SOS1 mutations are rare in human malignancies: implications for Noonan Syndrome patients.
Germ line gain-of-function mutations in several members of the RAS/ERK pathway, including PTPN11, KRAS, and RAF1, cause the autosomal dominant genetic disorder Noonan Syndrome (NS). NS patients are at increased risk of leukemia/myeloproliferative disease and possibly some solid tumors, such as neuroblastoma. Recently, SOS1 gain of function mutations have also been shown to cause NS. Somatic PTPN11, KRAS, and RAF1 mutations occur (although at different frequencies) in a variety of sporadic neoplasms, but whether SOS1 mutations are associated with human cancer has not been evaluated. We sequenced DNA from a total of 810 primary malignancies, including pancreatic, lung, breast, and colon carcinomas, and acute myelogenous leukemia, as well as several neuroblastoma cell lines. From this large, diverse series, missense SOS1 mutations were identified in a single pancreatic tumor, one lung adenocarcinoma, and a T-cell acute lymphoblastic leukemia cell line. Our findings suggest that SOS1 is not a significant human oncogene in most cancers. Furthermore, NS patients with SOS1 mutations may not be at increased risk of developing cancer.
Cancer Biology Program, Division of Hematology/Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts, USA.
Kenneth D
KD
Swanson
Jordan M
JM
Winter
Marcelo
M
Reis
Mohamed
M
Bentires-Alj
Heidi
H
Greulich
Rupinder
R
Grewal
Ralph H
RH
Hruban
Charles J
CJ
Yeo
Yosuf
Y
Yassin
Oleg
O
Iartchouk
Kate
K
Montgomery
Susan P
SP
Whitman
Michael A
MA
Caligiuri
Mignon L
ML
Loh
D Gary
DG
Gilliland
A Thomas
AT
Look
Raju
R
Kucherlapati
Scott E
SE
Kern
Matthew
M
Meyerson
Benjamin G
BG
Neel
D004273:DNA, Neoplasm; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000209:etiology / Q000235:genetics*; D009634:Noonan Syndrome / Q000150:complications* / Q000235:genetics; D016133:Polymerase Chain Reaction; D020837:SOS1 Protein / Q000235:genetics*; D017422:Sequence Analysis, DNA
D004273:DNA, Neoplasm; D020837:SOS1 Protein