Limits...
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

Validation of synthetic lethal interactions against GARP essentiality scores from cell line screens [31, 32]. The left-hand plots compare the ranges for GARP scores of our predicted genes B (amplified/upregulated) with that of the entire set (~16000) of profiled genes. While it is difficult to directly compare the two ranges because of the difference in the number of genes in them, for majority of the cell lines the gene B at the 25th percentile had lower GARP scores than the corresponding gene from the entire profiled set. By χ2 test, genes B were significantly enriched (p < 10−5) within the top-quartile essential genes in these cell lines. The right-hand plots show GE ranks vs ME ranks for genes B in cell lines that are deficient in genes A: aATM, bBRCA1, cBRCA2, dPTEN and eTP53
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Validation of synthetic lethal interactions against GARP essentiality scores from cell line screens [31, 32]. The left-hand plots compare the ranges for GARP scores of our predicted genes B (amplified/upregulated) with that of the entire set (~16000) of profiled genes. While it is difficult to directly compare the two ranges because of the difference in the number of genes in them, for majority of the cell lines the gene B at the 25th percentile had lower GARP scores than the corresponding gene from the entire profiled set. By χ2 test, genes B were significantly enriched (p < 10−5) within the top-quartile essential genes in these cell lines. The right-hand plots show GE ranks vs ME ranks for genes B in cell lines that are deficient in genes A: aATM, bBRCA1, cBRCA2, dPTEN and eTP53

Mentions: We expect that targeting genes B in conjunction with genes A could induce lethality. To validate this, we analysed the GARP essentiality scores of genes B in cell lines deficient with genes A. We chose ten cell lines (Table 2) that harbour a deficiency in at least one of the genes A [31, 32]. The left-hand side plots of Fig. 3 compare the ranges of GARP essentialities of our predicted genes B with that of the entire set of ~16000 profiled genes in these cell lines. While it is difficult to directly compare the two ranges because of the difference in number of genes in them, for the majority of cell lines the genes B at the 25th percentile had lower GARP scores than the corresponding genes from the entire profiled set. In particular, our predicted genes B were enriched significantly (χ2 test p < 10−5) with the top-quartile of essential genes (approximately the top 5000) from these ~16000 genes.Fig. 3


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

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

Validation of synthetic lethal interactions against GARP essentiality scores from cell line screens [31, 32]. The left-hand plots compare the ranges for GARP scores of our predicted genes B (amplified/upregulated) with that of the entire set (~16000) of profiled genes. While it is difficult to directly compare the two ranges because of the difference in the number of genes in them, for majority of the cell lines the gene B at the 25th percentile had lower GARP scores than the corresponding gene from the entire profiled set. By χ2 test, genes B were significantly enriched (p < 10−5) within the top-quartile essential genes in these cell lines. The right-hand plots show GE ranks vs ME ranks for genes B in cell lines that are deficient in genes A: aATM, bBRCA1, cBRCA2, dPTEN and eTP53
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig3: Validation of synthetic lethal interactions against GARP essentiality scores from cell line screens [31, 32]. The left-hand plots compare the ranges for GARP scores of our predicted genes B (amplified/upregulated) with that of the entire set (~16000) of profiled genes. While it is difficult to directly compare the two ranges because of the difference in the number of genes in them, for majority of the cell lines the gene B at the 25th percentile had lower GARP scores than the corresponding gene from the entire profiled set. By χ2 test, genes B were significantly enriched (p < 10−5) within the top-quartile essential genes in these cell lines. The right-hand plots show GE ranks vs ME ranks for genes B in cell lines that are deficient in genes A: aATM, bBRCA1, cBRCA2, dPTEN and eTP53
Mentions: We expect that targeting genes B in conjunction with genes A could induce lethality. To validate this, we analysed the GARP essentiality scores of genes B in cell lines deficient with genes A. We chose ten cell lines (Table 2) that harbour a deficiency in at least one of the genes A [31, 32]. The left-hand side plots of Fig. 3 compare the ranges of GARP essentialities of our predicted genes B with that of the entire set of ~16000 profiled genes in these cell lines. While it is difficult to directly compare the two ranges because of the difference in number of genes in them, for the majority of cell lines the genes B at the 25th percentile had lower GARP scores than the corresponding genes from the entire profiled set. In particular, our predicted genes B were enriched significantly (χ2 test p < 10−5) with the top-quartile of essential genes (approximately the top 5000) from these ~16000 genes.Fig. 3

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