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Ref Type Journal Article
PMID (27478040)
Authors Berger AH, Brooks AN, Wu X, Shrestha Y, Chouinard C, Piccioni F, Bagul M, Kamburov A, Imielinski M, Hogstrom L, Zhu C, Yang X, Pantel S, Sakai R, Watson J, Kaplan N, Campbell JD, Singh S, Root DE, Narayan R, Natoli T, Lahr DL, Tirosh I, Tamayo P, Getz G, Wong B, Doench J, Subramanian A, Golub TR, Meyerson M, Boehm JS
Title High-throughput Phenotyping of Lung Cancer Somatic Mutations.
URL
Abstract Text Recent genome sequencing efforts have identified millions of somatic mutations in cancer. However, the functional impact of most variants is poorly understood. Here we characterize 194 somatic mutations identified in primary lung adenocarcinomas. We present an expression-based variant-impact phenotyping (eVIP) method that uses gene expression changes to distinguish impactful from neutral somatic mutations. eVIP identified 69% of mutations analyzed as impactful and 31% as functionally neutral. A subset of the impactful mutations induces xenograft tumor formation in mice and/or confers resistance to cellular EGFR inhibition. Among these impactful variants are rare somatic, clinically actionable variants including EGFR S645C, ARAF S214C and S214F, ERBB2 S418T, and multiple BRAF variants, demonstrating that rare mutations can be functionally important in cancer.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
BRAF NCBI B-raf|B-RAF1|BRAF-1|BRAF1|NS7|RAFB1 BRAF, serine/threonine-protein kinase B-raf, is a member of the Raf family of serine/threonine protein kinases, which signals through the MAP kinase pathway to regulate cell proliferation and cell growth (PMID: 24737949, PMID: 29540830). BRAF mutations and fusions have been identified in a variety of cancers, including, colorectal (PMID: 30122982), lung (PMID: 29729495), thyroid (PMID: 12970315), and melanoma (PMID: 24737949), and a number of mutations have also been demonstrated to confer drug resistance (PMID: 27478040). Oncogene
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
BRAF A762E missense unknown BRAF A762E does not lie within any known functional domains of the Braf protein (UniProt.org). A762E has been demonstrated to confer secondary resistance to Egfr inhibitors in culture (PMID: 27478040), but has not been biochemically characterized and therefore, its effect on Braf protein function is unknown (PubMed, Jan 2024). Y
BRAF G469S missense gain of function BRAF G469S is a hotspot mutation within the protein kinase domain of the Braf protein (UniProt.org). G469S results in increased Erk phosphorylation (PMID: 27478040) and induces increased cell proliferation and cell viability compared to wild-type Braf in culture (PMID: 29533785).
BRAF H574N missense no effect - predicted BRAF H574N lies within the protein kinase domain of the Braf protein (UniProt.org). H574N results in Erk phosphorylation similar to wild-type Braf in culture (PMID: 27478040), and therefore, is predicted to have no effect on Braf protein function.
BRAF H574Q missense gain of function BRAF H574Q lies within the protein kinase domain of the Braf protein (UniProt.org). H574Q confers a gain of function to the Braf protein as indicated by increased Erk phosphorylation in culture and tumor formation in animal models, and confers resistance to Egfr inhibitors in culture (PMID: 27478040). Y
BRAF P367R missense gain of function BRAF P367R does not lie within any known functional domains within the Braf protein (UniProt.org). P367R confers a gain of function to the Braf protein as indicated by increased Erk phosphorylation in culture and tumor formation in animal models, and demonstrates resistance to Egfr inhibitors in culture (PMID: 27478040). Y
BRAF R682W missense unknown BRAF R682W lies within the protein kinase domain of the Braf protein (UniProt.org). R682W has been demonstrated to confer resistance to an EGFR inhibitor in the context of EGFR exon 19 deletions in cultured cells (PMID: 27478040), but has not been biochemically characterized and therefore, its effect on Braf protein function is unknown (PubMed, Nov 2023). Y
IDH2 K130del deletion unknown IDH2 K130del results in the deletion of an amino acid of the Idh2 protein at amino acid 130 (UniProt.org). K130del is not associated with induction of tumor formation in mice (PMID: 27478040), but has not been fully biochemically characterized and therefore, its effect on Idh2 protein function is unknown.
KEAP1 D389Y missense loss of function - predicted KEAP1 D389Y lies within Kelch repeat 2 of the Keap1 protein (UniProt.org). D389Y is predicted to lead to a loss of Keap1 protein function as indicated by partial inhibition of Nfe2l2 (Nrf2) target gene expression in cell lines in culture (PMID: 27478040).
KEAP1 D479G missense loss of function KEAP1 D479G lies within Kelch repeat 4 of the Keap1 protein (UniProt.org). D479G confers a loss of function to the Keap1 protein as demonstrated by impaired binding and ubiquitination of Ikk-beta and Nrf2, leading to increased NF-kappaB signaling in cultured cells (PMID: 19818716), and partial inhibition of Nfe2l2 (Nrf2) target gene expression in cell lines in culture (PMID: 27478040).
KEAP1 E117K missense loss of function KEAP1 E117K lies within the BTB domain of the Keap1 protein (UniProt.org). E117K results in a loss of Keap1 protein function as indicated by failure to inhibit Nfe2l2 (Nrf2) target gene expression in cell lines in culture (PMID: 27478040).
KEAP1 E611D missense loss of function - predicted KEAP1 E611D lies within Kelch repeat 6 of the Keap1 protein (UniProt.org). E611D inhibits Nfe2l2 (Nrf2) target gene expression to similar levels of wild-type Keap1 in culture (PMID: 27478040), but fails to bind and destabilize Sox9 in cultured cells (PMID: 33173725), and therefore, is predicted to lead to a loss of Keap1 protein function.
KEAP1 G333C missense loss of function KEAP1 G333C lies within Kelch repeat 1 of the Keap1 protein (UniProt.org). G333C confers a loss of function to the Keap1 protein as demonstrated by loss of Nfe2l2 inhibition and increased transcription of Nfe2l2 target genes (PMID: 24322982, PMID: 27478040), and failure to bind and ubiquitinate Ikk-beta in cultured cells (PMID: 19818716).
KEAP1 G417R missense loss of function KEAP1 G417R lies within Kelch repeat 2 of the Keap1 protein (UniProt.org). G417R results in a loss of Keap1 protein function as indicated by failure to inhibit Nfe2l2 (Nrf2) target gene expression in cell lines in culture (PMID: 27478040).
KEAP1 G419W missense loss of function KEAP1 G419W lies within Kelch repeat 2 of the Keap1 protein (UniProt.org). G419W results in a loss of Keap1 protein function as indicated by failure to inhibit Nfe2l2 (Nrf2) target gene expression in cell lines in culture (PMID: 27478040).
KEAP1 G524C missense loss of function KEAP1 G524C lies within Kelch repeat 5 of the Keap1 protein (UniProt.org). G524C results in a loss of Keap1 protein function as indicated by failure to inhibit Nfe2l2 (Nrf2) target gene expression in cell lines in culture (PMID: 27478040).
KEAP1 G603W missense loss of function KEAP1 G603W lies within Kelch repeat 6 of the Keap1 protein (UniProt.org). G603W results in a loss of Keap1 protein function as indicated by failure to inhibit Nfe2l2 (Nrf2) target gene expression in cell lines in culture (PMID: 27478040), and failure to bind and destabilize Sox9 in cultured cells (PMID: 33173725).
KEAP1 L268P missense loss of function - predicted KEAP1 L268P lies within the BACK domain of the Keap1 protein (UniProt.org). L268P is predicted to lead to a loss of Keap1 protein function as indicated by partial inhibition of Nfe2l2 (Nrf2) target gene expression in cell lines in culture (PMID: 27478040).
KEAP1 P278S missense loss of function KEAP1 P278S lies within the BACK domain of the Keap1 protein (UniProt.org). P278S results in a loss of Keap1 protein function as indicated by failure to inhibit Nfe2l2 (Nrf2) target gene expression in cell lines in culture (PMID: 27478040).
KEAP1 R204P missense loss of function KEAP1 R204P lies within the BACK domain of the Keap1 protein (UniProt.org). R204P confers a loss of function to the Keap1 protein as indicated by partial inhibition of Nfe2l2 (Nrf2) target gene expression in culture (PMID: 27478040), and failure to bind and destabilize Sox9 in cultured cells (PMID: 33173725).
KEAP1 R470H missense loss of function KEAP1 R470H lies within Kelch repeat 3 of the Keap1 protein (UniProt.org). R470H results in a loss of Keap1 protein function as indicated by failure to inhibit Nfe2l2 (Nrf2) target gene expression in cell lines in culture (PMID: 30150714, PMID: 27478040).
KEAP1 R470S missense loss of function KEAP1 R470S lies within Kelch repeat 3 of the Keap1 protein (UniProt.org). R470S results in a loss of Keap1 protein function as indicated by failure to inhibit Nfe2l2 (Nrf2) target gene expression in cell lines in culture (PMID: 30150714, PMID: 27478040).
KEAP1 R601W missense loss of function KEAP1 R601W lies within Kelch repeat 6 of the Keap1 protein (UniProt.org). R601W results in a loss of Keap1 protein function as indicated by failure to inhibit Nfe2l2 (Nrf2) target gene expression in cell lines in culture (PMID: 27478040).
KEAP1 S102L missense loss of function - predicted KEAP1 S102L lies within the BTB domain of the Keap1 protein (UniProt.org). S102L is predicted to lead to a loss of Keap1 protein function as indicated by partial inhibition of Nfe2l2 (Nrf2) target gene expression in cell lines in culture (PMID: 27478040).
KEAP1 S144F missense no effect - predicted KEAP1 S144F lies within the BTB domain of the Keap1 protein (UniProt.org). S144F inhibits Nfe2l2 (Nrf2) target gene transcription to similar levels of wild-type Keap1 in culture (PMID: 27478040), and therefore, is predicted to have no effect on Keap1 protein function.
KEAP1 T142M missense loss of function - predicted KEAP1 T142M lies within the BTB domain of the Keap1 protein (UniProt.org). T142M is predicted to lead to a loss of Keap1 protein function as indicated by partial inhibition of Nfe2l2 (Nrf2) target gene expression in cell lines in culture (PMID: 27478040).
KEAP1 W497L missense loss of function KEAP1 W497L lies within Kelch repeat 4 of the Keap1 protein (UniProt.org). W497L results in a loss of Keap1 protein function as indicated by failure to inhibit Nfe2l2 (Nrf2) target gene expression in cell lines (PMID: 27478040), and failure to bind and destabilize Sox9 in cultured cells (PMID: 33173725).
RB1 Y756C missense unknown RB1 Y756C lies within domain B of the Rb1 protein (UniProt.org). Y756C has been identified in sequencing studies (PMID: 27478040), but has not been biochemically characterized and therefore, its effect on Rb1 protein function is unknown (PubMed, Nov 2023).
STK11 G251F missense unknown STK11 G251F lies within the protein kinase domain of the Stk11 protein (UniProt.org). G251F has been identified in sequencing studies (PMID: 27478040), but has not been biochemically characterized and therefore, its effect on Stk11 protein function is unknown (PubMed, Oct 2023).
STK11 G251V missense unknown STK11 G251V lies within the protein kinase domain of the Stk11 protein (UniProt.org). G251V has been identified in sequencing studies (PMID: 27478040, PMID: 29066508), but has not been biochemically characterized and therefore, its effect on Stk11 protein function is unknown (PubMed, Oct 2023).
STK11 G56V missense unknown STK11 G56V lies within the protein kinase domain of the Stk11 protein (UniProt.org). G56V has been identified in sequencing studies (PMID: 27478040, PMID: 34922300), but has not been biochemically characterized and therefore, its effect on Stk11 protein function is unknown (PubMed, Oct 2023).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References