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Inferring synthetic lethal interactions from mutual exclusivity of genetic events in cancer.

Srihari S, Singla J, Wong L, Ragan MA - Biol. Direct (2015)

Bottom Line: Synthetic lethality (SL) refers to the genetic interaction between two or more genes where only their co-alteration (e.g. by mutations, amplifications or deletions) results in cell death.It is based on the observation that pairs of genes that are altered in a (significantly) mutually exclusive manner in cancers are likely to constitute lethal combinations.These identified genes are essential in cell lines, and are potential candidates for targeted cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, 4072, Australia.

ABSTRACT

Background: Synthetic lethality (SL) refers to the genetic interaction between two or more genes where only their co-alteration (e.g. by mutations, amplifications or deletions) results in cell death. In recent years, SL has emerged as an attractive therapeutic strategy against cancer: by targeting the SL partners of altered genes in cancer cells, these cells can be selectively killed while sparing the normal cells. Consequently, a number of studies have attempted prediction of SL interactions in human, a majority by extrapolating SL interactions inferred through large-scale screens in model organisms. However, these predicted SL interactions either do not hold in human cells or do not include genes that are (frequently) altered in human cancers, and are therefore not attractive in the context of cancer therapy.

Results: Here, we develop a computational approach to infer SL interactions directly from frequently altered genes in human cancers. It is based on the observation that pairs of genes that are altered in a (significantly) mutually exclusive manner in cancers are likely to constitute lethal combinations. Using genomic copy-number and gene-expression data from four cancers, breast, prostate, ovarian and uterine (total 3980 samples) from The Cancer Genome Atlas, we identify 718 genes that are frequently amplified or upregulated, and are likely to be synthetic lethal with six key DNA-damage response (DDR) genes in these cancers. By comparing with published data on gene essentiality (~16000 genes) from ten DDR-deficient cancer cell lines, we show that our identified genes are enriched among the top quartile of essential genes in these cell lines, implying that our inferred genes are highly likely to be (synthetic) lethal upon knockdown in these cell lines. Among the inferred targets are tousled-like kinase 2 (TLK2) and the deubiquitinating enzyme ubiquitin-specific-processing protease 7 (USP7) whose overexpression correlates with poor survival in cancers.

Conclusion: Mutual exclusivity between frequently occurring genetic events identifies synthetic lethal combinations in cancers. These identified genes are essential in cell lines, and are potential candidates for targeted cancer therapy. Availability: http://bioinformatics.org.au/tools-data/underMutExSL

No MeSH data available.


Related in: MedlinePlus

Differential essentiality of genes Ba between nine DDR-deficient and MCF7 cell lines; and b between PTEN−/− and PTEN wild-type isogenic cell lines. We considered MCF7, which does not have any known DDR defect, as our control. Comparisons of GARP-score means for genes B between DDR-deficient lines and MCF7 showed significant differences (ANOVA p < 0.0001) between these cell lines. Similarly, comparison of GARP scores between two isogenic HCT116-derived cell lines, one with PTEN−/− and the other with wild type PTEN showed significant difference (paired t-test: p < 0.0001) between the two cell lines. This analysis indicated that the essentiality/lethality of genes B is specific to DDR-deficient/PTEN-deficient cell lines, and therefore context-dependent on DDR deficiency
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Fig5: Differential essentiality of genes Ba between nine DDR-deficient and MCF7 cell lines; and b between PTEN−/− and PTEN wild-type isogenic cell lines. We considered MCF7, which does not have any known DDR defect, as our control. Comparisons of GARP-score means for genes B between DDR-deficient lines and MCF7 showed significant differences (ANOVA p < 0.0001) between these cell lines. Similarly, comparison of GARP scores between two isogenic HCT116-derived cell lines, one with PTEN−/− and the other with wild type PTEN showed significant difference (paired t-test: p < 0.0001) between the two cell lines. This analysis indicated that the essentiality/lethality of genes B is specific to DDR-deficient/PTEN-deficient cell lines, and therefore context-dependent on DDR deficiency

Mentions: To understand whether the lethality observed for genes B is specific to A-deficient cell lines, we analysed the differential essentiality of B in the cell lines relative to the MCF7 cell line (due to lack of suitable data on normal cell lines, we chose MCF7 which is a typical luminal line with no known DDR defect, as our control for the comparison). We observed significant difference between the mean essentialities for B between the DDR-deficient and MCF7 cell lines (Fig. 5a). Similar results were observed using data [32] from two HCT116-derived isogenic cell lines, one PTEN−/− and the other with wild-type PTEN (Fig. 5b). This analysis indicated that the essentiality of B was highly specific to cell lines harbouring gene A deficiency, and hence B is synthetic lethal in the context of deficiencies in DDR genes.Fig. 5


Inferring synthetic lethal interactions from mutual exclusivity of genetic events in cancer.

Srihari S, Singla J, Wong L, Ragan MA - Biol. Direct (2015)

Differential essentiality of genes Ba between nine DDR-deficient and MCF7 cell lines; and b between PTEN−/− and PTEN wild-type isogenic cell lines. We considered MCF7, which does not have any known DDR defect, as our control. Comparisons of GARP-score means for genes B between DDR-deficient lines and MCF7 showed significant differences (ANOVA p < 0.0001) between these cell lines. Similarly, comparison of GARP scores between two isogenic HCT116-derived cell lines, one with PTEN−/− and the other with wild type PTEN showed significant difference (paired t-test: p < 0.0001) between the two cell lines. This analysis indicated that the essentiality/lethality of genes B is specific to DDR-deficient/PTEN-deficient cell lines, and therefore context-dependent on DDR deficiency
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4590705&req=5

Fig5: Differential essentiality of genes Ba between nine DDR-deficient and MCF7 cell lines; and b between PTEN−/− and PTEN wild-type isogenic cell lines. We considered MCF7, which does not have any known DDR defect, as our control. Comparisons of GARP-score means for genes B between DDR-deficient lines and MCF7 showed significant differences (ANOVA p < 0.0001) between these cell lines. Similarly, comparison of GARP scores between two isogenic HCT116-derived cell lines, one with PTEN−/− and the other with wild type PTEN showed significant difference (paired t-test: p < 0.0001) between the two cell lines. This analysis indicated that the essentiality/lethality of genes B is specific to DDR-deficient/PTEN-deficient cell lines, and therefore context-dependent on DDR deficiency
Mentions: To understand whether the lethality observed for genes B is specific to A-deficient cell lines, we analysed the differential essentiality of B in the cell lines relative to the MCF7 cell line (due to lack of suitable data on normal cell lines, we chose MCF7 which is a typical luminal line with no known DDR defect, as our control for the comparison). We observed significant difference between the mean essentialities for B between the DDR-deficient and MCF7 cell lines (Fig. 5a). Similar results were observed using data [32] from two HCT116-derived isogenic cell lines, one PTEN−/− and the other with wild-type PTEN (Fig. 5b). This analysis indicated that the essentiality of B was highly specific to cell lines harbouring gene A deficiency, and hence B is synthetic lethal in the context of deficiencies in DDR genes.Fig. 5

Bottom Line: Synthetic lethality (SL) refers to the genetic interaction between two or more genes where only their co-alteration (e.g. by mutations, amplifications or deletions) results in cell death.It is based on the observation that pairs of genes that are altered in a (significantly) mutually exclusive manner in cancers are likely to constitute lethal combinations.These identified genes are essential in cell lines, and are potential candidates for targeted cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Queensland, 4072, Australia.

ABSTRACT

Background: Synthetic lethality (SL) refers to the genetic interaction between two or more genes where only their co-alteration (e.g. by mutations, amplifications or deletions) results in cell death. In recent years, SL has emerged as an attractive therapeutic strategy against cancer: by targeting the SL partners of altered genes in cancer cells, these cells can be selectively killed while sparing the normal cells. Consequently, a number of studies have attempted prediction of SL interactions in human, a majority by extrapolating SL interactions inferred through large-scale screens in model organisms. However, these predicted SL interactions either do not hold in human cells or do not include genes that are (frequently) altered in human cancers, and are therefore not attractive in the context of cancer therapy.

Results: Here, we develop a computational approach to infer SL interactions directly from frequently altered genes in human cancers. It is based on the observation that pairs of genes that are altered in a (significantly) mutually exclusive manner in cancers are likely to constitute lethal combinations. Using genomic copy-number and gene-expression data from four cancers, breast, prostate, ovarian and uterine (total 3980 samples) from The Cancer Genome Atlas, we identify 718 genes that are frequently amplified or upregulated, and are likely to be synthetic lethal with six key DNA-damage response (DDR) genes in these cancers. By comparing with published data on gene essentiality (~16000 genes) from ten DDR-deficient cancer cell lines, we show that our identified genes are enriched among the top quartile of essential genes in these cell lines, implying that our inferred genes are highly likely to be (synthetic) lethal upon knockdown in these cell lines. Among the inferred targets are tousled-like kinase 2 (TLK2) and the deubiquitinating enzyme ubiquitin-specific-processing protease 7 (USP7) whose overexpression correlates with poor survival in cancers.

Conclusion: Mutual exclusivity between frequently occurring genetic events identifies synthetic lethal combinations in cancers. These identified genes are essential in cell lines, and are potential candidates for targeted cancer therapy. Availability: http://bioinformatics.org.au/tools-data/underMutExSL

No MeSH data available.


Related in: MedlinePlus