Pietro Pinoli1, Sriganesh Srihari2, Limsoon Wong3, Stefano Ceri4. 1. Department of Electronic, Information and Bioengineering, Politecnico di Milano, Piazza Leonardo da Vinci 32, Milan, Italy. pietro.pinoli@polimi.it. 2. Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia. 3. School of Computing, National University of Singapore, Computing Drive 13, Singapore, Singapore. 4. Department of Electronic, Information and Bioengineering, Politecnico di Milano, Piazza Leonardo da Vinci 32, Milan, Italy.
Abstract
BACKGROUND: A pair of genes is defined as synthetically lethal if defects on both cause the death of the cell but a defect in only one of the two is compatible with cell viability. Ideally, if A and B are two synthetic lethal genes, inhibiting B should kill cancer cells with a defect on A, and should have no effects on normal cells. Thus, synthetic lethality can be exploited for highly selective cancer therapies, which need to exploit differences between normal and cancer cells. RESULTS: In this paper, we present a new method for predicting synthetic lethal (SL) gene pairs. As neighbouring genes in the genome have highly correlated profiles of copy number variations (CNAs), our method clusters proximal genes with a similar CNA profile, then predicts mutually exclusive group pairs, and finally identifies the SL gene pairs within each group pairs. For mutual-exclusion testing we use a graph-based method which takes into account the mutation frequencies of different subjects and genes. We use two different methods for selecting the pair of SL genes; the first is based on the gene essentiality measured in various conditions by means of the "Gene Activity Ranking Profile" GARP score; the second leverages the annotations of gene to biological pathways. CONCLUSIONS: This method is unique among current SL prediction approaches, it reduces false-positive SL predictions compared to previous methods, and it allows establishing explicit collateral lethality relationship of gene pairs within mutually exclusive group pairs.
BACKGROUND: A pair of genes is defined as synthetically lethal if defects on both cause the death of the cell but a defect in only one of the two is compatible with cell viability. Ideally, if A and B are two synthetic lethal genes, inhibiting B should kill cancer cells with a defect on A, and should have no effects on normal cells. Thus, synthetic lethality can be exploited for highly selective cancer therapies, which need to exploit differences between normal and cancer cells. RESULTS: In this paper, we present a new method for predicting synthetic lethal (SL) gene pairs. As neighbouring genes in the genome have highly correlated profiles of copy number variations (CNAs), our method clusters proximal genes with a similar CNA profile, then predicts mutually exclusive group pairs, and finally identifies the SL gene pairs within each group pairs. For mutual-exclusion testing we use a graph-based method which takes into account the mutation frequencies of different subjects and genes. We use two different methods for selecting the pair of SL genes; the first is based on the gene essentiality measured in various conditions by means of the "Gene Activity Ranking Profile" GARP score; the second leverages the annotations of gene to biological pathways. CONCLUSIONS: This method is unique among current SL prediction approaches, it reduces false-positive SL predictions compared to previous methods, and it allows establishing explicit collateral lethality relationship of gene pairs within mutually exclusive group pairs.
Entities:
Keywords:
Copy number alteration; DNA damage repair genes; Synthetic lethality
Authors: H Sun; R Lesche; D M Li; J Liliental; H Zhang; J Gao; N Gavrilova; B Mueller; X Liu; H Wu Journal: Proc Natl Acad Sci U S A Date: 1999-05-25 Impact factor: 11.205
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