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Leclerc J, Beaumont M, Vibert R, Pinson S, Vermaut C, Flament C, Lovecchio T, Delattre L, Demay C, Coulet F, Guillerm E, Hamzaoui N, Benusiglio PR, Brahimi A, Cornelis F, Delhomelle H, Fert-Ferrer S, Fournier BPJ, Hovnanian A, Legrand C, Lortholary A, Malka D, Petit F, Saurin JC, Lejeune S, Colas C, Buisine MP. AXIN2 germline testing in a French cohort validates pathogenic variants as a rare cause of predisposition to colorectal polyposis and cancer. Genes Chromosomes Cancer 2023; 62:210-222. [PMID: 36502525 PMCID: PMC10107344 DOI: 10.1002/gcc.23112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/23/2022] [Accepted: 11/29/2022] [Indexed: 12/14/2022] Open
Abstract
Only a few patients with germline AXIN2 variants and colorectal adenomatous polyposis or cancer have been described, raising questions about the actual contribution of this gene to colorectal cancer (CRC) susceptibility. To assess the clinical relevance for AXIN2 testing in patients suspected of genetic predisposition to CRC, we collected clinical and molecular data from the French Oncogenetics laboratories analyzing AXIN2 in this context. Between 2004 and June 2020, 10 different pathogenic/likely pathogenic AXIN2 variants were identified in 11 unrelated individuals. Eight variants were from a consecutive series of 3322 patients, which represents a frequency of 0.24%. However, loss-of-function AXIN2 variants were strongly associated with genetic predisposition to CRC as compared with controls (odds ratio: 11.89, 95% confidence interval: 5.103-28.93). Most of the variants were predicted to produce an AXIN2 protein devoid of the SMAD3-binding and DIX domains, but preserving the β-catenin-binding domain. Ninety-one percent of the AXIN2 variant carriers who underwent colonoscopy had adenomatous polyposis. Forty percent of the variant carriers developed colorectal or/and other digestive cancer. Multiple tooth agenesis was present in at least 60% of them. Our report provides further evidence for a role of AXIN2 in CRC susceptibility, arguing for AXIN2 testing in patients with colorectal adenomatous polyposis or cancer.
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Affiliation(s)
- Julie Leclerc
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277 CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France.,Molecular Oncogenetics, Department of Biochemistry and Molecular Biology, Lille University Hospital, Lille, France
| | - Marie Beaumont
- Laboratoire de Génétique Moléculaire et Génomique, CHU Rennes, Rennes, France
| | - Roseline Vibert
- UF d'Oncogénétique Clinique, Département de Génétique et Institut Universitaire de Cancérologie, Hôpitaux Pitié-Salpêtrière et Saint-Antoine, AP-HP. Sorbonne Université, Paris, France
| | - Stéphane Pinson
- Human Genetics Department, Hospices Civils de Lyon, Lyon, France
| | - Catherine Vermaut
- Molecular Oncogenetics, Department of Biochemistry and Molecular Biology, Lille University Hospital, Lille, France
| | - Cathy Flament
- Molecular Oncogenetics, Department of Biochemistry and Molecular Biology, Lille University Hospital, Lille, France
| | - Tonio Lovecchio
- Molecular Oncogenetics, Department of Biochemistry and Molecular Biology, Lille University Hospital, Lille, France
| | - Lucie Delattre
- Molecular Oncogenetics, Department of Biochemistry and Molecular Biology, Lille University Hospital, Lille, France
| | - Christophe Demay
- Bioinformatics Unit, Molecular Biology Facility, Lille University Hospital, Lille, France
| | - Florence Coulet
- Sorbonne University, INSERM, Saint-Antoine Research Center, Microsatellites instability and Cancer, CRSA, Genetics Department, AP-HP, Hôpital Pitié Salpêtrière, Sorbonne University, Paris, France
| | - Erell Guillerm
- Sorbonne University, INSERM, Saint-Antoine Research Center, Microsatellites instability and Cancer, CRSA, Genetics Department, AP-HP, Hôpital Pitié Salpêtrière, Sorbonne University, Paris, France
| | - Nadim Hamzaoui
- Service de Génétique et Biologie Moléculaires, Hôpital Cochin, AP-HP Centre, Université de Paris, and INSERM UMR_S1016, Institut Cochin, Université de Paris, Paris, France
| | - Patrick R Benusiglio
- UF d'Oncogénétique Clinique, Département de Génétique et Institut Universitaire de Cancérologie, Hôpitaux Pitié-Salpêtrière et Saint-Antoine, AP-HP. Sorbonne Université, Paris, France
| | | | - François Cornelis
- Department of Genetics-Oncogénétics-Prevention, Clermont-Ferrand Hospital, Clermont-Auvergne University, Clermont Ferrand, France
| | - Hélène Delhomelle
- Department of Genetics, Curie Institute, Paris Sciences & Lettres Research University, Paris, France
| | | | - Benjamin P J Fournier
- Centre de Recherche des Cordeliers, University of Paris, Sorbonne University, INSERM UMRS 1138 - Molecular Oral Pathophysiology, Paris, France.,Dental Faculty Garanciere, Oral Biology Department, Centre of Reference for Oral and Dental Rare Diseases, AP-HP, University of Paris, Paris, France
| | - Alain Hovnanian
- INSERM UMR 1163 - Laboratory of Genetic Skin Diseases, Imagine Institute, Paris, France.,University of Paris, Paris, France.,Department of Genetics, Necker Hospital for sick children, AP-HP, Paris, France
| | - Clémentine Legrand
- Service de Génétique, Génomique et Procréation, CHU Grenoble Alpes, Grenoble, France
| | - Alain Lortholary
- Centre Catherine de Sienne, hôpital privé du Confluent, Nantes, France
| | - David Malka
- Department of Cancer Medicine, Gustave Roussy, Paris-Saclay University, INSERM UMR 1279 - Unité Dynamique des Cellules Tumorales, Villejuif, France
| | - Florence Petit
- Clinique de Génétique, CHU Lille, Lille, France.,Univ. Lille, EA7364 - RADEME, CHU Lille, Lille, France
| | | | | | - Chrystelle Colas
- Department of Genetics, Curie Institute, Paris Sciences & Lettres Research University, Paris, France
| | - Marie-Pierre Buisine
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277 CANTHER - Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France.,Molecular Oncogenetics, Department of Biochemistry and Molecular Biology, Lille University Hospital, Lille, France
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Gupta N, Drogan C, Kupfer SS. How many is too many? Polyposis syndromes and what to do next. Curr Opin Gastroenterol 2022; 38:39-47. [PMID: 34839308 PMCID: PMC8648991 DOI: 10.1097/mog.0000000000000796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
PURPOSE OF REVIEW The goal of this review is to help providers recognize, diagnose and manage gastrointestinal (GI) polyposis syndromes. RECENT FINDINGS Intestinal polyps include a number of histological sub-types such as adenomas, serrated, hamartomas among others. Over a quarter of individuals undergoing screening colonoscopy are expected to have colonic adenomas. Although it is not uncommon for adults to have a few GI polyps in their lifetime, some individuals are found to have multiple polyps of varying histology throughout the GI tract. In these individuals, depending on polyp histology, number, location and size as well as extra-intestinal features and/or family history, a polyposis syndrome should be considered with appropriate testing and management. SUMMARY Diagnosis and management of polyposis syndromes has evolved with advent of multigene panel testing and new data on optimal surveillance strategies. Evidence-based recommendations and current practice guidelines for polyposis syndromes are reviewed here. Areas of uncertainty and future research are also highlighted.
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Affiliation(s)
- Nina Gupta
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois, USA
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3
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Dhooge M, Baert-Desurmont S, Corsini C, Caron O, Andrieu N, Berthet P, Bonadona V, Cohen-Haguenauer O, De Pauw A, Delnatte C, Dussart S, Lasset C, Leroux D, Maugard C, Moretta-Serra J, Popovici C, Buecher B, Colas C, Noguès C. National recommendations of the French Genetics and Cancer Group - Unicancer on the modalities of multi-genes panel analyses in hereditary predispositions to tumors of the digestive tract. Eur J Med Genet 2020; 63:104080. [PMID: 33039684 DOI: 10.1016/j.ejmg.2020.104080] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 09/29/2020] [Accepted: 09/29/2020] [Indexed: 12/13/2022]
Abstract
In case of suspected hereditary predisposition to digestive cancers, next-generation sequencing can analyze simultaneously several genes associated with an increased risk of developing these tumors. Thus, "Gastro Intestinal" (GI) gene panels are commonly used in French molecular genetic laboratories. Lack of international recommendations led to disparities in the composition of these panels and in the management of patients. To harmonize practices, the Genetics and Cancer Group (GGC)-Unicancer set up a working group who carried out a review of the literature for 31 genes of interest in this context and established a list of genes for which the estimated risks associated with pathogenic variant seemed sufficiently reliable and high for clinical use. Pancreatic cancer susceptibility genes have been excluded. This expertise defined a panel of 14 genes of confirmed clinical interest and relevant for genetic counseling: APC, BMPR1A, CDH1, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, POLD1, POLE, PTEN, SMAD4 and STK11. The reasons for the exclusion of the others 23 genes have been discussed. The paucity of estimates of the associated tumor risks led to the exclusion of genes, in particular CTNNA1, MSH3 and NTHL1, despite their implication in the molecular pathways involved in the pathophysiology of GI cancers. A regular update of the literature is planned to up-grade this panel of genes in case of new data on candidate genes. Genetic and epidemiological studies and international collaborations are needed to better estimate the risks associated with the pathogenic variants of these genes either selected or not in the current panel.
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Affiliation(s)
- Marion Dhooge
- APHP.Centre (Cochin Hospital), Paris University, Paris, France.
| | - Stéphanie Baert-Desurmont
- Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics, Normandy Center for Genomic and Personalized Medicine, Rouen, France
| | - Carole Corsini
- Arnaud de Villeneuve University Hospital, Montpellier, France
| | - Olivier Caron
- Gustave-Roussy University Hospital, Villejuif, France
| | - Nadine Andrieu
- Institut Curie, PSL Research University, Department of Tumor Biology, Paris, France; Unité Inserm, Institut Curie, Paris, France
| | | | | | | | - Antoine De Pauw
- Institut Curie, PSL Research University, Department of Tumor Biology, Paris, France
| | | | | | | | - Dominique Leroux
- Grenoble University Hospital, Couple-Enfant Hospital, Grenoble, France
| | | | - Jessica Moretta-Serra
- Institut Paoli-Calmettes, Department of Clinical Cancer Genetics, Aix Marseille Univ, INSERM, IRD, SESSTIM, Marseille, France
| | - Cornel Popovici
- Institut Paoli-Calmettes, Department of Clinical Cancer Genetics, Aix Marseille Univ, INSERM, IRD, SESSTIM, Marseille, France
| | - Bruno Buecher
- Institut Curie, PSL Research University, Department of Tumor Biology, Paris, France
| | - Chrystelle Colas
- Institut Curie, PSL Research University, Department of Tumor Biology, Paris, France
| | - Catherine Noguès
- Institut Paoli-Calmettes, Department of Clinical Cancer Genetics, Aix Marseille Univ, INSERM, IRD, SESSTIM, Marseille, France
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Lorca V, Garre P. Current status of the genetic susceptibility in attenuated adenomatous polyposis. World J Gastrointest Oncol 2019; 11:1101-1114. [PMID: 31908716 PMCID: PMC6937445 DOI: 10.4251/wjgo.v11.i12.1101] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 08/18/2019] [Accepted: 10/14/2019] [Indexed: 02/05/2023] Open
Abstract
Adenomatous polyposis (AP) is classified according to cumulative adenoma number in classical AP (CAP) and attenuated AP (AAP). Genetic susceptibility is the major risk factor in CAP due to mutations in the known high predisposition genes APC and MUTYH. However, the contribution of genetic susceptibility to AAP is lower and less understood. New predisposition genes have been recently proposed, and some of them have been validated, but their scarcity hinders accurate risk estimations and prevalence calculations. AAP is a heterogeneous condition in terms of severity, clinical features and heritability. Therefore, clinicians do not have strong discriminating criteria for the recommendation of the genetic study of known predisposition genes, and the detection rate is low. Elucidation and knowledge of new AAP high predisposition genes are of great importance to offer accurate genetic counseling to the patient and family members. This review aims to update the genetic knowledge of AAP, and to expound the difficulties involved in the genetic analysis of a highly heterogeneous condition such as AAP.
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Affiliation(s)
- Víctor Lorca
- Laboratorio de Oncología Molecular, Grupo de Investigación Clínica y Traslacional en Oncología, Hospital Clínico San Carlos, Madrid 28040, Spain
| | - Pilar Garre
- Laboratorio de Oncología Molecular, Servicio de Oncología, Hospital Clínico San Carlos, Madrid 28040, Spain
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Mazzoni SM, Fearon ER. AXIN1 and AXIN2 variants in gastrointestinal cancers. Cancer Lett 2014; 355:1-8. [PMID: 25236910 DOI: 10.1016/j.canlet.2014.09.018] [Citation(s) in RCA: 109] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Revised: 09/08/2014] [Accepted: 09/10/2014] [Indexed: 01/12/2023]
Abstract
Mutations in the APC (adenomatous polyposis coli) gene, which encodes a multi-functional protein with a well-defined role in the canonical Wnt pathway, underlie familial adenomatous polypsosis, a rare, inherited form of colorectal cancer (CRC) and contribute to the majority of sporadic CRCs. However, not all sporadic and familial CRCs can be explained by mutations in APC or other genes with well-established roles in CRC. The AXIN1 and AXIN2 proteins function in the canonical Wnt pathway, and AXIN1/2 alterations have been proposed as key defects in some cancers. Here, we review AXIN1 and AXIN2 sequence alterations reported in gastrointestinal cancers, with the goal of vetting the evidence that some of the variants may have key functional roles in cancer development.
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Affiliation(s)
- Serina M Mazzoni
- Department of Human Genetics, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA
| | - Eric R Fearon
- Department of Human Genetics, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA; Department of Internal Medicine, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA; Department of Pathology, University of Michigan Medical School, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
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Lindor NM, Win AK, Gallinger S, Daftary D, Thibodeau SN, Silva R, Letra A. Colorectal cancer and self-reported tooth agenesis. Hered Cancer Clin Pract 2014; 12:7. [PMID: 24607150 PMCID: PMC3975307 DOI: 10.1186/1897-4287-12-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Accepted: 02/24/2014] [Indexed: 01/18/2023] Open
Abstract
Background Germline mutations in APC and AXIN2 are both associated with colon neoplasia as well as anomalous dental development. We tested the hypothesis that congenitally missing teeth may occur more commonly in individuals diagnosed with colorectal cancer than in individuals without this diagnosis. Methods Via a survey conducted on 1636 individuals with colorectal cancer (CRC) and 2788 individuals with no colorectal cancer from the Colon Cancer Family Registry, self-reported information on congenitally missing teeth was collected. The frequency of missing teeth between cases and controls was compared using Pearson’s chi-squared test or Fisher’s exact test. Results 4.8% of cases and 5.7% of controls reported having at least one missing tooth (p = 0.20). When we stratified by recruitment site, gender, and mutation status where available, frequency of missing teeth was not statistically significantly different between cases and controls. Conclusions This study did not provide support for there being a general predisposition to missing teeth among a large cohort of CRC patients. The study neither addresses nor excludes the possibility, however, that individuals presenting with notable hypodontia/oligodontia might still have an increased risk for colorectal neoplasia.
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Affiliation(s)
- Noralane M Lindor
- Department of Health Sciences Research, Mayo Clinic, 13400 East Shea Blvd,, Scottsdale, AZ 85259, USA.
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A novel AXIN2 germline variant associated with attenuated FAP without signs of oligondontia or ectodermal dysplasia. Eur J Hum Genet 2013; 22:423-6. [PMID: 23838596 DOI: 10.1038/ejhg.2013.146] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Revised: 05/26/2013] [Accepted: 06/06/2013] [Indexed: 11/08/2022] Open
Abstract
Truncating mutations in the AXIN2 gene, a key regulator of β-catenin degradation in the Wnt pathway, have been reported in three families with gastrointestinal adenomatous polyposis and features of ectodermal dysplasia. However, the role of AXIN2 in familial adenomatous polyposis (FAP) syndrome is not completely understood. We performed an in-depth study of APC and MUTYH, and ruled out their implication in 23 FAP families. We then investigated the role of other genes involved in the Wnt pathway, including AXIN2, and identified a novel missense variant in AXIN2 in one family with attenuated FAP. Carriers of the variant exhibited a variable number of polyps but none showed any sign of ectodermal dysplasia. We have demonstrated the pathogenicity of this novel variant by establishing its low frequency in controls as well as by LOH analysis, a segregation study, and immunofluorescent staining of AXIN2 and β-catenin proteins. This report expands the phenotype known to be related to AXIN2 alterations and raises the question of whether to screen AXIN2 in FAP cases negative for alterations in APC and MUTYH.
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8
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Naghibalhossaini F, Zamani M, Mokarram P, Khalili I, Rasti M, Mostafavi-Pour Z. Epigenetic and genetic analysis of WNT signaling pathway in sporadic colorectal cancer patients from Iran. Mol Biol Rep 2012; 39:6171-6178. [PMID: 22207181 DOI: 10.1007/s11033-011-1434-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2011] [Accepted: 12/19/2011] [Indexed: 12/11/2022]
Abstract
The WNT signaling is deregulated in most human colorectal cancers (CRC). Promoter methylation has been proposed as an alternative mechanism to inactivate genes in tumors. To gain insight into the methylation silencing of the WNT pathway during colorectal carcinogenesis, we examined the aberrant methylation profile of four genes, APC, Axin1, Axin2, and GSK3β in an unselected series of 112 sporadic colorectal tumors by methylation specific PCR. It has been suggested that the Axin2 C148T SNP is associated with the risk of developing certain types of cancers. To assess the contribution of Axin2 SNP to CRC susceptibility, we examined the Axin2 C148T genotype in CRC patients and 170 healthy controls by PCR-RFLP. The frequency of CRCs with at least one gene methylated was 18.75%. Promoter methylation of Axin2 and APC genes was detected in 7.1 and 11.9% of tumors, respectively. No aberrant methylation was found in Gsk3β and Axin1 gene in these tumor series. The methylation status of APC had no significant association with clinical parameters. But, promoter methylation of Axin2 was sex-related, occurring more frequently in females (P = 0.002). The frequency of Axin2 C148T genotypes were similar in patients and controls. Moreover, we observed no association between the Axin2 SNP and risk of CRC in patients stratified by age, sex, and smoking status. However, the heterozygote CT genotype was associated with a reduced CRC risk in distal patients compared with proximal patients (OR = 0.3; 95% CI 0.1-0.9, P = 0.04). Our findings indicate that Axin1 and GSK3β methylation play a minor role in colorectal carcinogenesis.
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Affiliation(s)
- Fakhraddin Naghibalhossaini
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Zand Street, Shiraz, Iran.
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Mongin C, Coulet F, Lefevre JH, Colas C, Svrcek M, Eyries M, Lahely Y, Fléjou JF, Soubrier F, Parc Y. Unexplained polyposis: a challenge for geneticists, pathologists and gastroenterologists. Clin Genet 2011; 81:38-46. [PMID: 21476993 DOI: 10.1111/j.1399-0004.2011.01676.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Two main colorectal polyposis syndromes have been described, familial adenomatous polyposis and MUTYH-associated polyposis syndromes. Some polyposis remains unexplained: 20% of adenomatous polyposis and serrated polyposis. The aim of this study was to evaluate in a cohort of patients with unexplained polyposis whether a genetic defect could be detected. Individuals presenting polyposis with more than 40 adenomas or more than 20 serrated polyps (hyperplastic, sessile serrated and mixed), without causative mutation identified, were included. Complementary explorations on APC or MUTYH were performed: search for APC mosaicism, splicing-affecting mutations, large genomic rearrangement of MUTYH. Four genes of Wnt pathway (AXIN2, PPP2R1B, WIF1, SFRP1) and two genes of transforming growth factor-β (TGF-β) pathway (SMAD4, BMPR1A) were screened for germline mutation. Twenty-five patients had an unexplained adenomatous polyposis (familial or sporadic). Five pathogenic mutations were found: four in APC gene (with one case of mosaicism) and one in BMPR1A gene. The exploration of APC mosaicism was better performed from adenoma DNA with high-resolution melting. The screening of the candidate genes did not find any causative mutation. Thirteen individuals had an unexplained serrated polyposis and a frameshift on SMAD4 gene was identified. All mutations were identified in familial cases of polyposis. After new pathological examination, both BMPR1A and SMAD4 cases were found to be associated with a juvenile polyposis while the polyposis was initially described as adenomatous or undetermined. In 17% (6/38) of the patients the causative mutation of the polyposis was identified. Genetic causes were heterogeneous. Sporadic polyposis patients must be considered as potential APC mosaicism. The histological classification of polyposis is strongly important in direct genetic exploration.
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Affiliation(s)
- C Mongin
- Oncogenetic and Molecular Angiogenetic Laboratory, Hospital Pitié-Salpêtrière AP-HP, Paris, France
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Koch A, Hrychyk A, Hartmann W, Waha A, Mikeska T, Waha A, Schüller U, Sörensen N, Berthold F, Goodyer CG, Wiestler OD, Birchmeier W, Behrens J, Pietsch T. Mutations of the Wnt antagonist AXIN2 (Conductin) result in TCF-dependent transcription in medulloblastomas. Int J Cancer 2007; 121:284-91. [PMID: 17373666 DOI: 10.1002/ijc.22675] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Medulloblastomas (MBs) represent the most common malignant brain tumors in children. Most MBs develop sporadically in the cerebellum, but their incidence is highly elevated in patients with familial adenomatous polyposis coli. These patients carry germline mutations in the APC tumor suppressor gene. APC is part of a multiprotein complex involved in the Wnt signaling pathway that controls the stability of beta-catenin, the central effector in this cascade. Previous genetic studies in MBs have identified mutations in genes coding for beta-catenin and its partners, APC and AXIN1, which cause activation of Wnt signaling. The pathway is negatively controlled by the tumor suppressor AXIN2 (Conductin), a scaffold protein of this signaling complex. To investigate whether alterations in AXIN2 may also be involved in the pathogenesis of sporadic MBs, we performed a mutational screening of the AXIN2 gene in 116 MB biopsy samples and 11 MB cell lines using single-strand conformation polymorphism and sequencing analysis. One MB displayed a somatic, tumor-specific 2 bp insertion in exon 5, leading to carboxy-terminal truncation of the AXIN2 protein. This tumor biopsy showed nuclear accumulation of beta-catenin protein, indicating an activation of Wnt signaling. In 2 further MB biopsies, mutations were identified in exon 5 (Glu408Lys) and exon 8 (Ser738Phe) of the AXIN2 gene, which are due to predicted germline mutations and rare polymorphisms. mRNA expression analysis in 22 MBs revealed reduced expression of AXIN2 mRNA compared to 8 fetal cerebellar tissues. Promoter hypermethylation could be ruled out as a major cause for transcriptional silencing by bisulfite sequencing. To study the functional role of AXIN2 in MBs, wild-type AXIN2 was overexpressed in MB cell lines in which the Wnt signaling pathway was activated by Wnt-3a. In this assay, AXIN2 inhibited Wnt signaling demonstrated in luciferase reporter assays. In contrast, overexpression of mutated AXIN2 with a deleted C-terminal DIX-domain resulted in an activation of the Wnt signaling pathway. These findings indicate that mutations of AXIN2 can lead to an oncogenic activation of the Wnt pathway in MBs.
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Affiliation(s)
- Arend Koch
- Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
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