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Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation

Nature Genetics volume 45, pages 253–261 (2013)Cite this article

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Abstract

Aberrant Wnt signaling can drive cancer development. In many cancer types, the genetic basis of Wnt pathway activation remains incompletely understood. Here, we report recurrent somatic mutations of the Drosophila melanogaster tumor suppressor–related gene FAT1 in glioblastoma (20.5%), colorectal cancer (7.7%), and head and neck cancer (6.7%). FAT1 encodes a cadherin-like protein, which we found is able to potently suppress cancer cell growth in vitro and in vivo by binding β-catenin and antagonizing its nuclear localization. Inactivation of FAT1 via mutation therefore promotes Wnt signaling and tumorigenesis and affects patient survival. Taken together, these data strongly point to FAT1 as a tumor suppressor gene driving loss of chromosome 4q35, a prevalent region of deletion in cancer. Loss of FAT1 function is a frequent event during oncogenesis. These findings address two outstanding issues in cancer biology: the basis of Wnt activation in non-colorectal tumors and the identity of a 4q35 tumor suppressor.

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Figure 1: The FAT1 gene is deleted and mutated at high prevalence across multiple human cancers, and FAT1 suppresses cancer cell growth and proliferation.
Figure 2: The growth-suppressive properties of FAT1 are abrogated by mutations observed in cancer.
Figure 3: FAT1 inactivation results in increased cancer cell growth and proliferation.
Figure 4: FAT1 is a β-catenin–binding partner, and loss of binding causes aberrant Wnt pathway activation, translocation of β-catenin to the nucleus and enhanced β-catenin–mediated transcription.
Figure 5: Functional relationship between β-catenin and FAT1 in the regulation of proliferation.
Figure 6: Effects of FAT1 inactivation on Wnt/β-catenin signaling.

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Acknowledgements

We thank A. Heguy, A. Viale, K. Huberman, I. Dolgalev, S. Thomas, A. Kayserian and R. Spektor for excellent technical assistance. We are grateful to N. Sibinga (Albert Einstein College of Medicine) for providing an antibody to FAT1. This work was supported in part by US National Institutes of Health (NIH) grants NIH T32 CA009685 (L.G.T.M.) and NIH R01CA154767-01 (T.A.C.), the Memorial Sloan-Kettering Cancer Center, Department of Surgery Junior Faculty Award (L.G.T.M.), the Louis Gerstner Foundation (T.A.C.), the STARR Cancer Consortium (T.A.C.), The Geoffrey Beene Cancer Center (T.A.C.), the Doris Duke Charitable Foundation (T.A.C. and I.K.M.), the AVON Foundation (T.A.C.), the Flight Attendant Medical Research Institute (T.A.C.) and the Sontag Foundation (T.A.C.).

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  1. Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Luc G T Morris, Andrew M Kaufman, Yongxing Gong, Deepa Ramaswami, Logan A Walsh, Şevin Turcan, Stephanie Eng, Kasthuri Kannan, Yilong Zou, Luke Peng, David Solit, Ingo K Mellinghoff & Timothy A Chan

  2. Department of Surgery, Head and Neck Service, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Luc G T Morris, Victoria E Banuchi, Bhuvanesh Singh & Ian Ganly

  3. Department of Surgery, Colorectal Service, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Phillip Paty & Zhaoshi Zeng

  4. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Efsevia Vakiani

  5. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    David Solit

  6. David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.,

    Linda Liau, Timothy C Cloughesy & Paul S Mischel

  7. Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Ingo K Mellinghoff

  8. Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Ingo K Mellinghoff & Timothy A Chan

  9. Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA

    Timothy A Chan

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Contributions

L.G.T.M. and T.A.C. designed the experiments. L.G.T.M., A.M.K., Y.G., D.R., L.A.W., Ş.T., V.E.B., S.E. and Y.Z. performed the experiments. L.G.T.M., Ş.T., L.P., K.K. and T.A.C. analyzed the data. B.S., I.G., P.P., Z.Z., E.V., D.S., L.L., T.C.C., P.S.M. and I.K.M. contributed new reagents and/or analytic tools. L.G.T.M. and T.A.C. wrote the manuscript.

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Correspondence to Timothy A Chan.

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Supplementary Figures 1–8, Supplementary Tables 1–4 and 6–9 and Supplementary Note (PDF 2157 kb)

Supplementary Table 5

Genes differentially expressed after FAT1 knockdown across all 3 cell lines. (XLSX 214 kb)

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Morris, L., Kaufman, A., Gong, Y. et al. Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation. Nat Genet 45, 253–261 (2013). https://doi.org/10.1038/ng.2538

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