Dataset Information

Synthetic Lethal and Convergent Biological Effects of Cancer-Associated Spliceosomal Gene Mutations.

ABSTRACT: Mutations affecting RNA splicing factors are the most common genetic alterations in myelodysplastic syndrome (MDS) patients and occur in a mutually exclusive manner. The basis for the mutual exclusivity of these mutations and how they contribute to MDS is not well understood. Here we report that although different spliceosome gene mutations impart distinct effects on splicing, they are negatively selected for when co-expressed due to aberrant splicing and downregulation of regulators of hematopoietic stem cell survival and quiescence. In addition to this synthetic lethal interaction, mutations in the splicing factors SF3B1 and SRSF2 share convergent effects on aberrant splicing of mRNAs that promote nuclear factor ?B signaling. These data identify shared consequences of splicing-factor mutations and the basis for their mutual exclusivity.

SUBMITTER: Lee SC

PROVIDER: S-EPMC6373472 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Publications

Synthetic Lethal and Convergent Biological Effects of Cancer-Associated Spliceosomal Gene Mutations.

Lee Stanley Chun-Wei SC North Khrystyna K Kim Eunhee E Jang Eunjung E Obeng Esther E Lu Sydney X SX Liu Bo B Inoue Daichi D Yoshimi Akihide A Ki Michelle M Yeo Mirae M Zhang Xiao Jing XJ Kim Min Kyung MK Cho Hana H Chung Young Rock YR Taylor Justin J Durham Benjamin H BH Kim Young Joon YJ Pastore Alessandro A Monette Sebastien S Palacino James J Seiler Michael M Buonamici Silvia S Smith Peter G PG Ebert Benjamin L BL Bradley Robert K RK Abdel-Wahab Omar O

Cancer cell 20180801 2

Mutations affecting RNA splicing factors are the most common genetic alterations in myelodysplastic syndrome (MDS) patients and occur in a mutually exclusive manner. The basis for the mutual exclusivity of these mutations and how they contribute to MDS is not well understood. Here we report that although different spliceosome gene mutations impart distinct effects on splicing, they are negatively selected for when co-expressed due to aberrant splicing and downregulation of regulators of hematopo ...[more]

PMID: 30107174

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Project description:The mutation status of cancer driver genes may correlate with different degrees of malignancy of cancers. The doubling time and multidrug resistance are 2 phenotypes that reflect the degree of malignancy of cancer cells. Because most of cancer driver genes are hard to target, identification of their synthetic lethal partners might be a viable approach to treatment of the cancers with the relevant mutations.The genome-wide screening for synthetic lethal partners is costly and labor intensive. Thus, a computational approach facilitating identification of candidate genes for a focus synthetic lethal RNAi screening will accelerate novel anticancer drug discovery.We used several publicly available cancer cell lines and tumor tissue genomic data in this study.We compared the doubling time and multidrug resistance between the NCI-60 cell lines with mutations in some cancer driver genes and those without the mutations. We identified some candidate synthetic lethal genes to the cancer driver genes APC, KRAS, BRAF, PIK3CA, and TP53 by comparison of their gene phenotype values in cancer cell lines with the relevant mutations and wild-type background. Further, we experimentally validated some of the synthetic lethal relationships we predicted.We reported that mutations in some cancer driver genes mutations in some cancer driver genes such as APC, KRAS, or PIK3CA might correlate with cancer proliferation or drug resistance. We identified 40, 21, 5, 43, and 18 potential synthetic lethal genes to APC, KRAS, BRAF, PIK3CA, and TP53, respectively. We found that some of the potential synthetic lethal genes show significantly higher expression in the cancers with mutations of their synthetic lethal partners and the wild-type counterparts. Further, our experiments confirmed several synthetic lethal relationships that are novel findings by our methods.We experimentally validated a part of the synthetic lethal relationships we predicted. We plan to perform further experiments to validate the other synthetic lethal relationships predicted by this study.Our computational methods achieve to identify candidate synthetic lethal partners to cancer driver genes for further experimental screening with multiple lines of evidences, and therefore contribute to development of anticancer drugs.

Dataset Information

Synthetic Lethal and Convergent Biological Effects of Cancer-Associated Spliceosomal Gene Mutations.

Publications

Synthetic Lethal and Convergent Biological Effects of Cancer-Associated Spliceosomal Gene Mutations.

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