<i>AMER1</i> Is a Frequently Mutated Gene in Colorectal Cancer—Letter
Authors: Pilar Mur, Gemma Aiza, Rebeca Sanz-Pamplona, Sara González, Matilde Navarro, Victor Moreno, Gabriel Capellá, Laura Valle
Journal: Clinical Cancer Research (2015)

In the article by Sanz-Pamplona and colleagues (1), functionally relevant mutations in AMER1 were identified in approximately 10% of stage II colorectal tumors, reinforcing its role as a driver gene in colorectal cancer, as occurs with APC, KRAS, or TP53. AMER1 codifies a membrane protein that acts as scaffold for β-catenin degradation, assembling the destruction complex at the plasma membrane by recruiting β-catenin, APC, and Axin/Conductin, and therefore acting as a key negative regulator of Wnt signaling (2). Germline mutations in the APC tumor suppressor gene cause colonic adenomatous polyposis and increased colorectal cancer risk, i.e., the familial adenomatous polyposis syndrome (3). However, germline APC mutations account for only a subset of polyposis cases. Currently, there is some evidence of the involvement of germline mutations in AXIN2, another player in the Wnt pathway, in the development of gastrointestinal polyposis and colorectal cancer, although additional data are required to confirm this association (4).Based on the relevance of AMER1 in colorectal carcinogenesis and the causal association of Wnt pathway members with polyposis, we hypothesized that germline mutations in AMER1 might be responsible for a fraction of polyposis cases without mutations in the already-known causal genes. We sequenced the entire coding region of AMER1 in DNA extracted from the peripheral blood of 94 polyposis patients without mutations in APC, MUTYH, POLE, POLD1, BMPR1A, or SMAD4, using direct automated (Sanger) sequencing. The studied series included polyposis patients referred to the genetic counseling and diagnostic units of the Hereditary Cancer Program of the Catalan Institute of Oncology in the different regions of Catalonia (Spain). These were classified as classic adenomatous polyposes (16%; 15/94), attenuated adenomatous polyposes (43.6%; 41/94), nonadenomatous polyposes (14.9%; 14/94), and patients referred to the corresponding units of genetic diagnostics as "polyposis" but with no specific clinic and histologic information available (25.5%; 24/94).Three previously reported single-nucleotide variants in AMER1 (NM_152424) were identified in four unrelated patients, none of them showing evidence of deleteriousness: Two synonymous changes, rs34504794 c.135C>T (p.S45=) and rs190629808 c.315C>T (p.G105=) (MAFESP6500_Caucasian: 1.31% and 0.03%, respectively), and one missense variant, rs34677493 c.477T>G (p.F159L) (MAFESP6500_Caucasian: 0.63%), classified as neutral by in silico predictors Polyphen 2 and Mutation Taster.In conclusion, despite its role in colorectal carcinogenesis and its relevance in the Wnt signaling pathway, our findings indicate that the contribution of germline mutations in AMER1 to the yet-to-be-characterized colonic polyposis cases is nonexistent or very rare.No potential conflicts of interest were disclosed.This work has been funded by the Spanish Ministry of Economy and Competitiveness and co-funded by FEDER funds- a way to build Europe- (SAF2012-38885 to L. Valle; SAF2012-33636 to G. Capellá), the Carlos III Health Institute (PI11-01439 to V. Moreno), Red Temática de Investigación Cooperativa en Cáncer (RTICC RD12/0036/0031), Scientific Foundation Asociación Española Contra el Cáncer, the Catalan Health Institute and the Autonomous Government of Catalonia (2014SGR338).