Unregulated smooth-muscle myosin in human intestinal neoplasia

doi:10.1073/pnas.0801213105

Unregulated smooth-muscle myosin in human intestinal neoplasia

^aDepartment of Medical Genetics and
ⁿDivision of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and Genome Scale Biology Program, Biomedicum Helsinki, University of Helsinki, 00014, Helsinki, Finland;
^bDepartment of Physiology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6085;
^cBioinformatics Unit, Biomedicum Helsinki, 00251, Helsinki, Finland;
^dInstitute of Cell and Molecular Sciences, Barts and The London Hospital, Queen Mary's University of London;
^eDepartment of Clinical Biochemistry, Aarhus University Hospital Skejby, DK-8200 Aarhus, Denmark;
^fDepartment of Surgery, Jyväskylä Central Hospital, 40620, Jyväskylä, Finland;
^gSecond Department of Surgery, Helsinki University Hospital, 00029, Helsinki, Finland;
^hGenomic Medicine Institute, Lerner Research Institute and Taussig Cancer Center, Cleveland Clinic Foundation and Department of Genetics and CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44195;
ⁱDeptartment of Surgery, St. Josefs Hospital Bochum-Linden, 44791 Bochum, Germany;
^jDepartment of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089-9176;
^kSection of Cancer Genetics, Institute of Cancer Research, Surrey SM2 5NG, Sutton, United Kingdom;
^lWessex Clinical Genetics Service, The Princess Anne Hospital, Southampton SO16 5YA, United Kingdom;
^mLaboratory of Molecular and Population Genetics, London Research Institute, Cancer Research United Kingdom, London WC2A 3PX, United Kingdom; and
^oMolecular Oncology Group, Molecular Biology and Biochemistry Research Center, Centre d'Investigacions en Bioquímica i Biologia Molecular-Nanomedicine, Vall d'Hebron Hospital Research Institute, 08035 Barcelona, Spain

Communicated by Albert de la Chapelle, Ohio State University, Columbus, OH, February 8, 2008 (received for review December 14, 2007)

Abstract

A recent study described a recessive ATPase activating germ-line mutation in smooth-muscle myosin (smmhc/myh11) underlying the zebrafish meltdown (mlt) phenotype. The mlt zebrafish develops intestinal abnormalities reminiscent of human Peutz–Jeghers syndrome (PJS) and juvenile polyposis (JP). To examine the role of MYH11 in human intestinal neoplasia, we searched for MYH11 mutations in patients with colorectal cancer (CRC), PJS and JP. We found somatic protein-elongating frameshift mutations in 55% of CRCs displaying microsatellite instability and in the germ-line of one individual with PJS. Additionally, two somatic missense mutations were found in one microsatellite stable CRC. These two missense mutations, R501L and K1044N, and the frameshift mutations were functionally evaluated. All mutations resulted in unregulated molecules displaying constitutive motor activity, similar to the mutant myosin underlying mlt. Thus, MYH11 mutations appear to contribute also to human intestinal neoplasia. Unregulated MYH11 may affect the cellular energy balance or disturb cell lineage decisions in tumor progenitor cells. These data challenge our view on MYH11 as a passive differentiation marker functioning in muscle contraction and add to our understanding of intestinal neoplasia.

Footnotes

^pTo whom correspondence should be addressed. E-mail: lauri.aaltonen{at}helsinki.fi
Author contributions: P.A., D.P., I.P.M.T., V.L., D.A., A.K., H.L.S., and L.A.A. designed research; P.A., D.P., S.T., H.S., M.N., J.P.R., Z.Y., L.-Q.C., D.S., and D.A. performed research; P.A., D.P., S.T., M.N., J.S., J.P.R., Z.Y., D.S., A.R., D.A., A.K., H.L.S., and L.A.A. analyzed data; P.A., D.P., T.O., J.-P.M., H.J., C.E., G.M., R.S.H., A.L., I.P.M.T., A.K., H.L.S., and L.A.A. wrote the paper; and T.O., J.-P.M., H.J., C.E., G.M., R.S.H., A.L., and I.P.M.T. contributed patient samples and clinical data.
The authors declare no conflict of interest.
Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. EU489063).
This article contains supporting information online at www.pnas.org/cgi/content/full/0801213105/DCSupplemental.
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