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

Mohamed Bentires-Alj, J. Guillermo Paez, Frank S. David, Heike Keilhack, Balazs Halmos, Katsuhiko Naoki, John M. Maris, Andrea Richardson, Alberto Bardelli, David J. Sagarbaker, William G. Richards, Jinyan Du, Luc Girard, John D. Minna, Mignon L. Loh, David E. Fisher, Victor E. Velculescu, Bert Vogelstein, Matthew Meyerson, William R. Sellers & 1 others Benjamin G. Neel

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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.

Original languageEnglish
Pages (from-to)8816-8820
Number of pages5
JournalCancer Research
Volume64
Issue number24
DOIs
Publication statusPublished - 2004 Dec 15
Externally publishedYes

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Noonan Syndrome
Acute Myeloid Leukemia
Mutation
Genes
Neoplasms
Juvenile Myelomonocytic Leukemia
Neuroblastoma
Precursor Cell Lymphoblastic Leukemia-Lymphoma
SH2 Domain-Containing Protein Tyrosine Phosphatases
Missense Mutation
Germ Cells
Antineoplastic Agents
Extracellular Matrix

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Bentires-Alj, M., Paez, J. G., David, F. S., Keilhack, H., Halmos, B., Naoki, K., ... Neel, B. G. (2004). Activating mutations of the Noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. Cancer Research, 64(24), 8816-8820. https://doi.org/10.1158/0008-5472.CAN-04-1923

Activating mutations of the Noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. / Bentires-Alj, Mohamed; Paez, J. Guillermo; David, Frank S.; Keilhack, Heike; Halmos, Balazs; Naoki, Katsuhiko; Maris, John M.; Richardson, Andrea; Bardelli, Alberto; Sagarbaker, David J.; Richards, William G.; Du, Jinyan; Girard, Luc; Minna, John D.; Loh, Mignon L.; Fisher, David E.; Velculescu, Victor E.; Vogelstein, Bert; Meyerson, Matthew; Sellers, William R.; Neel, Benjamin G.

In: Cancer Research, Vol. 64, No. 24, 15.12.2004, p. 8816-8820.

Research output: Contribution to journalArticle

Bentires-Alj, M, Paez, JG, David, FS, Keilhack, H, Halmos, B, Naoki, K, Maris, JM, Richardson, A, Bardelli, A, Sagarbaker, DJ, Richards, WG, Du, J, Girard, L, Minna, JD, Loh, ML, Fisher, DE, Velculescu, VE, Vogelstein, B, Meyerson, M, Sellers, WR & Neel, BG 2004, 'Activating mutations of the Noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia', Cancer Research, vol. 64, no. 24, pp. 8816-8820. https://doi.org/10.1158/0008-5472.CAN-04-1923
Bentires-Alj, Mohamed ; Paez, J. Guillermo ; David, Frank S. ; Keilhack, Heike ; Halmos, Balazs ; Naoki, Katsuhiko ; Maris, John M. ; Richardson, Andrea ; Bardelli, Alberto ; Sagarbaker, David J. ; Richards, William G. ; Du, Jinyan ; Girard, Luc ; Minna, John D. ; Loh, Mignon L. ; Fisher, David E. ; Velculescu, Victor E. ; Vogelstein, Bert ; Meyerson, Matthew ; Sellers, William R. ; Neel, Benjamin G. / Activating mutations of the Noonan syndrome-associated SHP2/PTPN11 gene in human solid tumors and adult acute myelogenous leukemia. In: Cancer Research. 2004 ; Vol. 64, No. 24. pp. 8816-8820.
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AU - Paez, J. Guillermo

AU - David, Frank S.

AU - Keilhack, Heike

AU - Halmos, Balazs

AU - Naoki, Katsuhiko

AU - Maris, John M.

AU - Richardson, Andrea

AU - Bardelli, Alberto

AU - Sagarbaker, David J.

AU - Richards, William G.

AU - Du, Jinyan

AU - Girard, Luc

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AU - Loh, Mignon L.

AU - Fisher, David E.

AU - Velculescu, Victor E.

AU - Vogelstein, Bert

AU - Meyerson, Matthew

AU - Sellers, William R.

AU - Neel, Benjamin G.

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N2 - 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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