Please use this identifier to cite or link to this item: https://doi.org/10.1158/0008-5472.CAN-10-1749
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dc.titleGenetic and structural variation in the gastric cancer kinome revealed through targeted deep sequencing
dc.contributor.authorZang, Z.J.
dc.contributor.authorOng, C.K.
dc.contributor.authorCutcutache, I.
dc.contributor.authorYu, W.
dc.contributor.authorZhang, S.L.
dc.contributor.authorHuang, D.
dc.contributor.authorLer, L.D.
dc.contributor.authorDykema, K.
dc.contributor.authorGan, A.
dc.contributor.authorTao, J.
dc.contributor.authorLim, S.
dc.contributor.authorLiu, Y.
dc.contributor.authorFutreal, P.A.
dc.contributor.authorGrabsch, H.
dc.contributor.authorFurge, K.A.
dc.contributor.authorGoh, L.K.
dc.contributor.authorRozen, S.
dc.contributor.authorTeh, B.T.
dc.contributor.authorTan, P.
dc.date.accessioned2013-07-23T09:23:51Z
dc.date.available2013-07-23T09:23:51Z
dc.date.issued2011
dc.identifier.citationZang, Z.J., Ong, C.K., Cutcutache, I., Yu, W., Zhang, S.L., Huang, D., Ler, L.D., Dykema, K., Gan, A., Tao, J., Lim, S., Liu, Y., Futreal, P.A., Grabsch, H., Furge, K.A., Goh, L.K., Rozen, S., Teh, B.T., Tan, P. (2011). Genetic and structural variation in the gastric cancer kinome revealed through targeted deep sequencing. Cancer Research 71 (1) : 29-39. ScholarBank@NUS Repository. https://doi.org/10.1158/0008-5472.CAN-10-1749
dc.identifier.issn00085472
dc.identifier.urihttp://scholarbank.nus.edu.sg/handle/10635/43059
dc.description.abstractGenetic alterations in kinases have been linked to multiple human pathologies. To explore the landscape of kinase genetic variation in gastric cancer (GC), we used targeted, paired-end deep sequencing to analyze 532 protein and phosphoinositide kinases in 14 GC cell lines. We identified 10,604 single-nucleotide variants (SNV) in kinase exons including greater than 300 novel nonsynonymous SNVs. Family-wise analysis of the nonsynonymous SNVs revealed a significant enrichment in mitogen-activated protein kinase (MAPK)-related genes (P < 0.01), suggesting a preferential involvement of this kinase family in GC. A potential antioncogenic role for MAP2K4, a gene exhibiting recurrent alterations in 2 lines, was functionally supported by siRNA knockdown and overexpression studies in wild-type and MAP2K4 variant lines. The deep sequencing data also revealed novel, large-scale structural rearrangement events involving kinases including gene fusions involving CDK12 and the ERBB2 receptor tyrosine kinase in MKN7 cells. Integrating SNVs and copy number alterations, we identified Hs746T as a cell line exhibiting both splice-site mutations and genomic amplification of MET, resulting in MET protein overexpression. When applied to primary GCs, we identified somatic mutations in 8 kinases, 4 of which were recurrently altered in both primary tumors and cell lines (MAP3K6, STK31, FER, and CDKL5). These results demonstrate that how targeted deep sequencing approaches can deliver unprecedented multilevel characterization of a medically and pharmacologically relevant gene family. The catalog of kinome genetic variants assembled here may broaden our knowledge on kinases and provide useful information on genetic alterations in GC. ©2010 AACR.
dc.description.urihttp://libproxy1.nus.edu.sg/login?url=http://dx.doi.org/10.1158/0008-5472.CAN-10-1749
dc.sourceScopus
dc.typeArticle
dc.contributor.departmentDUKE-NUS GRADUATE MEDICAL SCHOOL S'PORE
dc.contributor.departmentCOMPUTER SCIENCE
dc.description.doi10.1158/0008-5472.CAN-10-1749
dc.description.sourcetitleCancer Research
dc.description.volume71
dc.description.issue1
dc.description.page29-39
dc.description.codenCNREA
dc.identifier.isiut000285826800005
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