Oncogenic RIT1 mutations in lung adenocarcinoma
[Paper-level Aggregated] PMCID: PMC4150988
Evidence Type(s): Functional
Summary: Mutation: p.M90I | Summary: The p.M90I mutation is being studied for its role in altering the molecular function of RIT1 in the context of human cancer pathogenesis and is associated with human primary lung adenocarcinomas, suggesting it may contribute to tumor development or progression.
Gene→Variant (gene-first): RIT1(6016):p.M90I
Genes: RIT1(6016)
Variants: p.M90I
Oncogenic RIT1 mutations in lung adenocarcinoma
[Paper-level Aggregated] PMCID: PMC4150988
Evidence Type(s): Oncogenic
Summary: Mutation: p.M90I | Summary: The p.M90I mutation in RIT1 is associated with tumor development or progression, being recurrently observed in lung adenocarcinoma and myeloid malignancies. It is suggested to contribute to tumor development based on its presence in 'oncogene-negative' lung cancer cell lines.
Evidence Type: Oncogenic Mutation: p.A77P | Summary: The p.A77P mutation in RIT1 is associated with tumor development as it was observed in a recurrent alteration among mutated samples.
Evidence Type: Oncogenic Mutation: p.R122L | Summary: The p.R122L mutation is suggested to function as an oncogene in the context of RAS/RTK pathway lung adenocarcinoma, indicating its potential role in tumor development or progression.
Evidence Type: Oncogenic Mutation: F82L | Summary: The F82L mutation is associated with tumor development or progression, as it has been observed in lung adenocarcinoma and myeloid malignancies.
Evidence Type: Oncogenic Mutation: G12V | Summary: The KRAS G12V mutation is associated with inducing cellular transformation and tumor formation in NIH3T3 cells.
Evidence Type: Oncogenic Mutation: L858R | Summary: The EGFR L858R mutation contributes to tumor formation, as evidenced by its ability to induce significant colony formation in soft agar.
Evidence Type: Oncogenic Mutation: Q79L | Summary: The RIT1 Q79L mutation is capable of inducing cellular transformation and tumor formation in NIH3T3 cells.
Evidence Type: Oncogenic Mutation: Q40L | Summary: The RIT1 Q40L mutation shows intermediate transforming capability in the xenograft assay and is associated with the activation of MEK and ERK pathways, contributing to tumor development and progression. It is part of a group of RIT1 mutations that induce phosphorylation of signaling proteins, indicating its oncogenic potential.
Gene→Variant (gene-first): RIT1(6016):p.M90I RIT1(6016):p.A77P RIT1(6016):p.R122L RIT1(6016):F82L KRAS(3845):G12V EGFR(1956):L858R RIT1(6016):Q79L RIT1(6016):Q40L
Genes: RIT1(6016) KRAS(3845) EGFR(1956)
Variants: p.M90I p.A77P p.R122L F82L G12V L858R Q79L Q40L
Oncogenic RIT1 mutations in lung adenocarcinoma
[Paper-level Aggregated] PMCID: PMC4150988
Evidence Type(s): Predisposing
Summary: Mutation: p.A77S | Summary: The p.A77S mutation may represent a rare germline variant, suggesting a potential inherited risk for disease, although this is unlikely based on the absence in normal genome data.
Evidence Type: Predisposing
Gene→Variant (gene-first): RIT1(6016):p.A77S
Genes: RIT1(6016)
Variants: p.A77S
Given the prevalence of RIT1 mutation in primary human lung adenocarcinomas, we hypothesized that human lung adenocarcinoma cell lines may also harbor mutations in RIT1 and that identification of these cell lines would f
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 11
Evidence Type(s): Oncogenic, Functional
Summary: Evidence Type: Oncogenic | Mutation: p.M90I | Summary: The p.M90I mutation in RIT1 is associated with human primary lung adenocarcinomas and is suggested to contribute to tumor development or progression based on its presence in 'oncogene-negative' lung cancer cell lines. Evidence Type: Functional | Mutation: p.M90I | Summary: The p.M90I mutation is being studied for its role in altering the molecular function of RIT1 in the context of human cancer pathogenesis.
Gene→Variant (gene-first): 6016:p.M90I
Genes: 6016
Variants: p.M90I
RIT1 mutation is mutually exclusive with mutations in other RAS/RTK-pathway genes, so we hypothesized that RIT1 may activate PI3K and MEK. To investigate the signaling changes induced by mutated RIT1, we expressed wild-t
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 9
Evidence Type(s): Oncogenic
Summary: Evidence Type: Oncogenic | Mutation: Q40L | Summary: The RIT1 Q40L mutation is associated with the activation of MEK and ERK pathways, contributing to tumor development and progression. It is part of a group of RIT1 mutations that induce phosphorylation of signaling proteins, indicating its oncogenic potential.
Gene→Variant (gene-first): 6016:Q40L
Genes: 6016
Variants: Q40L
To test whether mutated RIT1 is capable of inducing cellular transformation, we expressed wild-type or mutated RIT1 cDNA constructs in NIH3T3 cells and assayed the ability of these cells to form colonies in soft agar. A
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 7
Evidence Type(s): Oncogenic
Summary: Evidence Type: Oncogenic | Mutation: G12V | Summary: The KRAS G12V mutation is associated with inducing cellular transformation and tumor formation in NIH3T3 cells. Evidence Type: Oncogenic | Mutation: L858R | Summary: The EGFR L858R mutation contributes to tumor formation, as evidenced by its ability to induce significant colony formation in soft agar. Evidence Type: Oncogenic | Mutation: Q79L | Summary: The RIT1 Q79L mutation is capable of inducing cellular transformation and tumor formation in NIH3T3 cells. Evidence Type: Oncogenic | Mutation: Q40L | Summary: The RIT1 Q40L mutation shows intermediate transforming capability in the xenograft assay, indicating its potential oncogenic properties.
Gene→Variant (gene-first): 3845:G12V 1956:L858R 6016:Q40 6016:Q40L 6016:Q79L
Genes: 3845 1956 6016
Variants: G12V L858R Q40 Q40L Q79L
We surveyed recent exome sequencing data from other diverse cancer types to determine whether RIT1 is mutated in malignancies other than lung adenocarcinoma. Most tumor types had no mutations, or rare RIT1 variants of un
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 6
Evidence Type(s): Oncogenic
Summary: Evidence Type: Oncogenic | Mutation: F82L | Summary: The F82L mutation is associated with tumor development or progression, as it has been observed in lung adenocarcinoma and myeloid malignancies. Evidence Type: Oncogenic | Mutation: M90I | Summary: The M90I mutation contributes to tumor development or progression, being recurrently observed in lung adenocarcinoma and also found in myeloid malignancies. Evidence Type: Oncogenic | Mutation: p.M90I | Summary: The p.M90I mutation is implicated in tumor development or progression, as it has been identified in both lung adenocarcinoma and myeloid malignancies.
Gene→Variant (gene-first): 6016:F82L 6016:M90I 6016:p.M90I
Genes: 6016
Variants: F82L M90I p.M90I
All seven samples with switch II domain RIT1 mutations lacked oncogenic driver mutations in EGFR, KRAS, BRAF, ERBB2, HRAS, NRAS and MAP2K1. This pattern of mutational mutual exclusivity is consistent with the possibility
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 5
Evidence Type(s): Oncogenic
Summary: Evidence Type: Oncogenic | Mutation: p.R122L | Summary: The p.R122L mutation is suggested to function as an oncogene in the context of RAS/RTK pathway lung adenocarcinoma, indicating its potential role in tumor development or progression.
Gene→Variant (gene-first): 6016:p.R122L
Genes: 6016
Variants: p.R122L
Recurrent alteration of RIT1 alanine 77 was also observed; one of the ten mutated samples from this analysis harbored a p.A77P mutation and an additional TCGA sample (TCGA-73-4666) harbored a p.A77S mutation. TCGA-73-466
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 4
Evidence Type(s): Oncogenic, Predisposing
Summary: Evidence Type: Oncogenic | Mutation: p.A77P | Summary: The p.A77P mutation in RIT1 is associated with tumor development as it was observed in a recurrent alteration among mutated samples. Evidence Type: Predisposing | Mutation: p.A77S | Summary: The p.A77S mutation may represent a rare germline variant, suggesting a potential inherited risk for disease, although this is unlikely based on the absence in normal genome data.
Gene→Variant (gene-first): NA:alanine 77 6016:p.A77P 6016:p.A77S
Genes: NA 6016
Variants: alanine 77 p.A77P p.A77S
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 mut
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 3
Evidence Type(s): Oncogenic
Summary: Evidence Type: Oncogenic | Mutation: p.M90I | Summary: The p.M90I mutation in RIT1 is identified as a non-synonymous somatic mutation found in lung adenocarcinomas, suggesting its contribution to tumor development or progression.
Gene→Variant (gene-first): 6016:p.M90I
Genes: 6016
Variants: p.M90I
Oncogenic RIT1 mutations in lung adenocarcinoma
[Paper-level Aggregated] PMCID: PMC4150988
Evidence Type(s): Oncogenic, Functional, Predictive
Justification: Oncogenic: The text indicates that RIT1 mutations, particularly in the switch II domain, are associated with the ability to induce cellular transformation and tumor formation, suggesting their role as oncogenes in lung adenocarcinoma. Functional: The study demonstrates that mutated RIT1 can activate signaling pathways (MEK/ERK and PI3K/AKT) and induce cellular transformation, indicating a functional impact of these mutations on cellular behavior. Predictive: The presence of RIT1 mutations, particularly in the context of lung adenocarcinoma, may predict the activation of specific signaling pathways and the potential for tumor formation, as evidenced by the transformation assays conducted in the study.
Gene→Variant (gene-first): RIT1(6016):F82L RIT1(6016):M90I RIT1(6016):p.M90I KRAS(3845):G12V EGFR(1956):L858R RIT1(6016):Q40 RIT1(6016):Q40L RIT1(6016):Q79L NA:alanine 77 RIT1(6016):p.A77P RIT1(6016):p.A77S RIT1(6016):p.R122L
Genes: RIT1(6016) KRAS(3845) EGFR(1956) NA
Variants: F82L M90I p.M90I G12V L858R Q40 Q40L Q79L alanine 77 p.A77P p.A77S p.R122L
Given the prevalence of RIT1 mutation in primary human lung adenocarcinomas, we hypothesized that human lung adenocarcinoma cell lines may also harbor mutations in RIT1 and that identification of these cell lines would f
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 11
Evidence Type(s): Oncogenic, Diagnostic
Justification: Oncogenic: The passage discusses the presence of the p.M90I mutation in lung adenocarcinoma cell lines and its association with human primary lung adenocarcinomas, indicating that this somatic variant contributes to tumor development or progression. Diagnostic: The p.M90I mutation is mentioned as being seen in human primary lung adenocarcinomas, suggesting its role in defining or classifying the disease.
Gene→Variant (gene-first): 6016:p.M90I
Genes: 6016
Variants: p.M90I
RIT1 mutation is mutually exclusive with mutations in other RAS/RTK-pathway genes, so we hypothesized that RIT1 may activate PI3K and MEK. To investigate the signaling changes induced by mutated RIT1, we expressed wild-t
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 9
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses how the RIT1 Q40L mutation contributes to tumor development by activating MEK and ERK pathways, indicating its role in oncogenic signaling. Functional: The variant Q40L alters the molecular function of RIT1, as it induces phosphorylation of MEK and ERK, demonstrating a change in biochemical activity associated with the mutation.
Gene→Variant (gene-first): 6016:Q40L
Genes: 6016
Variants: Q40L
To test whether mutated RIT1 is capable of inducing cellular transformation, we expressed wild-type or mutated RIT1 cDNA constructs in NIH3T3 cells and assayed the ability of these cells to form colonies in soft agar. A
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 7
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses how mutated RIT1 variants, including Q79L, G12V, and L858R, induce cellular transformation and tumor formation, indicating their role in tumor development. Functional: The passage describes the ability of specific RIT1 mutations to induce colony formation in soft agar, suggesting that these variants alter the molecular function of RIT1 in a way that promotes transformation.
Gene→Variant (gene-first): 3845:G12V 1956:L858R 6016:Q40 6016:Q40L 6016:Q79L
Genes: 3845 1956 6016
Variants: G12V L858R Q40 Q40L Q79L
We surveyed recent exome sequencing data from other diverse cancer types to determine whether RIT1 is mutated in malignancies other than lung adenocarcinoma. Most tumor types had no mutations, or rare RIT1 variants of un
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 6
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the presence of the RIT1 p.M90I variant in different cancer types, indicating its association with malignancies, which supports its use in defining or classifying disease subtypes. Oncogenic: The mention of somatic RIT1 mutations in myeloid malignancies and their overlap with mutations in lung adenocarcinoma suggests that these variants contribute to tumor development or progression.
Gene→Variant (gene-first): 6016:F82L 6016:M90I 6016:p.M90I
Genes: 6016
Variants: F82L M90I p.M90I
All seven samples with switch II domain RIT1 mutations lacked oncogenic driver mutations in EGFR, KRAS, BRAF, ERBB2, HRAS, NRAS and MAP2K1. This pattern of mutational mutual exclusivity is consistent with the possibility
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 5
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage suggests that RIT1 switch II domain mutations, including p.R122L, may function as oncogenes in lung adenocarcinoma, indicating a role in tumor development or progression.
Gene→Variant (gene-first): 6016:p.R122L
Genes: 6016
Variants: p.R122L
Recurrent alteration of RIT1 alanine 77 was also observed; one of the ten mutated samples from this analysis harbored a p.A77P mutation and an additional TCGA sample (TCGA-73-4666) harbored a p.A77S mutation. TCGA-73-466
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 4
Evidence Type(s): Diagnostic, Predisposing
Justification: Diagnostic: The passage discusses the recurrent alteration of RIT1 alanine 77 and mentions that one of the mutated samples harbored a p.A77P mutation, indicating its association with tumor classification. Predisposing: The passage suggests that p.A77S may represent a rare germline variant, indicating a potential inherited risk for disease, although it is noted to be unlikely.
Gene→Variant (gene-first): NA:alanine 77 6016:p.A77P 6016:p.A77S
Genes: NA 6016
Variants: alanine 77 p.A77P p.A77S
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 mut
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 3
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage discusses non-synonymous somatic mutations of RIT1, including the p.M90I variant, in the context of lung adenocarcinomas, indicating that these mutations contribute to tumor development or progression.
Gene→Variant (gene-first): 6016:p.M90I
Genes: 6016
Variants: p.M90I
Given the prevalence of RIT1 mutation in primary human lung adenocarcinomas, we hypothesized that human lung adenocarcinoma cell lines may also harbor mutations in RIT1 and that identification of these cell lines would f
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 11
Evidence Type(s): Oncogenic, Diagnostic
Justification: Oncogenic: The passage discusses the presence of the p.M90I mutation in lung adenocarcinoma cell lines and its association with human primary lung adenocarcinomas, indicating that this somatic variant contributes to tumor development or progression. Diagnostic: The p.M90I mutation is mentioned as being seen in human primary lung adenocarcinomas, suggesting its role in defining or classifying the disease.
Gene→Variant (gene-first): 6016:p.M90I
Genes: 6016
Variants: p.M90I
RIT1 mutation is mutually exclusive with mutations in other RAS/RTK-pathway genes, so we hypothesized that RIT1 may activate PI3K and MEK. To investigate the signaling changes induced by mutated RIT1, we expressed wild-t
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 9
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses how the RIT1 Q40L mutation contributes to tumor development by activating MEK and ERK pathways, indicating its role in oncogenic signaling. Functional: The variant Q40L alters the molecular function of RIT1, as it induces phosphorylation of MEK and ERK, demonstrating a change in biochemical activity associated with the mutation.
Gene→Variant (gene-first): 6016:Q40L
Genes: 6016
Variants: Q40L
To test whether mutated RIT1 is capable of inducing cellular transformation, we expressed wild-type or mutated RIT1 cDNA constructs in NIH3T3 cells and assayed the ability of these cells to form colonies in soft agar. A
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 7
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses how mutated RIT1 variants, including Q79L, G12V, and L858R, induce cellular transformation and tumor formation, indicating their role in tumor development. Functional: The passage describes the ability of specific RIT1 mutations to induce colony formation in soft agar, suggesting that these variants alter the molecular function of RIT1 in a way that promotes transformation.
Gene→Variant (gene-first): 3845:G12V 1956:L858R 6016:Q40 6016:Q40L 6016:Q79L
Genes: 3845 1956 6016
Variants: G12V L858R Q40 Q40L Q79L
We surveyed recent exome sequencing data from other diverse cancer types to determine whether RIT1 is mutated in malignancies other than lung adenocarcinoma. Most tumor types had no mutations, or rare RIT1 variants of un
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 6
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the presence of the RIT1 p.M90I variant in different cancer types, indicating its association with malignancies, which supports its use in defining or classifying disease subtypes. Oncogenic: The mention of somatic RIT1 mutations in myeloid malignancies and their overlap with mutations in lung adenocarcinoma suggests that these variants contribute to tumor development or progression.
Gene→Variant (gene-first): 6016:F82L 6016:M90I 6016:p.M90I
Genes: 6016
Variants: F82L M90I p.M90I
All seven samples with switch II domain RIT1 mutations lacked oncogenic driver mutations in EGFR, KRAS, BRAF, ERBB2, HRAS, NRAS and MAP2K1. This pattern of mutational mutual exclusivity is consistent with the possibility
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 5
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage suggests that RIT1 switch II domain mutations, including p.R122L, may function as oncogenes in lung adenocarcinoma, indicating a role in tumor development or progression.
Gene→Variant (gene-first): 6016:p.R122L
Genes: 6016
Variants: p.R122L
Recurrent alteration of RIT1 alanine 77 was also observed; one of the ten mutated samples from this analysis harbored a p.A77P mutation and an additional TCGA sample (TCGA-73-4666) harbored a p.A77S mutation. TCGA-73-466
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 4
Evidence Type(s): Diagnostic, Predisposing
Justification: Diagnostic: The passage discusses the recurrent alteration of RIT1 alanine 77 and mentions that one of the mutated samples harbored a p.A77P mutation, indicating its association with tumor classification. Predisposing: The passage suggests that p.A77S may represent a rare germline variant, indicating a potential inherited risk for disease, although it is noted to be unlikely.
Gene→Variant (gene-first): NA:alanine 77 6016:p.A77P 6016:p.A77S
Genes: NA 6016
Variants: alanine 77 p.A77P p.A77S
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 mut
[Paragraph-level] PMCID: PMC4150988 Section: RESULTS PassageIndex: 3
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage discusses non-synonymous somatic mutations of RIT1, including the p.M90I variant, in the context of lung adenocarcinomas, indicating that these mutations contribute to tumor development or progression.
Gene→Variant (gene-first): 6016:p.M90I
Genes: 6016
Variants: p.M90I