Reference Detail

Ref Type

Journal Article

PMID

(29247016)

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	8	2	2018 02	174-183	Cancer Discov

URL

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.

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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
BRAF	N486_A489delinsK	indel	unknown	BRAF N486_A489delinsK results in a deletion of four 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, Dec 2023).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF L485W	gallbladder cancer	sensitive	Ulixertinib	Case Reports/Case Series	Actionable	In a Phase I trial, treatment with Ulixertinib (BVD-523) resulted in a complete response lasting almost 1 year in a gallbladder cancer patient harboring BRAF L485W (PMID: 29247016, PMID: 29247021; (PMID: 29247021; NCT01781429).).	29247021 29247016