Author(s): Bentires-Alj M; Paez JG; David FS; Keilhack H; Halmos B; Naoki K; Maris JM; Richardson A; Bardelli A; Sugarbaker DJ; Richards WG; Du JY; Girard L; Minna JD; Loh ML; Fisher DE; Velculescu VE; Vogelstein B; Meyerson M; Sellers WR; Neel BG

Title: Activating mutations of the Noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia

Source: CANCER RESEARCH 64 (24): 8816-8820

Date: 2004 DEC 15

Document Type: Journal : Article

Language: English

LCR: 3   CR: 20   LCS: 0   GCS: 73

Comment:  

Address: Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Canc Biol Program, Boston, MA 02215 USA.
Univ Liege, Ctr Cellular & Mol Therapy, Lab Med Chem & Human Genet, Liege, Belgium.
Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA.
Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA.
Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA.
Univ Turin, Sch Med, Inst Canc Res & Treatment, Oncogenom Ctr, Turin, Italy.
Dana Farber Canc Inst, Dept Surg Serv, Boston, MA 02115 USA.
Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA.
Dana Farber Canc Inst, Dept Pediat Hematol Oncol, Boston, MA 02115 USA.
Childrens Hosp, Boston, MA 02115 USA.
Univ Texas, SW Med Ctr, Hamon Ctr Therapeut Oncol Res, Dallas, TX USA.
Univ Texas, SW Med Ctr, Dept Internal Med, Dallas, TX USA.
Univ Texas, SW Med Ctr, Dept Pharmacol, Dallas, TX USA.
Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA.
Univ Calif San Francisco, Ctr Comprehens Canc, San Francisco, CA 94143 USA.
Johns Hopkins Univ, Howard Hughes Med Inst, Baltimore, MD USA.
Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA.
Harvard Univ, Sch Med, Dept Med, Broad Inst, Boston, MA USA.
MIT, Boston, MA USA.

Reprint: Bentires-Alj, M, Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr,
Canc Biol Program, New Res Bldg 1038,77 Louis Pasteur Ave, Boston, MA
02215 USA.

E-mail: mbentire@bidmc.harvard.edu

Abstract: 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.