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The contribution of CHEK2 to the TP53-negative Li-Fraumeni phenotype
Marielle WG Ruijs, Annegien Broeks, Fred H Menko, Margreet GEM Ausems, Anja Wagner, Rogier Oldenburg, Hanne Meijers-Heijboer, Laura J van't Veer, Senno Verhoef
Hereditary Cancer in Clinical Practice , 2009, DOI: 10.1186/1897-4287-7-4
Abstract: We have screened 65 Dutch TP53-negative LFS/LFL candidate patients for CHEK2 germline mutations to determine their contribution to the LFS/LFL phenotype.We identified six index patients with a CHEK2 sequence variant, four with the c.1100delC variant and two sequence variants of unknown significance, p.Phe328Ser and c.1096-?_1629+?del.Our data show that CHEK2 is not a major LFS susceptibility gene in the Dutch population. However, CHEK2 might be a factor contributing to individual tumour development in TP53-negative cancer-prone families.Li-Fraumeni syndrome (LFS) is a rare autosomal dominant cancer syndrome predisposing for bone and soft tissue sarcoma, breast cancer, brain tumour, adrenocortical carcinoma and leukaemia [1]. The classical LFS criteria are: a proband with sarcoma aged under 45 years and a first-degree relative with any cancer aged under 45 years, plus a first or second-degree relative in the same lineage with any cancer under the age of 45 years or sarcoma at any age [2]. In addition, Li-Fraumeni-like syndrome (LFL) criteria have been formulated as a proband with any childhood tumour or a sarcoma, brain tumour or adrenocortical tumour diagnosed under 45 years of age and a first or second-degree relative in the same lineage with a typical LFS tumour at any age, plus a first or second-degree relative in the same lineage younger than 60 years with any cancer [3]. Less stringent LFL criteria were formulated by Eeles et al. as two first or second-degree relatives with typical LFS-extended tumours (classical LFS tumours plus melanoma, prostate cancer and pancreatic cancer) at any age [4]. The Chompret criteria for TP53 germline mutation testing have been updated in 2008 as: (1) a proband with a tumour belonging to the LFS tumour spectrum (sarcomas, brain tumours, pre-menopausal breast cancer, adrenocortical carcinoma, leukaemia, lung bronchoalveolar cancer) cancer before 46 years of age and at least one first or second-degree relative with an LFS tumour be
Combined effects of single nucleotide polymorphisms TP53 R72P and MDM2 SNP309, and p53 expression on survival of breast cancer patients
Marjanka K Schmidt, Johanna Tommiska, Annegien Broeks, Flora E van Leeuwen, Laura J Van't Veer, Paul DP Pharoah, Douglas F Easton, Mitul Shah, Manjeet Humphreys, Thilo D?rk, Scarlett A Reincke, Rainer Fagerholm, Carl Blomqvist, Heli Nevanlinna
Breast Cancer Research , 2009, DOI: 10.1186/bcr2460
Abstract: We pooled data from four breast cancer cohorts within the Breast Cancer Association Consortium for which both TP53 R72P and MDM2 SNP309 were genotyped and follow-up was available (n = 3,749). Overall and breast cancer-specific survival analyses were performed using Kaplan-Meier analysis and multivariate Cox's proportional hazards regression models.Survival of patients did not differ by carriership of either germ-line variant, R72P (215G>C) or SNP309 (-410G>T) alone. Immunohistochemical p53 staining of the tumor was available for two cohorts (n = 1,109 patients). Survival was worse in patients with p53-positive tumors (n = 301) compared to patients with p53-negative tumors (n = 808); breast cancer-specific survival: HR 1.6 (95% CI 1.2 to 2.1), P = 0.001. Within the patient group with p53-negative tumors, TP53 rare homozygous (CC) carriers had a worse survival than G-allele (GG/GC) carriers; actuarial breast cancer-specific survival 71% versus 80%, P = 0.07; HR 1.8 (1.1 to 3.1), P = 0.03. We also found a differential effect of combinations of the two germ-line variants on overall survival; homozygous carriers of the G-allele in MDM2 had worse survival only within the group of TP53 C-allele carriers; actuarial overall survival (GG versus TT/TG) 64% versus 75%, P = 0.001; HR (GG versus TT) 1.5 (1.1 to 2.0), P = 0.01. We found no evidence for a differential effect of MDM2 SNP309 by p53 protein expression on survival.The TP53 R72P variant may be an independent predictor for survival of patients with p53-negative tumors. The combined effect of TP53 R72P and MDM2 SNP309 on survival is in line with our a priori biologically-supported hypothesis, that is, the role of enhanced DNA repair function of the TP53 Pro-variant, combined with increased expression of the Mdm2 protein, and thus overall attenuation of the p53 pathway in the tumor cells.Breast cancer outcome may be affected by germ-line variants in genes that play a role in DNA damage control and repair such as TP53 (R72P
Identification of women with an increased risk of developing radiation-induced breast cancer: a case only study
Annegien Broeks, Linde M Braaf, Angelina Huseinovic, Anke Nooijen, Jos Urbanus, Frans BL Hogervorst, Marjanka K Schmidt, Jan GM Klijn, Nicola S Russell, Flora E Van Leeuwen, Laura J Van 't Veer
Breast Cancer Research , 2007, DOI: 10.1186/bcr1668
Abstract: We evaluated the contribution of germline mutations in the DDRP genes BRCA1, BRCA2, CHEK2 and ATM to the risk of radiation-induced contralateral breast cancer (CBC). The germline mutation frequency was assessed, in a case-only study, in women who developed a CBC after they had a first breast cancer diagnosed before the age of 50 years, and who were (n = 169) or were not (n = 78) treated with radiotherapy for their first breast tumour.We identified 27 BRCA1, 5 BRCA2, 15 CHEK2 and 4 truncating ATM germline mutation carriers among all CBC patients tested (21%). The mutation frequency was 24.3% among CBC patients with a history of radiotherapy, and 12.8% among patients not irradiated for the first breast tumour (odds ratio 2.18 (95% confidence interval 1.03 to 4.62); p = 0.043). The association between DDRP germline mutation carriers and risk of radiation-induced CBC seemed to be strongest in women who developed their second primary breast tumour at least 5 years after radiotherapy. Those patients had an odds ratio of 2.51 (95% confidence interval 1.03 to 6.10; p = 0.049) of developing radiation-induced breast cancer, in comparison with non-carriers.This study shows that carriers of germline mutations in a DDRP gene have an increased risk of developing (contralateral) breast cancer after radiotherapy; that is, over and above the risk associated with their carrier status. The increased risk indicates that knowledge of germline status of these DDRP genes at the time of breast cancer diagnosis may have important implications for the choice of treatment.Several risk factors for the development of breast cancer, such as family history, reproductive factors and exposure to radiation, have been identified. Out of all breast cancers, 5 to 10% can be attributed to germline mutations in familial high-risk genes such as BRCA1 or BRCA2 that result in a lifetime breast cancer risk of about 45 to 65% [1]. The penetrance varies between families, depending on 'risk modifiers' such as h
Subtyping of Breast Cancer by Immunohistochemistry to Investigate a Relationship between Subtype and Short and Long Term Survival: A Collaborative Analysis of Data for 10,159 Cases from 12 Studies
Fiona M. Blows equal contributor,Kristy E. Driver equal contributor,Marjanka K. Schmidt,Annegien Broeks,Flora E. van Leeuwen,Jelle Wesseling,Maggie C. Cheang,Karen Gelmon,Torsten O. Nielsen,Carl Blomqvist,P?ivi Heikkil?,Tuomas Heikkinen,Heli Nevanlinna,Lars A. Akslen,Louis R. Bégin,William D. Foulkes,Fergus J. Couch,Xianshu Wang,Vicky Cafourek,Janet E. Olson,Laura Baglietto,Graham G. Giles,Gianluca Severi,Catriona A. McLean,Melissa C. Southey,Emad Rakha,Andrew R. Green,Ian O. Ellis,Mark E. Sherman,Jolanta Lissowska,William F. Anderson,Angela Cox,Simon S. Cross,Malcolm W. R. Reed,Elena Provenzano,Sarah-Jane Dawson,Alison M. Dunning,Manjeet Humphreys,Douglas F. Easton,Montserrat García-Closas,Carlos Caldas,Paul D. Pharoah ,David Huntsman
PLOS Medicine , 2010, DOI: 10.1371/journal.pmed.1000279
Abstract: Background Immunohistochemical markers are often used to classify breast cancer into subtypes that are biologically distinct and behave differently. The aim of this study was to estimate mortality for patients with the major subtypes of breast cancer as classified using five immunohistochemical markers, to investigate patterns of mortality over time, and to test for heterogeneity by subtype. Methods and Findings We pooled data from more than 10,000 cases of invasive breast cancer from 12 studies that had collected information on hormone receptor status, human epidermal growth factor receptor-2 (HER2) status, and at least one basal marker (cytokeratin [CK]5/6 or epidermal growth factor receptor [EGFR]) together with survival time data. Tumours were classified as luminal and nonluminal tumours according to hormone receptor expression. These two groups were further subdivided according to expression of HER2, and finally, the luminal and nonluminal HER2-negative tumours were categorised according to expression of basal markers. Changes in mortality rates over time differed by subtype. In women with luminal HER2-negative subtypes, mortality rates were constant over time, whereas mortality rates associated with the luminal HER2-positive and nonluminal subtypes tended to peak within 5 y of diagnosis and then decline over time. In the first 5 y after diagnosis the nonluminal tumours were associated with a poorer prognosis, but over longer follow-up times the prognosis was poorer in the luminal subtypes, with the worst prognosis at 15 y being in the luminal HER2-positive tumours. Basal marker expression distinguished the HER2-negative luminal and nonluminal tumours into different subtypes. These patterns were independent of any systemic adjuvant therapy. Conclusions The six subtypes of breast cancer defined by expression of five markers show distinct behaviours with important differences in short term and long term prognosis. Application of these markers in the clinical setting could have the potential to improve the targeting of adjuvant chemotherapy to those most likely to benefit. The different patterns of mortality over time also suggest important biological differences between the subtypes that may result in differences in response to specific therapies, and that stratification of breast cancers by clinically relevant subtypes in clinical trials is urgently required. Please see later in the article for the Editors' Summary
Breast Cancer Risk and 6q22.33: Combined Results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/2
Tomas Kirchhoff, Mia M. Gaudet, Antonis C. Antoniou, Lesley McGuffog, Manjeet K. Humphreys, Alison M. Dunning, Stig E. Bojesen, B?rge G. Nordestgaard, Henrik Flyger, Daehee Kang, Keun-Young Yoo, Dong-Young Noh, Sei-Hyun Ahn, Thilo Dork, Peter Schürmann, Johann H. Karstens, Peter Hillemanns, Fergus J. Couch, Janet Olson, Celine Vachon, Xianshu Wang, Angela Cox, Ian Brock, Graeme Elliott, Malcolm W.R. Reed, Barbara Burwinkel, Alfons Meindl, Hiltrud Brauch, Ute Hamann, Yon-Dschun Ko, GENICA Network , Annegien Broeks, Marjanka K. Schmidt, Laura J. Van ‘t Veer, Linde M. Braaf, Nichola Johnson, Olivia Fletcher, Lorna Gibson, Julian Peto, Clare Turnbull, Sheila Seal, Anthony Renwick, Nazneen Rahman, Pei-Ei Wu, Jyh-Cherng Yu, Chia-Ni Hsiung, Chen-Yang Shen, Melissa C. Southey, John L. Hopper, Fleur Hammet, Thijs Van Dorpe, Anne-Sophie Dieudonne, Sigrid Hatse, Diether Lambrechts, Irene L. Andrulis, Natalia Bogdanova, Natalia Antonenkova, Juri I. Rogov, Daria Prokofieva, Marina Bermisheva, Elza Khusnutdinova, Christi J. van Asperen, Robert A.E.M. Tollenaar, Maartje J. Hooning, Peter Devilee, Sara Margolin, Annika Lindblom, Roger L. Milne, José Ignacio Arias, M. Pilar Zamora, Javier Benítez, Gianluca Severi, Laura Baglietto, Graham G. Giles, kConFab, AOCS Study Group, Amanda B. Spurdle, Jonathan Beesley, Xiaoqing Chen, Helene Holland, Sue Healey, Shan Wang-Gohrke, Jenny Chang-Claude, Arto Mannermaa, Veli-Matti Kosma, Jaana Kauppinen, Vesa Kataja, Bjarni A. Agnarsson, Maria A. Caligo
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0035706
Abstract: Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00–1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I2 = 49.3%; p = <0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95%CI 0.80–1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.
Comparison of 6q25 Breast Cancer Hits from Asian and European Genome Wide Association Studies in the Breast Cancer Association Consortium (BCAC)
Rebecca Hein, Melanie Maranian, John L. Hopper, Miroslaw K. Kapuscinski, Melissa C. Southey, Daniel J. Park, Marjanka K. Schmidt, Annegien Broeks, Frans B. L. Hogervorst, H. Bas Bueno-de-Mesquit, Kenneth R. Muir, Artitaya Lophatananon, Suthee Rattanamongkongul, Puttisak Puttawibul, Peter A. Fasching, Alexander Hein, Arif B. Ekici, Matthias W. Beckmann, Olivia Fletcher, Nichola Johnson, Isabel dos Santos Silva, Julian Peto, Elinor Sawyer, Ian Tomlinson, Michael Kerin, Nicola Miller, Frederick Marmee, Andreas Schneeweiss, Christof Sohn, Barbara Burwinkel, Pascal Guénel, Emilie Cordina-Duverger, Florence Menegaux, Thérèse Truong, Stig E. Bojesen, B?rge G. Nordestgaard, Henrik Flyger, Roger L. Milne, Jose Ignacio Arias Perez, M. Pilar Zamora, Javier Benítez, Hoda Anton-Culver, Argyrios Ziogas, Leslie Bernstein, Christina A. Clarke, Hermann Brenner, Heiko Müller, Volker Arndt, Christa Stegmaier, Nazneen Rahman, Sheila Seal, Clare Turnbull, Anthony Renwick, Alfons Meindl, Sarah Schott, Claus R. Bartram, Rita K. Schmutzler, Hiltrud Brauch, Ute Hamann, Yon-Dschun Ko, The GENICA Network , Shan Wang-Gohrke, Thilo D?rk, Peter Schürmann, Johann H. Karstens, Peter Hillemanns, Heli Nevanlinna, Tuomas Heikkinen, Kristiina Aittom?ki, Carl Blomqvist, Natalia V. Bogdanova, Iosif V. Zalutsky, Natalia N. Antonenkova, Marina Bermisheva, Darya Prokovieva, Albina Farahtdinova, Elza Khusnutdinova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana Hartikainen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042380
Abstract: The 6q25.1 locus was first identified via a genome-wide association study (GWAS) in Chinese women and marked by single nucleotide polymorphism (SNP) rs2046210, approximately 180 Kb upstream of ESR1. There have been conflicting reports about the association of this locus with breast cancer in Europeans, and a GWAS in Europeans identified a different SNP, tagged here by rs12662670. We examined the associations of both SNPs in up to 61,689 cases and 58,822 controls from forty-four studies collaborating in the Breast Cancer Association Consortium, of which four studies were of Asian and 39 of European descent. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Case-only analyses were used to compare SNP effects in Estrogen Receptor positive (ER+) versus negative (ER?) tumours. Models including both SNPs were fitted to investigate whether the SNP effects were independent. Both SNPs are significantly associated with breast cancer risk in both ethnic groups. Per-allele ORs are higher in Asian than in European studies [rs2046210: OR (A/G) = 1.36 (95% CI 1.26–1.48), p = 7.6×10?14 in Asians and 1.09 (95% CI 1.07–1.11), p = 6.8×10?18 in Europeans. rs12662670: OR (G/T) = 1.29 (95% CI 1.19–1.41), p = 1.2×10?9 in Asians and 1.12 (95% CI 1.08–1.17), p = 3.8×10?9 in Europeans]. SNP rs2046210 is associated with a significantly greater risk of ER? than ER+ tumours in Europeans [OR (ER?) = 1.20 (95% CI 1.15–1.25), p = 1.8×10?17 versus OR (ER+) = 1.07 (95% CI 1.04–1.1), p = 1.3×10?7, pheterogeneity = 5.1×10?6]. In these Asian studies, by contrast, there is no clear evidence of a differential association by tumour receptor status. Each SNP is associated with risk after adjustment for the other SNP. These results suggest the presence of two variants at 6q25.1 each independently associated with breast cancer risk in Asians and in Europeans. Of these two, the one tagged by rs2046210 is associated with a greater risk of ER? tumours.
RNF12 Activates Xist and Is Essential for X Chromosome Inactivation
Tahsin Stefan Barakat,Nilhan Gunhanlar,Cristina Gontan Pardo,Eskeatnaf Mulugeta Achame,Mehrnaz Ghazvini,Ruben Boers,Annegien Kenter,Eveline Rentmeester,J. Anton Grootegoed,Joost Gribnau
PLOS Genetics , 2011, DOI: 10.1371/journal.pgen.1002001
Abstract: In somatic cells of female placental mammals, one of the two X chromosomes is transcriptionally silenced to accomplish an equal dose of X-encoded gene products in males and females. Initiation of random X chromosome inactivation (XCI) is thought to be regulated by X-encoded activators and autosomally encoded suppressors controlling Xist. Spreading of Xist RNA leads to silencing of the X chromosome in cis. Here, we demonstrate that the dose dependent X-encoded XCI activator RNF12/RLIM acts in trans and activates Xist. We did not find evidence for RNF12-mediated regulation of XCI through Tsix or the Xist intron 1 region, which are both known to be involved in inhibition of Xist. In addition, we found that Xist intron 1, which contains a pluripotency factor binding site, is not required for suppression of Xist in undifferentiated ES cells. Analysis of female Rnf12?/? knockout ES cells showed that RNF12 is essential for initiation of XCI and is mainly involved in the regulation of Xist. We conclude that RNF12 is an indispensable factor in up-regulation of Xist transcription, thereby leading to initiation of random XCI.
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