AXIS inhibition protein 2, orofacial clefts and a family history of cancer

Menezes, Renato; Marazita, Mary L.; McHenry, Toby; Cooper, Margaret E.; Bardi, Kathleen; Brandon, Carla A.; Letra, Ariadne; Martin, Rick A.; Vieira, Alexandre R.

doi:10.14219/jada.archive.2009.0022

Cited by 82 publications

(109 citation statements)

References 21 publications

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“…However, other conditions such as oral cleft and different types of cancer have been recently related to mutations in AXIN2. 4,5 Although it is possible that AXIN2 has a role in colorectal tumor predisposition, few reports to date have tested the AXIN2 gene in CRC/poliposis patients. Leujene et al 6 studied 39 patients, one of AXIN2 overexpression was present in probandus compared with the APC and MUTYH mutation carriers.…”

Section: Discussionmentioning

confidence: 99%

A novel AXIN2 germline variant associated with attenuated FAP without signs of oligondontia or ectodermal dysplasia

et al. 2013

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Truncating mutations in the AXIN2 gene, a key regulator of b-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 b-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. European Journal of Human Genetics (2014) 22, 423-426; doi:10.1038/ejhg.2013.146; published online 10 July 2013Keywords: familal adenomatous polyposis; AXIN2 mutation; oligodontia; ectodermal dysplasia; Wnt pathway INTRODUCTION Familial Adenomatous Polyposis (FAP) is a syndrome characterized by the development of hundreds of colorectal polyps in early adolescence; it predisposes sufferers to cancer and has dominant inheritance. Attenuated FAP (AFAP) is diagnosed when patients present with less (10-99) polyps, and tends to occur 15-20 years later than for classical FAP. Mutations in the APC gene are responsible for the majority of FAP cases, and also explain some AFAP cases. In 2002, the implication of MUTYH, a BER-pathway gene, was discovered in milder cases of polyposis. Nevertheless, a considerable proportion (20-50%) of FAP and AFAP cases is not found to carry germline mutations in APC or MUTYH, and their genetic etiology remains unclear.As APC has a key role in maintaining the b-catenin turnover in the Wnt pathway, other Wnt genes involved in this regulation might be also implicated in the syndrome. It has been suggested that AXIN2, the scaffold protein of the b-catenin destruction complex, is the main negative regulator in the pathway. 1 Little is known regarding the role of AXIN2 in CRC, but AXIN2 mutations have been reported in three families with gastrointestinal polyposis and ectodermal dysplasia; 2,3 the AXIN2 truncating mutations were located in a narrow region of the gene, and the phenotype associated with them, while highly heterogeneous, always included colonic polyposis and ectodermal dysplasia.Here we describe a family with a novel missense variant in the AXIN2 gene, and thereby expand on the phenotype associated with alterations in this gene.

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Section: Discussionmentioning

confidence: 99%

A novel AXIN2 germline variant associated with attenuated FAP without signs of oligondontia or ectodermal dysplasia

et al. 2013

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“…Several genes-including, but not limited to, MSX1, IRF6, CRISPLD2, FOXE1, and members of the WNT and FGF gene families-have been associated with oral clefts (Jezewski et al, 2003;Zucchero et al, 2004;Chiquet et al, 2007;Riley et al, 2007;Menezes et al, 2009Menezes et al, , 2010Moreno et al, 2009). Recently, genome-wide association studies have implicated additional loci on 1p22, 8q24, 10q25.3, 17q22, and 20q12 in the etiology of oral clefts (Birnbaum et al, 2009;Beaty et al, 2010;Mangold et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Members of the WNT gene family have been associated with clefts in humans and mice (Lan et al, 2006;Chiquet et al, 2008;Menezes et al, 2009). The AXIN2 (axis inhibition protein 2) gene is a negative regulator of the WNT pathway due to its role in the degradation of β-catenin.…”

Section: Introductionmentioning

confidence: 99%

Association ofAXIN2with Non-syndromic Oral Clefts in Multiple Populations

et al. 2012

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“…Several studies from different countries (USA, Latvia, Denmark, and Brazil) have identified an association between cleft palate and cancer [90][91][92][93][94][95]. The first epidemiological studies addressed the presence of cancer in cleft lip/palate subjects and their families.…”

Section: Cleft Palate and Cancermentioning

confidence: 99%

8 Epidemiology of Cleft Lip and Palate

Losee¹,

Kirschner²

2016

Comprehensive Cleft Care, Volume 1

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Orofacial cleft (OFC) anomalies are amongst the most common congenital anomalies and the most common craniofacial anomalies. Despite their poorly characterized etiologies, cases of OFC are usually grouped by epidemiological studies as cleft lip, with or without cleft palate (CL/P), and cleft palate alone (CPO). Incidence of CL/P and CPO differs according to gender and ancestry and may vary widely across studies. Cases of OFC are characterized as either "syndromic" or "nonsyndromic," with further classification of nonsyndromic cases into isolated cases and cases that present with additional malformations. The genetic bases for many syndromic cases of OFC have been previously elucidated. Genetic associations have been described for nonsyndromic OFC as well. Importantly, etiology of OFC is known to involve interaction between genetic and environmental factors, including maternal nutrition and exposure to teratogenic agents. Furthermore, evidence points toward epigenetic as well as genetic factors influencing OFC etiology. Recent studies have begun to explore the association between CL/P and cancer. These studies report higher incidence of cancer among patients with CL/P and their family members as well as identification of common genetic markers mediating this increased risk, although much remains unknown about this link.

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AXIS inhibition protein 2, orofacial clefts and a family history of cancer

Cited by 82 publications

References 21 publications

A novel AXIN2 germline variant associated with attenuated FAP without signs of oligondontia or ectodermal dysplasia

A novel AXIN2 germline variant associated with attenuated FAP without signs of oligondontia or ectodermal dysplasia

Association ofAXIN2with Non-syndromic Oral Clefts in Multiple Populations

8 Epidemiology of Cleft Lip and Palate

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