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Oncogenic RIT1 mutations in lung adenocarcinoma.

Berger AH, Imielinski M, Duke F, Wala J, Kaplan N, Shi GX, Andres DA, Meyerson M - Oncogene (2014)

Bottom Line: However, such mutations have been reported in only ∼55% of lung adenocarcinoma cases in the United States, suggesting other mechanisms of malignancy are involved in the remaining cases.Ectopic expression of mutated RIT1 induces cellular transformation in vitro and in vivo, which can be reversed by combined PI3K and MEK inhibition.These data identify RIT1 as a driver oncogene in a specific subset of lung adenocarcinomas and suggest PI3K and MEK inhibition as a potential therapeutic strategy in RIT1-mutated tumors.

View Article: PubMed Central - PubMed

Affiliation: 1] Cancer Program, The Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, MA, USA [2] Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.

ABSTRACT
Lung adenocarcinoma is comprised of distinct mutational subtypes characterized by mutually exclusive oncogenic mutations in RTK/RAS pathway members KRAS, EGFR, BRAF and ERBB2, and translocations involving ALK, RET and ROS1. Identification of these oncogenic events has transformed the treatment of lung adenocarcinoma via application of therapies targeted toward specific genetic lesions in stratified patient populations. However, such mutations have been reported in only ∼55% of lung adenocarcinoma cases in the United States, suggesting other mechanisms of malignancy are involved in the remaining cases. Here we report somatic mutations in the small GTPase gene RIT1 in ∼2% of lung adenocarcinoma cases that cluster in a hotspot near the switch II domain of the protein. RIT1 switch II domain mutations are mutually exclusive with all other known lung adenocarcinoma driver mutations. Ectopic expression of mutated RIT1 induces cellular transformation in vitro and in vivo, which can be reversed by combined PI3K and MEK inhibition. These data identify RIT1 as a driver oncogene in a specific subset of lung adenocarcinomas and suggest PI3K and MEK inhibition as a potential therapeutic strategy in RIT1-mutated tumors.

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Somatic RIT1 mutations in lung adenocarcinoma. (a) 2D protein structure schematics of RIT1 and KRAS with major protein domains shaded as indicated. Numbers indicate amino-acid positions. Each box represents an independent somatic RIT1 mutation with missense and in-frame indel mutations represented in black or blue, respectively. Arrows indicate two mutational hotspots in KRAS. (b) Predicted protein structure of RIT1. A homology model of RIT1 was generated from an alignment with HRAS (1AGP) using SWISS model and displayed using PYMOL. Amino acids near the switch II domain found mutated in this study are highlighted in yellow, in addition to Q79, which is shown for reference.
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fig1: Somatic RIT1 mutations in lung adenocarcinoma. (a) 2D protein structure schematics of RIT1 and KRAS with major protein domains shaded as indicated. Numbers indicate amino-acid positions. Each box represents an independent somatic RIT1 mutation with missense and in-frame indel mutations represented in black or blue, respectively. Arrows indicate two mutational hotspots in KRAS. (b) Predicted protein structure of RIT1. A homology model of RIT1 was generated from an alignment with HRAS (1AGP) using SWISS model and displayed using PYMOL. Amino acids near the switch II domain found mutated in this study are highlighted in yellow, in addition to Q79, which is shown for reference.

Mentions: In total, non-synonymous somatic mutations of RIT1 were identified in 10/413 (2.4%) lung adenocarcinomas subjected to whole exome sequencing (Figure 1a, Supplementary Table 1). Mutations in RIT1 consisted of missense mutations and small in-frame insertion/deletions. In all, 7/10 RIT1 mutations were clustered near the switch II domain region (Figures 1a and b), including three recurrent p.M90I mutations. The switch II domain in RIT1 is homologous to the switch II region in RAS genes that contains glutamine 61 (Supplementary Figure 1), which is directly involved in GTP hydrolysis and also a hotspot of mutation in RAS genes.17 This switch II domain hotspot is distinct from the P29 hotspot in RAC genes recently reported in melanoma and other cancers18, 19, 20 (Supplementary Figure 1).


Oncogenic RIT1 mutations in lung adenocarcinoma.

Berger AH, Imielinski M, Duke F, Wala J, Kaplan N, Shi GX, Andres DA, Meyerson M - Oncogene (2014)

Somatic RIT1 mutations in lung adenocarcinoma. (a) 2D protein structure schematics of RIT1 and KRAS with major protein domains shaded as indicated. Numbers indicate amino-acid positions. Each box represents an independent somatic RIT1 mutation with missense and in-frame indel mutations represented in black or blue, respectively. Arrows indicate two mutational hotspots in KRAS. (b) Predicted protein structure of RIT1. A homology model of RIT1 was generated from an alignment with HRAS (1AGP) using SWISS model and displayed using PYMOL. Amino acids near the switch II domain found mutated in this study are highlighted in yellow, in addition to Q79, which is shown for reference.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150988&req=5

fig1: Somatic RIT1 mutations in lung adenocarcinoma. (a) 2D protein structure schematics of RIT1 and KRAS with major protein domains shaded as indicated. Numbers indicate amino-acid positions. Each box represents an independent somatic RIT1 mutation with missense and in-frame indel mutations represented in black or blue, respectively. Arrows indicate two mutational hotspots in KRAS. (b) Predicted protein structure of RIT1. A homology model of RIT1 was generated from an alignment with HRAS (1AGP) using SWISS model and displayed using PYMOL. Amino acids near the switch II domain found mutated in this study are highlighted in yellow, in addition to Q79, which is shown for reference.
Mentions: In total, non-synonymous somatic mutations of RIT1 were identified in 10/413 (2.4%) lung adenocarcinomas subjected to whole exome sequencing (Figure 1a, Supplementary Table 1). Mutations in RIT1 consisted of missense mutations and small in-frame insertion/deletions. In all, 7/10 RIT1 mutations were clustered near the switch II domain region (Figures 1a and b), including three recurrent p.M90I mutations. The switch II domain in RIT1 is homologous to the switch II region in RAS genes that contains glutamine 61 (Supplementary Figure 1), which is directly involved in GTP hydrolysis and also a hotspot of mutation in RAS genes.17 This switch II domain hotspot is distinct from the P29 hotspot in RAC genes recently reported in melanoma and other cancers18, 19, 20 (Supplementary Figure 1).

Bottom Line: However, such mutations have been reported in only ∼55% of lung adenocarcinoma cases in the United States, suggesting other mechanisms of malignancy are involved in the remaining cases.Ectopic expression of mutated RIT1 induces cellular transformation in vitro and in vivo, which can be reversed by combined PI3K and MEK inhibition.These data identify RIT1 as a driver oncogene in a specific subset of lung adenocarcinomas and suggest PI3K and MEK inhibition as a potential therapeutic strategy in RIT1-mutated tumors.

View Article: PubMed Central - PubMed

Affiliation: 1] Cancer Program, The Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, MA, USA [2] Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.

ABSTRACT
Lung adenocarcinoma is comprised of distinct mutational subtypes characterized by mutually exclusive oncogenic mutations in RTK/RAS pathway members KRAS, EGFR, BRAF and ERBB2, and translocations involving ALK, RET and ROS1. Identification of these oncogenic events has transformed the treatment of lung adenocarcinoma via application of therapies targeted toward specific genetic lesions in stratified patient populations. However, such mutations have been reported in only ∼55% of lung adenocarcinoma cases in the United States, suggesting other mechanisms of malignancy are involved in the remaining cases. Here we report somatic mutations in the small GTPase gene RIT1 in ∼2% of lung adenocarcinoma cases that cluster in a hotspot near the switch II domain of the protein. RIT1 switch II domain mutations are mutually exclusive with all other known lung adenocarcinoma driver mutations. Ectopic expression of mutated RIT1 induces cellular transformation in vitro and in vivo, which can be reversed by combined PI3K and MEK inhibition. These data identify RIT1 as a driver oncogene in a specific subset of lung adenocarcinomas and suggest PI3K and MEK inhibition as a potential therapeutic strategy in RIT1-mutated tumors.

Show MeSH
Related in: MedlinePlus