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Activating Mutations of the Noonan Syndrome-Associated SHP2/PTPN11 Gene in Human Solid Tumors and Adult Acute Myelogenous Leukemia

¹ Cancer Biology Program, Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts; ² Laboratory of Medical Chemistry and Human Genetics, Center for Cellular and Molecular Therapy, University of Liège, Liège, Belgium; ³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; ⁴ Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; ⁵ Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts; ⁶ The Oncogenomics Center, Institute for Cancer Research and Treatment, University of Torino Medical School, Turin, Italy; ⁷ Department of Surgical Services, Dana-Farber Cancer Institute, Boston, Massachusetts; ⁸ Department of Surgery, Brigham and Women’s Hospital, Boston, Massachusetts; ⁹ Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and Children’s Hospital, Boston, Massachusetts; ¹⁰ Hamon Center for Therapeutic Oncology Research and Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas; ¹¹ Department of Pediatrics and Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California; ¹² The Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center, John Hopkins University Medical Institutions, Baltimore, Maryland; and ¹³ Department of Medicine, Harvard Medical School, Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, Massachusetts

The SH2 domain-containing protein-tyrosine phosphatase PTPN11 (Shp2) is required for normal development and is an essential component of signaling pathways initiated by growth factors, cytokines, and extracellular matrix. In many of these pathways, Shp2 acts upstream of Ras. About 50% of patients with Noonan syndrome have germ-line PTPN11 gain of function mutations. Associations between Noonan syndrome and an increased risk of some malignancies, notably leukemia and neuroblastoma, have been reported, and recent data indicate that somatic PTPN11 mutations occur in children with sporadic juvenile myelomonocytic leukemia, myelodysplasic syndrome, B-cell acute lymphoblastic leukemia, and acute myelogenous leukemia (AML). Juvenile myelomonocytic leukemia patients without PTPN11 mutations have either homozygotic NF-1 deletion or activating RAS mutations. Given the role of Shp2 in Ras activation and the frequent mutation of RAS in human tumors, these data raise the possibility that PTPN11 mutations play a broader role in cancer. We asked whether PTPN11 mutations occur in other malignancies in which activating RAS mutations occur at low but significant frequency. Sequencing of PTPN11 from 13 different human neoplasms including breast, lung, gastric, and neuroblastoma tumors and adult AML and acute lymphoblastic leukemia revealed 11 missense mutations. Five are known mutations predicted to result in an activated form of Shp2, whereas six are new mutations. Biochemical analysis confirmed that several of the new mutations result in increased Shp2 activity. Our data demonstrate that mutations in PTPN11 occur at low frequency in several human cancers, especially neuroblastoma and AML, and suggest that Shp2 may be a novel target for antineoplastic therapy.

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