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Identification and clinical impact of potentially actionable somatic oncogenic mutations in solid tumor samples.

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posted on 26.08.2020 by Sinead Toomey, Aoife Carr, Mateusz Janusz Mezynski, Yasir Elamin, Shereen Rafee, Mattia Cremona, Clare Morgan, Stephen Madden, Khairun Izlinda Abdul Jalil, Kathy Gately, Angela Farrelly, Elaine Kay, Susan Kennedy, Kenneth O’Byrne, Liam Grogan, Oscar Breathnach, Patrick G Morris, Alexander J Eustace, Joanna Fay, Robert Cummins, Anthony O'Grady, Roshni Kalachand, Norma O'Donovan, Fergal Kelleher, Aine O’Reilly, Mark Doherty, John Crown, Bryan Hennessy

Background: An increasing number of anti-cancer therapeutic agents target specific mutant proteins that are expressed by many different tumor types. Successful use of these therapies is dependent on the presence or absence of somatic mutations within the patient's tumor that can confer clinical efficacy or drug resistance.

Methods: The aim of our study was to determine the type, frequency, overlap and functional proteomic effects of potentially targetable recurrent somatic hotspot mutations in 47 cancer-related genes in multiple disease sites that could be potential therapeutic targets using currently available agents or agents in clinical development.

Results: Using MassArray technology, of the 1300 patient tumors analysed 571 (43.9%) had at least one somatic mutation. Mutations were identified in 30 different genes. KRAS (16.5%), PIK3CA (13.6%) and BRAF (3.8%) were the most frequently mutated genes. Prostate (10.8%) had the lowest number of somatic mutations identified, while no mutations were identified in sarcoma. Ocular melanoma (90.6%), endometrial (72.4%) and colorectal (66.4%) tumors had the highest number of mutations. We noted high concordance between mutations in different parts of the tumor (94%) and matched primary and metastatic samples (90%). KRAS and BRAF mutations were mutually exclusive. Mutation co-occurrence involved mainly PIK3CA and PTPN11, and PTPN11 and APC. Reverse Phase Protein Array (RPPA) analysis demonstrated that PI3K and MAPK signalling pathways were more altered in tumors with mutations compared to wild type tumors.

Conclusions: Hotspot mutational profiling is a sensitive, high-throughput approach for identifying mutations of clinical relevance to molecular based therapeutics for treatment of cancer, and could potentially be of use in identifying novel opportunities for genotype-driven clinical trials.

Funding

Science Foundation Ireland-funded Molecular Therapeutics for Cancer Ireland (08-SRC-B1410)

Health Research Board (HPA/POR2012/054)

North East Cancer Research and Education Trust (NECRET)

Fox family

Kerins family

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The original article is available at www.biomedcentral.com

Published Citation

Toomey S, Carr A, Mezynski MJ, Elamin Y, Rafee S, Cremona M, Morgan C, Madden S, Abdul-Jalil KI, Gately K, Farrelly A, Kay EW, Kennedy S, O'Byrne K, Grogan L, Breathnach O, Morris PG, Eustace A, Fay J, Cummins R, O'Grady A, Kalachand R, O'Donovan N, Kelleher F, O'Reilly A, Doherty M, Crown J, Hennessy BT. Identification and clinical impact of potentially actionable somatic oncogenic mutations in solid tumor samples. Journal of Translational Medicine. 2020;18:99

Publication Date

2020

PubMed ID

32087721

Department/Unit

  • Molecular Medicine
  • Pathology
  • Data Science Centre
  • Beaumont Hospital

Publisher

BioMed Central

Version

  • Published Version (Version of Record)

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