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|Ref Type||Journal Article|
|Authors||Chang MT, Bhattarai TS, Schram AM, Bielski CM, Donoghue MTA, Jonsson P, Chakravarty D, Phillips S, Kandoth C, Penson A, Gorelick A, Shamu T, Patel S, Harris C, Gao J, Sumer SO, Kundra R, Razavi P, Li BT, Reales DN, Socci ND, Jayakumaran G, Zehir A, Benayed R, Arcila ME, Chandarlapaty S, Ladanyi M, Schultz N, Baselga J, Berger MF, Rosen N, Solit DB, Hyman DM, Taylor BS|
|Title||Accelerating Discovery of Functional Mutant Alleles in Cancer.|
|Abstract Text||Most mutations in cancer are rare, which complicates the identification of therapeutically significant mutations and thus limits the clinical impact of genomic profiling in patients with cancer. Here, we analyzed 24,592 cancers including 10,336 prospectively sequenced patients with advanced disease to identify mutant residues arising more frequently than expected in the absence of selection. We identified 1,165 statistically significant hotspot mutations of which 80% arose in 1 in 1,000 or fewer patients. Of 55 recurrent in-frame indels, we validated that novel AKT1 duplications induced pathway hyperactivation and conferred AKT inhibitor sensitivity. Cancer genes exhibit different rates of hotspot discovery with increasing sample size, with few approaching saturation. Consequently, 26% of all hotspots in therapeutically actionable oncogenes were novel. Upon matching a subset of affected patients directly to molecularly targeted therapy, we observed radiographic and clinical responses. Population-scale mutant allele discovery illustrates how the identification of driver mutations in cancer is far from complete.Significance: Our systematic computational, experimental, and clinical analysis of hotspot mutations in approximately 25,000 human cancers demonstrates that the long right tail of biologically and therapeutically significant mutant alleles is still incompletely characterized. Sharing prospective genomic data will accelerate hotspot identification, thereby expanding the reach of precision oncology in patients with cancer. Cancer Discov; 8(2); 174-83. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 127.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|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|
|AKT1||P68_C77dup||duplication||gain of function - predicted||AKT1 P68_C77dup indicates the insertion of 10 duplicate amino acids, proline (P)-68 through cysteine (C)-77 in the PH domain of the Akt1 protein (UniProt.org). P68_C77dup is predicted to confer a gain of function on the Akt1 protein as demonstrated by increased phosphorylation of Akt1 and downstream phosphorylation of S6 and PRAS40 in cell culture (PMID: 29247016).|
|BRAF||N486_A489delinsK||indel||unknown||BRAF N486_A489delinsK results in a deletion of 4 amino acids in the protein kinase domain of the Braf protein from amino acids 486 to 489, combined with the insertion of a lysine (K) at the same site (UniProt.org). N486_A489delinsK has been identified in sequencing studies (PMID: 29247016), but has not been biochemically characterized and therefore, its effect on Braf protein function is unknown (PubMed, Mar 2020).|
|ERBB2||V697L||missense||unknown||ERBB2 (HER2) V697L lies within the juxtamembrane domain of the Erbb2 (Her2) protein (PMID: 30449325). V697L has been identified in the scientific literature (PMID: 29247016, PMID: 28679771), but has not been biochemically characterized and therefore, its effect on Erbb2 (Her2) protein function is unknown (PubMed, Apr 2020).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|ERBB2 V697L||triple-receptor negative breast cancer||sensitive||Neratinib||Phase II||Actionable||In a Phase II trial, a triple-negative breast cancer patient harboring ERBB2 V697L demonstrated a response to treatment with Nerlynx (neratinib) (PMID: 29247016).||29247016|
|ERBB2 V697L||Advanced Solid Tumor||predicted - sensitive||Neratinib||Case Reports/Case Series||Actionable||In a Phase II trial, a patient with cancer of unknown primary involving the head and neck that harbored ERBB2 (HER2) V697L demonstrated a response to treatment with Nerlynx (neratinib) that lasted 13 months (PMID: 29247016).||29247016|
|AKT1 P68_C77dup||breast cancer||sensitive||Capivasertib||Preclinical - Cell culture||Actionable||In a preclinical study, breast epithelial cells expressing AKT1 P68_C77dup demonstrated sensitivity by AZD5363 in culture, resulting in decreased cell survival (PMID: 29247016).||29247016|
|BRAF L485W||gallbladder cancer||sensitive||Ulixertinib||Phase I||Actionable||In a Phase I trial, treatment with BVD-523 (Ulixertinib) resulted in a complete response lasting almost 1 year in a gallbladder cancer patient harboring BRAF L485W (PMID: 29247016, PMID: 29247021).||29247021 29247016|