Novel Somatic Mutations to PI3K Pathway Genes in Metastatic Melanoma

Hdl Handle:
http://hdl.handle.net/10675.2/820
Title:
Novel Somatic Mutations to PI3K Pathway Genes in Metastatic Melanoma
Authors:
Shull, Austin Y.; Latham-Schwark, Alicia; Ramasamy, Poornema; Leskoske, Kristin; Oroian, Dora; Birtwistle, Marc R.; Buckhaults, Phillip J.
Abstract:
Background: BRAFV600 inhibitors have offered a new gateway for better treatment of metastatic melanoma. However, the overall efficacy of BRAFV600 inhibitors has been lower than expected in clinical trials, and many patients have shown resistance to the drugâ s effect. We hypothesized that somatic mutations in the Phosphoinositide 3-Kinase (PI3K) pathway, which promotes proliferation and survival, may coincide with BRAFV600 mutations and contribute to chemotherapeutic resistance.; Methods: We performed a somatic mutation profiling study using the 454 FLX pyrosequencing platform in order to identify candidate cancer genes within the MAPK and PI3K pathways of melanoma patients. Somatic mutations of theses candidate cancer genes were then confirmed using Sanger sequencing.; Results: As expected, BRAFV600 mutations were seen in 51% of the melanomas, whereas NRAS mutations were seen in 19% of the melanomas. However, PI3K pathway mutations, though more heterogeneous, were present in 41% of the melanoma, with PTEN being the highest mutated PI3K gene in melanomas (22%). Interestingly, several novel PI3K pathway mutations were discovered in MTOR, IRS4, PIK3R1, PIK3R4, PIK3R5, and NFKB1. PI3K pathway mutations co-occurred with BRAFV600 mutations in 17% of the tumors and co-occurred with 9% of NRAS mutant tumors, implying cooperativity between these pathways in terms of melanoma progression.; Conclusions: These novel PI3K pathway somatic mutations could provide alternative survival and proliferative pathways for metastatic melanoma cells. They therefore may be potential chemotherapeutic targets for melanoma patients who exhibit resistance to BRAFV600 inhibitors.
Citation:
PLoS One. 2012 Aug 17; 7(8):e43369
Issue Date:
17-Aug-2012
URI:
http://hdl.handle.net/10675.2/820
DOI:
10.1371/journal.pone.0043369
PubMed ID:
22912864
PubMed Central ID:
PMC3422312
Type:
Article
ISSN:
1932-6203
Appears in Collections:
Georgia Cancer Center: Faculty Research and Presentations

Full metadata record

DC FieldValue Language
dc.contributor.authorShull, Austin Y.en_US
dc.contributor.authorLatham-Schwark, Aliciaen_US
dc.contributor.authorRamasamy, Poornemaen_US
dc.contributor.authorLeskoske, Kristinen_US
dc.contributor.authorOroian, Doraen_US
dc.contributor.authorBirtwistle, Marc R.en_US
dc.contributor.authorBuckhaults, Phillip J.en_US
dc.date.accessioned2012-10-26T20:35:11Z-
dc.date.available2012-10-26T20:35:11Z-
dc.date.issued2012-08-17en_US
dc.identifier.citationPLoS One. 2012 Aug 17; 7(8):e43369en_US
dc.identifier.issn1932-6203en_US
dc.identifier.pmid22912864en_US
dc.identifier.doi10.1371/journal.pone.0043369en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/820-
dc.description.abstractBackground: BRAFV600 inhibitors have offered a new gateway for better treatment of metastatic melanoma. However, the overall efficacy of BRAFV600 inhibitors has been lower than expected in clinical trials, and many patients have shown resistance to the drugâ s effect. We hypothesized that somatic mutations in the Phosphoinositide 3-Kinase (PI3K) pathway, which promotes proliferation and survival, may coincide with BRAFV600 mutations and contribute to chemotherapeutic resistance.en_US
dc.description.abstractMethods: We performed a somatic mutation profiling study using the 454 FLX pyrosequencing platform in order to identify candidate cancer genes within the MAPK and PI3K pathways of melanoma patients. Somatic mutations of theses candidate cancer genes were then confirmed using Sanger sequencing.en_US
dc.description.abstractResults: As expected, BRAFV600 mutations were seen in 51% of the melanomas, whereas NRAS mutations were seen in 19% of the melanomas. However, PI3K pathway mutations, though more heterogeneous, were present in 41% of the melanoma, with PTEN being the highest mutated PI3K gene in melanomas (22%). Interestingly, several novel PI3K pathway mutations were discovered in MTOR, IRS4, PIK3R1, PIK3R4, PIK3R5, and NFKB1. PI3K pathway mutations co-occurred with BRAFV600 mutations in 17% of the tumors and co-occurred with 9% of NRAS mutant tumors, implying cooperativity between these pathways in terms of melanoma progression.en_US
dc.description.abstractConclusions: These novel PI3K pathway somatic mutations could provide alternative survival and proliferative pathways for metastatic melanoma cells. They therefore may be potential chemotherapeutic targets for melanoma patients who exhibit resistance to BRAFV600 inhibitors.en_US
dc.subjectResearch Articleen_US
dc.subjectBiologyen_US
dc.subjectGeneticsen_US
dc.subjectCancer Geneticsen_US
dc.subjectGenetic Mutationen_US
dc.subjectGenomicsen_US
dc.subjectGenome Sequencingen_US
dc.subjectMolecular Cell Biologyen_US
dc.subjectSignal Transductionen_US
dc.subjectMechanisms of Signal Transductionen_US
dc.subjectFeedback Regulationen_US
dc.subjectSignaling Cascadesen_US
dc.subjectMAPK signaling cascadesen_US
dc.subjectPolyphosphoinositide Signaling Cascadeen_US
dc.subjectSignaling in Cellular Processesen_US
dc.subjectMitogenic Signalingen_US
dc.subjectRas Signalingen_US
dc.subjectSignaling in Selected Disciplinesen_US
dc.subjectOncogenic Signalingen_US
dc.subjectMedicineen_US
dc.subjectClinical Geneticsen_US
dc.subjectPersonalized Medicineen_US
dc.subjectDermatologyen_US
dc.subjectSkin Neoplasmsen_US
dc.subjectMalignant Skin Neoplasmsen_US
dc.subjectMelanomasen_US
dc.subjectOncologyen_US
dc.subjectBasic Cancer Researchen_US
dc.titleNovel Somatic Mutations to PI3K Pathway Genes in Metastatic Melanomaen_US
dc.typeArticleen_US
dc.identifier.pmcidPMC3422312en_US
dc.contributor.corporatenameGHSU Cancer Center-

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