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Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129 [S. B. L., S. H. K., D. W. B., D. C. R. W., T. A. S., M. M. J., K. M. S., E. H., D. A. H.]; Molecular Pathology Unit, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129 [D. C. S.]; Division of Population Sciences, Dana Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02114 [J. E. G., F. P. L.]; Division of Pediatric Oncology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania [K. E. N.]; Cancer Research Campaign, Department of Cancer Genetics, Paterson Institute for Cancer Research, Manchester M20 4BX, United Kingdom [J. M. V.]; and Medical Science Division, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 [A. K. G.]
Li Fraumeni Syndrome (LFS) is a multicancer phenotype, most commonly associated with germ-line mutations in TP53. In a kindred with LFS without an inherited TP53 mutation, we have previously reported a truncating mutation (1100delC) in CHK2, encoding a kinase that phosphorylates p53 on Ser20. Here, we describe a CHK2 missense mutation (R145W) in another LFS family. This mutation destabilizes the encoded protein, reducing its half-life from >120 min to 30 min. This effect is abrogated by treatment of cells with a proteosome inhibitor, suggesting that CHK2R145W is targeted through this degradation pathway. Both 1100delC and R145W germ-line mutations in CHK2 are associated with loss of the wild-type allele in the corresponding tumor specimens, and neither tumor harbors a somatic TP53 mutation. Our observations support the functional significance of CHK2 mutations in rare cases of LFS and suggest that such mutations may substitute for inactivation of TP53.
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