Abstract 4010: New AXIN2 germline variant in a Spanish family with an attenuated form of FAP without oligondontia or ectodermal dysplasia signs

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Abstract Familial Adenomatous Polyposis (FAP) is a colorectal cancer syndrome caused mainly by mutations in the APC gene (50-80% of the cases), and some mutations in MUTYH, usually in recessive and milder cases. Additionally, the genetic cause of 20% of classic forms and 50% of attenuated forms of the disease remain unclear. AXIN2 is a partner of the APC protein in the b-catenin destruction complex. Mutations in AXIN2 have been described in patients with oligodontia and other ectodermal dysplasia features in association with colorectal neoplasia or adenomatous polyps. We studied the AXIN2 gene in a series of APC/MUTYH mutation negative families and identified a novel variant, c.1387C>T;p.R463P, as the possible genetic cause of an attenuated FAP phenotype (AFAP). The autosomal dominant AFAP phenotype was not associated with any extracholonic manifestations or ectodermal dysplasia features. However, hyperplastic polyps were observed in some AXIN2-variant carriers. Thus, from a clinical point of view this family displayed some features that differ from previously described families with AXIN2 mutations. The variant c.1387C>T;p.R463P is located in the b-catenin binding domain, an area highly conserved throughout evolution. The variant segregates with the affected family members and was not present in 800 healthy Spanish controls. We were able to confirm loss of heterozygosity in 3 out of 5 polyps from the proband and his affected sister. AXIN2 and b-catenin expression patterns were tested by inmunofluorescence staining: both proteins are overexpressed in adenomatous polyps compared with normal colorectal ephitelium from the proband. Moreover, no colocalization of the two proteins could be observed by confocal microscopy. These results support a possible pathogenic role for this AXIN2 variant in our family and highlight the implication of AXIN2 in some cases of FAP syndrome. We argue comprehensives and functional studies will be necessary to clarify the role of AXIN2 in familial colorectal cancer predisposition. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4010. doi:1538-7445.AM2012-4010

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