbert Arnold, Sandra Fert-Ferrer, Hilmi Ozcelik, Irene L. Andrulis, Susan M. Domchek, Valérie Bonadona, Kirsten B. Moysich, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Beth Y. Karlan, Jenny Gross, Gaia Roversi, Tadeusz Dębniak, Hanne Meijers-Heijboer, Susan J. Ramus, Dorthe G. Crüger, Zachary S. Fredericksen, Siranoush Manoukian, Viviana Gismondi, Maria A. Caligo, Helene Holland, Laure Barjhoux, Gord Glendon, Ana Osorio, Jacques Simard, John L. Hopper, Mercedes Durán, Kristiina Aittomäki, Håkan Olsson, Mads Thomassen, Fabio Capra, Patrick J. Morrison, Britta Fiebig, Mary Beth Terry, Marinus J. Blok, Evgeny N. Imyanitov, Joseph Vijai, Javier Benitez, Mark T. Rogers, D. Gareth Evans, Helmut Deissler, Tomasz Byrski, Sylvie Mazoyer, Laura Papi, Dominique Stoppa-Lyonnet, Marco Montagna, Kenneth Offit, Cezary Cybulski, Dominique Leroux, Georgia Chenevix-Trench, Danielle Bodmer, Lucy Side, Margaret Cook, Ros Eeles, Alan Donaldson, Christiana Kartsonaki, Carole Brewer, Matti A. Rookus, Jacek Gronwald, Dorothea Gadzicki, Shirley Hodgson, Jonathan Beesley, Gabriella Pichert, Andrew K. Godwin, Dieter Niederacher, Yuan Chun Ding, Torben A Kruse, Paolo Peterlongo, Rita K. Schmutzler, Xiaoqing Chen, Annika Lindblom, Fergus J. Couch, Maaike P.G. Vreeswijk, Mark H. Greene, Esther M. John, Raymonda Varon-Mateeva, Simon A. Gayther, Margreet G. E. M. Ausems, Tomas Kirchhoff, Lars Jønson, Madeleine M. A. Tilanus-Linthorst, Ute Hamann, Marie-Agnès Collonge-Rame, Antonis C. Antoniou, M John Kennedy, Karin Kast, Theo A. M. van Os, Penny Soucy, Debra Frost, Alison M. Dunning, Daniela Zaffaroni, Anna Allavena, Maria-Isabel Tejada, Yves-Jean Bignon, Lesley McGuffog, Bohdan Górski, Åke Borg, Fabienne Prieur, Bernard Peissel, Helen Gregory, Clare Oliver, Saundra S. Buys, Ana Dutra-Clarke, Alfons Meindl, Ramunas Janavicius, Uffe Birk Jensen, Miguel de la Hoya, Ramus, S, Kartsonaki, C, Gayther, S, Pharoah, P, Sinilnikova, O, Beesley, J, Chen, X, Mcguffog, L, Healey, S, Couch, F, Wang, X, Fredericksen, Z, Peterlongo, P, Manoukian, S, Peissel, B, Zaffaroni, D, Roversi, G, Barile, M, Viel, A, Allavena, A, Ottini, L, Papi, L, Gismondi, V, Capra, F, Radice, P, Greene, M, Mai, P, Andrulis, I, Glendon, G, Ozcelik, H, Thomassen, M, Gerdes, A, Kruse, T, Cruger, D, Jensen, U, Caligo, M, Olsson, H, Kristoffersson, U, Lindblom, A, Arver, B, Karlsson, P, Stenmark Askmalm, M, Borg, A, Neuhausen, S, Ding, Y, Nathanson, K, Domchek, S, Jakubowska, A, Lubiński, J, Huzarski, T, Byrski, T, Gronwald, J, Górski, B, Cybulski, C, Dębniak, T, Osorio, A, Durán, M, Tejada, M, Benítez, J, Hamann, U, Rookus, M, Verhoef, S, Tilanus Linthorst, M, Vreeswijk, M, Bodmer, D, Ausems, M, van Os, T, Asperen, C, Blok, M, Meijers Heijboer, H, Peock, S, Cook, M, Oliver, C, Frost, D, Dunning, A, Evans, D, Eeles, R, Pichert, G, Cole, T, Hodgson, S, Brewer, C, Morrison, P, Porteous, M, Kennedy, M, Rogers, M, Side, L, Donaldson, A, Gregory, H, Godwin, A, Stoppa Lyonnet, D, Moncoutier, V, Castera, L, Mazoyer, S, Barjhoux, L, Bonadona, V, Leroux, D, Faivre, L, Lidereau, R, Nogues, C, Bignon, Y, Prieur, F, Collonge Rame, M, Venat Bouvet, L, Fert Ferrer, S, Miron, A, Buys, S, Hopper, J, Daly, M, John, E, Terry, M, Goldgar, D, Hansen, T, Jønson, L, Ejlertsen, B, Agnarsson, B, Offit, K, Kirchhoff, T, Vijai, J, Dutra Clarke, A, Przybylo, J, Montagna, M, Casella, C, Imyanitov, E, Janavicius, R, Blanco, I, Lázaro, C, Moysich, K, Karlan, B, Gross, J, Beattie, M, Schmutzler, R, Wappenschmidt, B, Meindl, A, Ruehl, I, Fiebig, B, Sutter, C, Arnold, N, Deissler, H, Varon Mateeva, R, Kast, K, Niederacher, D, Gadzicki, D, Caldes, T, de la Hoya, M, Nevanlinna, H, Aittomäki, K, Simard, J, Soucy, P, Spurdle, A, Holland, H, Chenevix Trench, G, Easton, D, Antoniou, A, Faculteit Medische Wetenschappen/UMCG, Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Klinische Genetica, Genetica & Celbiologie, RS: GROW - School for Oncology and Reproduction, Clinical Genetics, Pediatric Surgery, Human genetics, CCA - Oncogenesis, and Human Genetics
Subjects: Oncology, Cancer Research, endocrine system diseases, Genes, BRCA2, Genes, BRCA1, Genome-wide association study, FAMILIES, 0302 clinical medicine, Risk Factors, Retrospective Studie, Genotype, Odds Ratio, skin and connective tissue diseases, POPULATION, Genetics, Ovarian Neoplasms, Aged, 80 and over, Allele, 0303 health sciences, education.field_of_study, Likelihood Functions, Articles, GERMLINE MUTATIONS, Middle Aged, Likelihood Function, female genital diseases and pregnancy complications, 3. Good health, 030220 oncology & carcinogenesis, Female, Chromosomes, Human, Pair 9, Human, Adult, [SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT], medicine.medical_specialty, Heterozygote, SUSCEPTIBILITY LOCI, PROTEINS, Population, Biology, Polymorphism, Single Nucleotide, BASONUCLIN-2, 03 medical and health sciences, Breast cancer, Germline mutation, SDG 3 - Good Health and Well-being, Internal medicine, medicine, BREAST-CANCER, Humans, GENOME-WIDE ASSOCIATION, education, Alleles, Germ-Line Mutation, 030304 developmental biology, Retrospective Studies, Aged, IDENTIFICATION, Risk Factor, Ovarian Neoplasm, Editorials, Cancer, medicine.disease, Minor allele frequency, Ovarian cancer
Abstract: [Background]: Germline mutations in the BRCA1 and BRCA2 genes are associated with increased risks of breast and ovarian cancers. Although several common variants have been associated with breast cancer susceptibility in mutation carriers, none have been associated with ovarian cancer susceptibility. A genome-wide association study recently identified an association between the rare allele of the single-nucleotide polymorphism (SNP) rs3814113 (ie, the C allele) at 9p22.2 and decreased risk of ovarian cancer for women in the general population. We evaluated the association of this SNP with ovarian cancer risk among BRCA1 or BRCA2 mutation carriers by use of data from the Consortium of Investigators of Modifiers of BRCA1/2. [Methods]: We genotyped rs3814113 in 10 029 BRCA1 mutation carriers and 5837 BRCA2 mutation carriers. Associations with ovarian and breast cancer were assessed with a retrospective likelihood approach. All statistical tests were two-sided. [Results]: The minor allele of rs3814113 was associated with a reduced risk of ovarian cancer among BRCA1 mutation carriers (per-allele hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.72 to 0.85; P = 4.8 × 10-9) and BRCA2 mutation carriers (hazard ratio of ovarian cancer = 0.78, 95% confidence interval = 0.67 to 0.90; P = 5.5 × 10-4). This SNP was not associated with breast cancer risk among either BRCA1 or BRCA2 mutation carriers. BRCA1 mutation carriers with the TT genotype at SNP rs3814113 were predicted to have an ovarian cancer risk to age 80 years of 48%, and those with the CC genotype were predicted to have a risk of 33%. [Conclusion]: Common genetic variation at the 9p22.2 locus was associated with decreased risk of ovarian cancer for carriers of a BRCA1 or BRCA2 mutation., Spanish National Cancer Center (CNIO) and the Spanish Consortium: Partially supported by Fundación Mutua Madrileña, Asociación Española Contra el Cáncer, and the Spanish Ministry of Science and Innovation (FIS PI08 1120).
Published: 2011
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19. Low expression of Ku70/80, but high expression of DNA-PKcs, predict good response to radiotherapy in early breast cancer

Author: Marie Stenmark Askmalm, Tommy Fornander, Siv Queseth, and Karin Söderlund Leifler
Subjects: Cancer Research, Cyclophosphamide, DNA repair, medicine.medical_treatment, Down-Regulation, Breast Neoplasms, DNA-Activated Protein Kinase, Biology, Disease-Free Survival, Breast cancer, medicine, Humans, Breast, Ku Autoantigen, Randomized Controlled Trials as Topic, Chemotherapy, Oncogene, Carcinoma, Cancer, Nuclear Proteins, Antigens, Nuclear, medicine.disease, Prognosis, Immunohistochemistry, Up-Regulation, Radiation therapy, DNA-Binding Proteins, Treatment Outcome, Oncology, Tissue Array Analysis, Cancer research, Disease Progression, Female, Breast disease, Tumor Suppressor Protein p53, medicine.drug
Abstract: The purpose was to study the prognostic and predictive roles of DNA protein kinase catalytic subunit (DNA-PKcs), Ku70/80 and p53 for the effect of radiotherapy in breast cancer patients. Protein expressions of Ku70/80, DNA-PKcs and p53 were examined using immunohistochemistry in tumours from 224 breast cancer patients, who were randomised to receive post-operative radiotherapy or adjuvant chemotherapy (cyclophosphamide, methotrexate, 5-fluorouracil). One hundred and twenty-nine (60%) of the tumours had low expression of Ku70/80, 122 (57%) had low expression of DNA-PKcs and 65 (30%) had altered p53 expression. None of the proteins were indicative to the prognosis of local recurrence-free survival. Even though the expression of Ku70/80 and DNA-PKcs correlated well, they were not associated with treatment outcome in the same way. Low expression of Ku70/80 predicted good effect of radiotherapy (RR=0.31, 95% CI 0.13-0.76, p=0.01). In contrast, the greatest benefit of radiotherapy over chemotherapy was seen in patients with high DNA-PKcs expression (RR=0.25, 95% CI 0.07-0.84, p=0.02). Altered p53 expression predicted poor response to radiotherapy. We believe that the results reflect the different roles of DNA-PKcs and Ku70/80 in repair and cell death regulation after DNA damage. These differences could be of importance when developing drugs that target DNA repair.
Published: 2010

20. Improved survival for women with stage I breast cancer in south-east Sweden: a comparison between two time periods before and after increased use of adjuvant systemic therapy

Author: Patrik Johansson, Helena Fohlin, Lars-Gunnar Arnesson, Monika Dufmats, Kerstin Nordenskjöld, Bo Nordenskjöld, Olle Stål, null The South-East Sweden Breast Cancer, Måns Agrup, Bengt Asking, Tord Blomkvist, Harald Bång, Charlotta Dabrosin, Eibert Einarsson, Rune Gustavsson, Claes Klintenberg, Barbro Linderholm, Annika Malmström, Rebecka Malterling, Marie Sundquist, Bengt Norberg, Ann Rundcrantz, Peter Skoog, Hans Starkhammar, Marie Stenmark Askmalm, Göran Tejler, Sten Thorstenson, Susanne Vahlin, and Bedrich Vitak
Subjects: Adult, medicine.medical_specialty, Antineoplastic Agents, Hormonal, medicine.medical_treatment, Population, Breast Neoplasms, Kaplan-Meier Estimate, Mastectomy, Segmental, Systemic therapy, Risk Assessment, Disease-Free Survival, Breast cancer, Risk Factors, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Odds Ratio, Humans, Radiology, Nuclear Medicine and imaging, education, Neoplasm Staging, Proportional Hazards Models, Gynecology, Sweden, education.field_of_study, business.industry, MEDICINE, Cytotoxins, Mortality rate, Hematology, General Medicine, Odds ratio, Middle Aged, medicine.disease, MEDICIN, Treatment Outcome, Oncology, Receptors, Estrogen, Chemotherapy, Adjuvant, Cohort, Multivariate Analysis, Female, business, Receptors, Progesterone, Tamoxifen, Mastectomy, medicine.drug
Abstract: Purpose. Continuous minor steps of improvement in the management of breast cancer have resulted in decreased mortality rates during the last decades. The aim of this study was to compare the clinical outcome of patients with stage I breast cancer diagnosed during two time periods that differed with respect to adjuvant systemic therapy. Material and methods. The studied population consisted of all women 60 years of age, who were diagnosed breast cancer stage I between 1986 and 1999 in south-east Sweden, a total of 1 407 cases. The cohort was divided into two groups based on the management programmes of 1986 and 1992, hereafter referred to as Period 1 and Period 2. Before 1992 the only adjuvant systemic therapy recommended was tamoxifen for hormone receptor positive patients aged 50 years or older. During Period 2 the use of adjuvant treatment was extended to younger patients at high risk, identified by a high tumour S-phase fraction, with either hormonal or cytotoxic treatment. Results. The estimated distant recurrence-free survival rate was significantly higher during Period 2 than during Period 1 (p = 0.008). Subgroup analysis showed that the most evident reduction of distant recurrence risk was among hormone receptor-negative patients (HR = 0.58, 95% CI 0.31-1.09, p = 0.09) and among patients with a high tumour S-phase fraction (HR = 0.53, 0.30-0.93, p = 0.028). The risk reduction between the periods was still statistically significant in multivariate analysis when adjusting for different tumour characteristics and treatment modalities, indicating an influence of other factors not controlled for. One such factor may be the duration of tamoxifen treatment, which likely was more frequently five years during Period 2 than during Period 1. Conclusions. We conclude that the causes of the increase in distant recurrence free survival for women with breast cancer stage I are complex. The results support though that high-risk subgroups of stage I breast cancer patients did benefit from increased use of systemic therapy as a consequence of an updated management programme. This is an electronic version of an article published in: Patrik Johansson, Helena Fohlin, Lars-Gunnar Arnesson, Monika Dufmats, Kerstin Nordenskjoeld, Bo Nordenskjöld and Olle Stål, Improved survival for women with stage I breast cancer in south-east Sweden: A comparison between two time periods before and after increased use of adjuvant systemic therapy, 2009, ACTA ONCOLOGICA, (48), 4, 504-513. ACTA ONCOLOGICA is available online at informaworldTM: http://dx.doi.org/10.1080/02841860902718754 Copyright: Taylor & Francis http://www.tandf.co.uk/journals/default.aspGroup Author(s):The South-East Sweden Breast Cancer Study GroupAnnika Malmström, Linköping University
Published: 2009

21. A new polymorphism in the coding region of exon four in HSD17B2 in relation to risk of sporadic and hereditary breast cancer

Author: Agneta Jansson, Sara Margolin, Petter Storm, Marie Stenmark-Askmalm, Anette Olsson, Jonas Carlsson, Cecilia Gunnarsson, Annika Lindblom, Bengt Persson, and Olle Stål
Subjects: Models, Molecular, Cancer Research, medicine.medical_specialty, Protein Conformation, DNA Mutational Analysis, Breast Neoplasms, Biology, Risk Assessment, Gene Expression Regulation, Enzymologic, Estradiol Dehydrogenases, Exon, Breast cancer, Risk Factors, Internal medicine, Catalytic Domain, Cell Line, Tumor, Genotype, medicine, Humans, Genetic Predisposition to Disease, skin and connective tissue diseases, Gene, Polymorphism, Single-Stranded Conformational, Aged, Regulation of gene expression, Case-control study, Cancer, Single-strand conformation polymorphism, Exons, Middle Aged, medicine.disease, Pedigree, Gene Expression Regulation, Neoplastic, Endocrinology, Oncology, Case-Control Studies, Cancer research, Female
Abstract: In situ synthesis of oestrogens is of great importance in the development and progression of breast cancer. 17beta-hydroxysteroid dehydrogenase (17HSD) type 2 catalyses oxidation from oestradiol to oestrone, and thereby protects the breast epithelial cells from oestradiol. Low expression of 17HSD type 2 has been associated with decreased survival in breast cancer, but no studies have investigated the mechanism behind the low expression. The 17HSD type 2 gene (HSD17B2) was screened for mutations with Single Stranded Conformation Polymorphism (SSCP)-DNA sequencing in 59 sporadic breast cancer cases, 19 hereditary breast cancer cases and seven breast cancer cell lines. DNA samples from 226 healthy individuals were used to identify if changes were previously unknown polymorphisms. No mutation was detected and therefore mutations in HSD17B2 do not explain why some breast tumours exhibit low 17HSD type 2 expression. However, a previously unknown polymorphism was found in exon four (Met226Val). Using molecular modelling, we found that the substituted residue is located at the outer part of the steroid binding site, probably causing minor alterations in the substrate binding. We further studied if the polymorphism contributes to breast cancer susceptibility in a larger material, but did not find an increased risk in the group of 317 sporadic breast cancer patients, 188 breast cancer patients with two close relatives with breast cancer or 122 hereditary breast cancer patients, compared to the healthy control group. We suggest that the detected polymorphism does not contribute to a higher risk of developing breast cancer.
Published: 2006

22. p53 polymorphic variants at codon 72 and the outcome of therapy in randomized breast cancer patients

Author: Sten Wingren, Pia Wegman, Marie Stenmark Askmalm, Bo Nordenskjöld, L E Rutqvist, and Olle Stål
Subjects: medicine.medical_specialty, Tumor suppressor gene, Antineoplastic Agents, Hormonal, Breast Neoplasms, Biology, Breast cancer, Internal medicine, Genetics, medicine, Humans, General Pharmacology, Toxicology and Pharmaceutics, Aromatase, skin and connective tissue diseases, Receptor, Codon, Molecular Biology, Genetics (clinical), Alleles, Predictive marker, Polymorphism, Genetic, Genetic Variation, medicine.disease, Genes, p53, Menopause, Tamoxifen, Endocrinology, Treatment Outcome, Chemotherapy, Adjuvant, biology.protein, Molecular Medicine, Female, Radiotherapy, Adjuvant, medicine.drug, Hormone
Abstract: Oestrogen is one of the most important hormonal regulators and is known to play a key role in the development and growth of breast cancer. The majority of tumours have a hormone dependent growth, and this is indicated by the presence of oestrogen receptors (ERs). About two thirds of breast cancers occur after the menopause when the ovaries have ceased to produce oestrogen and despite the low levels of circulating oestrogen’s the tumour concentrations of oestrone, oestradiol and their sulfates have been shown to be significant. Patients with hormone dependent tumours are candidates for treatment with the anti-oestrogen tamoxifen, which acts by competing with oestrogen for binding to the ER thereby, diminish the transcription of oestrogen regulated genes. The drug is mainly metabolised by cytochrome P450 enzymes in the liver and to a lesser extent locally in the breast, where upon several produced metabolites have higher affinity for the ER than the mother substance. Patients treated with tamoxifen have in general a prolonged disease-free survival. Even if most patients respond well to tamoxifen about 30-50 % either fail to respond or become resistant by incompletely understood mechanisms. Therefore, the aim of this thesis was to investigate possible mechanisms responsible for tamoxifen resistance. In paper I and II we studied genetic variants of enzymes participating in the metabolism of tamoxifen and assessed whether these variants correlated to breast cancer prognosis and/or to the benefit of tamoxifen. The results indicate an influence of CYP2D6, CYP3A5, and SULT1A1 genotypes in tamoxifen response. Further, tamoxifen has shown to compete with oestrogen for the binding to ER. In paper III we measured the expression levels of enzymes involved in the local synthesis of oestrogens in order to see if they correlated to clinical outcome. The protein expression of stromal aromatase was shown to have a prognostic significance, especially in ER-positive patients. Finally, tamoxifen and its ER-active metabolites have shown to induce both cell cycle arrest and apoptosis and one central mediator in these processes is the tumour suppressor protein p53. The proapoptotic activity of p53 is dependent on a proline rich domain containing a common Pro-to-Arg polymorphism. In paper IV we examined the value of this genetic variant as a predictive marker for anti-cancer therapy and found that patients carrying the Pro-allele might be good responders of tamoxifen therapy. The present thesis further indicates the complexity of the mechanisms underlying tamoxifen resistance. In summary, genetic variants of metabolic enzymes, genetic variants in p53, as well as expression levels of enzymes involved in local oestrogen synthesis, may have influence on breast cancer prognosis and may be useful markers in the prediction of tamoxifen response.
Published: 2006

23. TERT promoter mutations and polymorphisms as prognostic factors in primary glioblastoma

Author: Peter Milos, Malgorzata Lysiak, Charlotte Bratthäll, Annika Malmström, Peter Söderkvist, Martin Hallbeck, Anna-Lotta Hallbeck, Marie Stenmark-Askmalm, Mohamed Ali Mosrati, Michael Strandeus, and Adam Krysztofiak
Subjects: Male, medicine.medical_specialty, Interleukin-1beta, Telomere-Binding Proteins, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, IDH1 mutation, Shelterin Complex, TERT polymorphism, Biomarkers, Tumor, medicine, Humans, SNP, Telomerase reverse transcriptase, RNA, Messenger, Allele, TERT promoter mutations, glioblastoma, IL-6, Promoter Regions, Genetic, Telomerase, Medicinsk genetik, Binding Sites, Clinical pathology, Interleukin-6, Tumor Necrosis Factor-alpha, Promoter, Middle Aged, Prognosis, Isocitrate Dehydrogenase, humanities, 3. Good health, Isocitrate dehydrogenase, Oncology, Cancer research, Medical genetics, Female, Clinical Research Paper, Medical Genetics
Abstract: // Mohamed Ali Mosrati 1 , Annika Malmstrom 2 , Malgorzata Lysiak 1 , Adam Krysztofiak 1 , Martin Hallbeck 3 , Peter Milos 4 , Anna-Lotta Hallbeck 5 , Charlotte Bratthall 6 , Michael Strandeus 7 , Marie Stenmark-Askmalm 8 , Peter Soderkvist 1 1 Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden 2 Department of Advanced Home Care and Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden 3 Department of Clinical Pathology and Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden 4 Department of Neurosurgery and Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden 5 Department of Oncology and Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden 6 Department of Oncology, District Hospital, Kalmar, Sweden 7 Department of Oncology, Ryhov Hospital, Jonkoping, Sweden 8 Department of Clinical Pathology and Clinical Genetics and Department of Clinical and Experimental Medicine, Linkoping University, Linkoping, Sweden Correspondence to: Mohamed Ali Mosrati, e-mail: mohamed.ali.mosrati@liu.se Keywords: TERT polymorphism, TERT promoter mutations, IDH1 mutation, glioblastoma, IL-6 Received: March 26, 2015 Accepted: June 12, 2015 Published: June 22, 2015 ABSTRACT Telomerase reverse transcriptase (TERT) activity is up-regulated in several types of tumors including glioblastoma (GBM). In the present study, 128 primary glioblastoma patients were examined for single nucleotide polymorphisms of TERT in blood and in 92 cases for TERT promoter mutations in tumors. TERT promoter mutations were observed in 86% of the tumors and of these, C228T (−124 bp upstream start codon) was detected in 75% and C250T (−146 bp) in 25% of cases. TERT promoter mutations were associated with shorter overall survival (11 vs. 20 months p = 0.002 and 12 vs. 20, p = 0.04 for C228T and C250T, respectively). The minor alleles of rs2736100 and rs10069690 SNP’s, located in intron 2 and the promotor regions, respectively, were associated with an increased risk of developing GBM ( p = 0.004 and 0.001). GBM patients having both TERT promoter mutations and being homozygous carriers of the rs2853669 C-allele displayed significantly shorter overall survival than those with the wild type allele. The rs2853669 SNP is located in a putative Ets2 binding site in the promoter (−246 bp upstream start codon) close to the C228T and C250T mutation hot spots. Interleukin-6 (IL-6) expression regulated by TERT promoter status and polymorphism, what leads us to think that TERT and IL-6 plays a significant role in GBM, where specific SNPs increase the risk of developing GBM while the rs2853669 SNP and specific mutations in the TERT promoter of the tumor lead to shorter survival.

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23 results on '"Marie Stenmark Askmalm"'

1. Prevalence of germline pathogenic variants in 22 cancer susceptibility genes in Swedish pediatric cancer patients

2. Increased Cancer Risk in Families with Pediatric Cancer Is Associated with Gender, Age, Diagnosis, and Degree of Relation to the Child

3. ABCB1 single-nucleotide variants and survival in patients with glioblastoma treated with radiotherapy concomitant with temozolomide

4. Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population

5. Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

6. The gynecological surveillance of women with Lynch syndrome in Sweden

7. Association of Type and Location of BRCA1 and BRCA2 Mutations With Risk of Breast and Ovarian Cancer

8. Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment

9. What Information Do Cancer Genetic Counselees Prioritize?

10. Bilateral Prophylactic Mastectomy in Swedish Women at High Risk of Breast Cancer

11. Intact Mre11/Rad50/Nbs1 Complex Predicts Good Response to Radiotherapy in Early Breast Cancer

12. Mutation and accumulation of p53 related to results of adjuvant therapy of postmenopausal breast cancer patients

13. Genetic anticipation in Swedish Lynch syndrome families

14. P53 Expression and the Result of Adjuvant Therapy of Breast Cancer

15. Evidence of Gene-Environment Interactions between Common Breast Cancer Susceptibility Loci and Established Environmental Risk Factors

16. Ovarian cancer susceptibility alleles and risk of ovarian cancer in BRCA1 and BRCA2 mutation carriers

17. Cellular accumulation of p53 protein: an independent prognostic factor in stage II breast cancer

18. Genetic variation at 9p22.2 and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers

19. Low expression of Ku70/80, but high expression of DNA-PKcs, predict good response to radiotherapy in early breast cancer

20. Improved survival for women with stage I breast cancer in south-east Sweden: a comparison between two time periods before and after increased use of adjuvant systemic therapy

21. A new polymorphism in the coding region of exon four in HSD17B2 in relation to risk of sporadic and hereditary breast cancer

22. p53 polymorphic variants at codon 72 and the outcome of therapy in randomized breast cancer patients

23. TERT promoter mutations and polymorphisms as prognostic factors in primary glioblastoma

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23 results on '"Marie Stenmark Askmalm"'

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