Mutations in AXIN2 Cause Familial Tooth Agenesis and Predispose to Colorectal Cancer

Abstract

Wnt signaling regulates embryonic pattern formation and morphogenesis of most organs. Aberrations of regulation of Wnt signaling may lead to cancer. Here, we have used positional cloning to identify the causative mutation in a Finnish family in which severe permanent tooth agenesis (oligodontia) and colorectal neoplasia segregate with dominant inheritance. Eleven members of the family lacked at least eight permanent teeth, two of whom developed only three permanent teeth. Colorectal cancer or precancerous lesions of variable types were found in eight of the patients with oligodontia. We show that oligodontia and predisposition to cancer are caused by a nonsense mutation, Arg656Stop, in the Wnt-signaling regulator AXIN2. In addition, we identified a de novo frameshift mutation 1994-1995insG in AXIN2 in an unrelated young patient with severe tooth agenesis. Both mutations are expected to activate Wnt signaling. The results provide the first evidence of the importance of Wnt signaling for the development of dentition in humans and suggest that an intricate control of Wnt-signal activity is necessary for normal tooth development, since both inhibition and stimulation of Wnt signaling may lead to tooth agenesis. Our findings introduce a new gene for hereditary colorectal cancer and suggest that tooth agenesis may be an indicator of cancer susceptibility.

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

“…For example, Lammi et al 2 described a family with nine carriers of a nonsense mutation in AXIN2; the gastrointestinal phenotype in carriers varied from 68 adenomas in a 57-year-old carrier to no adenomas in a 26-year-old and one adenoma in a 58-year-old. Even greater clinical variability was reported by Marvin et al, 3 in terms of the number (from none to more than 100), type (adenomatous or hyperplastic) and location (colonic or gastric) of polyps, and the presence of neoplasias.…”

“…In a study of cases negative for APC and MUTYH mutations, Renkonen et al, 8 described an AXIN2 mutation in a family with previously reported oligodontia. 2 Mongin et al 9 described 38 patients with adenomas or serrated polyps in which AXIN2 screening gave negative results. In light of these studies, it is likely that the number of polyposis patients who have undergone testing for AXIN2 alterations is still insufficient to define the role of the gene in familial polyposis.…”

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

“…Perturbations in the levels of Axin, APC, β-catenin, LEF1 or TCF4, for example, contribute to the initiation and/or progression of several different types of cancer [7][8][9][10][11][12]. It is therefore not surprising that so much effort has gone into the development of new drugs based on our knowledge of Wnt signaling to treat disease.…”

Variability in dentofacial phenotypes in four families with WNT10A mutations

“…The proband was 19 years old at the time of inclusion (patient B II-3) with severe TA missing 12 permanent teeth (17,13,11,21,23,24,27,32,33,34,35,37,42,43,44,47). The upper anterior teeth show a conical aspect and the permanent upper first molars are hypoplastic.…”

“…Clinical examination proband. In her permanent dentition, she has severe TA of 23 teeth (17, 15, 14 (16,13,23, 33 and 46), two of which have a conical shape and one being hypoplastic. Although her mandible is also retruded, leading to a convex profile, the dished-in appearance is again the most catching feature in her facial profile.…”