identifying genetic vulnerabilities in cancers driven by defects in dna-damage response · 2016. 4....
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For a gene pair (A,B) and a (large) set of tumours, let
• |SA|: the subset of tumours carrying alterations in A;
• |SB|: the subset of tumours carrying alterations in B;
• |SAB|: the subset of tumours carrying alterations in both A and B;
• X: a random variable that counts the co-occurrence of
alterations in A and B.
We compute the statistical significance for the mutual exclusivity for
alterations in A and B based on the probability of observing at most
|SAB| tumours (out of |SB| tumours) showing co-occurrence of
the alterations (with |SA| tumours).
We estimate this probability P[X |SAB|] as:
𝑃[𝑋 |SAB|] = 1 − P[X > |SAB|],
where P[X > |SAB| ] is computed using the hypergeometric
probability mass function for X = k > |SAB|:
𝑃 𝑋 > 𝑆𝐴𝐵 =
𝑆𝐴𝑘
𝑆 − 𝑆𝐴𝑆𝐵 − 𝑘
𝑆𝑆𝐵
𝑆𝐵
𝑘= 𝑆𝐴𝐵 +1
.
This “1-hypergeometric test” p-value (Equation 1) is used to infer
SL pairs (at p<0.05) and rank them by their p-values.
Identifying Genetic Vulnerabilities in Cancers Driven by
Defects in DNA-damage Response
Authors’ Affiliations
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3. Prediction of Synthetic Lethal Partners of DDR Defects 1. Background
Cancers Driven by Defects in DNA-damage Response (DDR)
• Defects – e.g. via mutations, copy-number loss or underexpression –
of DNA-damage repair genes BRCA1 and BRCA2 are highly
penetrant and significantly increase the risk of breast (by 60-80%) and
ovarian (35%) cancers [1].
• Together with defects in
• the DNA-damage sensor ATM,
• the apoptosis effector TP53, and
• PTEN and CDH1 that closely regulate DDR,
these defects account for considerable proportions of sporadic
breast (63%) and ovarian (85%) cancers.
2. Our Approach
Mutually Exclusive Genetic Alterations Identify Synthetic
Lethal Gene Pairs
Genetic Vulnerabilities Arising from DDR Defects
Sriganesh Srihari, Murugan Kalimutho, Jitin Singla, Aimee Davidson, Limsoon Wong, Peter T. Simpson, Kum Kum Khanna and Mark A. Ragan
SS, AD, MAR: Institute for Molecular Bioscience, The University of Queensland,
St Lucia, Queensland 4072, Australia.
MK, KK: QIMR-Berghofer Medical Research Institute, Herston, Brisbane,
Queensland 4006, Australia.
JS: Computational Biology and Bioinformatics, University of Southern California,
Los Angeles, CA 90089-2910, USA
LW: Department of Computer Science, National University of Singapore,
Singapore 117417.
PTS: The University of Queensland, School of Medicine and Centre for Clinical
Research, Brisbane, Queensland 4006, Australia.
Our hypothesis: Genes altered in a mutually exclusive manner to
DDR defects in cancer cells constitute the synthetic lethal partners
of DDR genes, and if targeted in conjunction with DDR defects
could induce cancer cell death.
5. Pathway-based Models for Targeting Synthetic Lethal
Partners of DDR Defects in Cancer
Funding Acknowledgements
Proportions of cancers carrying mutations, homozygous deletions or
underexpression in six DDR genes ATM, BRCA1, BRCA2, CDH1,
PTEN and TP53.
Data from The Cancer Genome Atlas (TCGA) for Breast Invasive
Carcinoma and Ovarian Serous Cystadenocarcinoma:
Key References
1. Liu et al., A fine-scale dissection of the DNA double-strand break repair
machinery and its implications for breast cancer therapy. Nucleic Acids Res
2014, 42(10):6106-27.
2. Srihari et al., Inferring synthetic lethal interactions from mutual exclusivity of
genetic events in cancer. Biology Direct 2015, 10:57.
• Research funded by Australian National Health and Medical Research
Council grants# 1028742, 1080985 to MAR, PTS and Dr Nicola Waddell
(QIMR-Berghofer).
• Travel support to SS from: • Institute for Molecular Bioscience (UQ),
• The Ian Potter Foundation Australia (grant# 20160303)
• AACR Scholar-in-Training Award – Supported by Susan G. Komen
• Despite defects in DDR, cancer cells tolerate damage to their
DNA and continue to survive and proliferate.
• This is effected by rewiring of the DDR signalling network and by
(clonally) selecting optimal combinations of genetic alterations that
are amenable to cell survival.
• However, this exposes genetic vulnerabilities that could be
capitalized for selective targeting of cancer cells.
• In particular, via triggering significant DNA damage (genomic
catastrophe) in cancer cells.
Synthetic Lethality (SL): A combination between two genetic
events (typically affecting two different genes) in which their co-
occurrence results in severe loss of viability or death of the cell,
although the cell remains viable when only one of the two events
occurs [1].
DDR
Partner
Observation from a large set of tumours:
DDR
Partner
(Equation 1)
Genomic copy-number and gene-expression datasets from four
sporadic cancers, breast, prostrate, ovarian and uterine from TCGA,
composing a total of 3980 tumour samples.
Cancer Genomic Gene
expression Total
Breast 847 1182 2029
Prostate 152 471 623
Ovarian 562 266 828
Uterine 443 57 500
Total 2004 1976 3980
• Deletion/downregulation of A – Deletion/downregulation of B
• Deletion/downregulation of A – Amplification/upregulation of B
Distribution of DDR genes for involvement in SL combinations:
Parallel pathways model:
•The SL partner, typically a tumour
suppressor compensates for the
loss of DDR gene.
•Targeting it results in complete
loss of DDR functions, resulting in
genomic catastrophe and cell
death.
Negative feedback-loop model:
•In the presence of a DDR gene in the negative feedback loop, the
SL partner, typically an oncogene, is upregulated to drive the
pathway signals.
•However, in the event of DDR loss, upregulation of the partner
could be detrimental to cell survival, which cancer cells avoid.
•Targeting the partner shunts off the signal, and decreases cell
viability.
4. Experimental Validation of Predictions
Effect of BRF2 Knockdown in Breast Cancer Cell Lines
• siRNA-mediated knockdown of BRF2 reduces cell proliferation,
in particular up to 70% in MDA-MB-453 cell line.
• BRF2 could be a DDR-context-dependent oncogene.
Examples of identified SL partners of DDR genes and their network:
This poster is the intellectual property of the author/presenter. Contact them at [email protected] for permission to reprint and/or distribute.
Network of 718 genes synthetic lethal to the six DDR genes
Survival analysis based on 43 shortlisted genes in ER-negative /
basal-like breast tumours
Statistical Model to Infer Synthetic Lethal Gene Pairs
Bioinformatic Set-up and Datasets