Reference Detail

Ref Type

Journal Article

PMID

(35739269)

Authors

Church AJ, Corson LB, Kao PC, Imamovic-Tuco A, Reidy D, Doan D, Kang W, Pinto N, Maese L, Laetsch TW, Kim A, Colace SI, Macy ME, Applebaum MA, Bagatell R, Sabnis AJ, Weiser DA, Glade-Bender JL, Homans AC, Hipps J, Harris H, Manning D, Al-Ibraheemi A, Li Y, Gupta H, Cherniack AD, Lo YC, Strand GR, Lee LA, Pinches RS, Lazo De La Vega L, Harden MV, Lennon NJ, Choi S, Comeau H, Harris MH, Forrest SJ, Clinton CM, Crompton BD, Kamihara J, MacConaill LE, Volchenboum SL, Lindeman NI, Van Allen E, DuBois SG, London WB, Janeway KA

Title

Molecular profiling identifies targeted therapy opportunities in pediatric solid cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Nature medicine			2022 Jun 23	1581-1589	Nat Med

URL

Abstract Text

To evaluate the clinical impact of molecular tumor profiling (MTP) with targeted sequencing panel tests, pediatric patients with extracranial solid tumors were enrolled in a prospective observational cohort study at 12 institutions. In the 345-patient analytical population, median age at diagnosis was 12 years (range 0-27.5); 298 patients (86%) had 1 or more alterations with potential for impact on care. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 61, 16 and 65% of patients, respectively. After return of the results, impact on care included 17 patients with a clarified diagnostic classification and 240 patients with an MTP result that could be used to select molecularly targeted therapy matched to identified alterations (MTT). Of the 29 patients who received MTT, 24% had an objective response or experienced durable clinical benefit; all but 1 of these patients received targeted therapy matched to a gene fusion. Of the diagnostic variants identified in 209 patients, 77% were gene fusions. MTP with targeted panel tests that includes fusion detection has a substantial clinical impact for young patients with solid tumors.

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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
MSH6	A1320Sfs*5	frameshift	unknown	MSH6 A1320Sfs5 indicates a shift in the reading frame starting at amino acid 1320 and terminating 5 residues downstream causing a premature truncation of the 1360 amino acid Msh6 protein (UniProt.org). A1320Sfs5 has been identified in the scientific literature (PMID: 35739269, PMID: 33393477, PMID: 18809606), but has not been biochemically characterized and therefore, its effect on Msh6 protein function is unknown (PubMed, May 2024).
MSH6	Y1256*	nonsense	unknown	MSH6 Y1256* results in a premature truncation of the Msh6 protein at amino acid 1256 of 1360 (UniProt.org). Y1256* has been identified in the scientific literature (PMID: 35739269, PMID: 33393477, PMID: 26552419), but has not been biochemically characterized and therefore, its effect on Msh6 protein function is unknown (PubMed, May 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
MSH6 F1088Lfs5 MSH6 Y1256 MSH6 A1320Sfs*5	colorectal carcinoma	predicted - sensitive	Nivolumab	Case Reports/Case Series	Actionable	In a clinical case study, Opdivo (nivolumab) treatment resulted in stable disease lasting four months in a colorectal carcinoma patient harboring MSH6 F1088Lfs5, Y1256, and A1320Sfs*5 (PMID: 35739269).	35739269