Our laboratory asks how cancers develop by researching how the genome adapts to environmental change, ageing, and damage. Such genetic changes occur at two levels:

  • Germline (heritable) changes that affect families or species; and
  • Somatic (acquired) changes that affect the ageing tissues of individuals.

As such, we view the human genome not as a fixed genetic blueprint, but as a fluid organelle that is constantly responding to environmental change. The net outcome of this genomic-environmental interaction reflects the balance of two evolutionary selective pressures:

  • Negative selection, which involves genetic retention of essential functionalities; and
  • Positive selection, which involves (rare) gain of genetically advantageous traits.

The term 'cancer' denotes a heterogeneous group of disorders in which a critical sequence of genetic changes in somatic cells triggers a breakdown of normal intercellular regulation. Again, there are two main functional gene groups responsible for preventing such cancers:

  • 'Caretaker' tumour suppressor genes which maintain genetic repair and stability; and
  • 'Gatekeeper' tumour suppressor genes that regulate normal cell growth and death.

Our work supports the view that this dynamic interplay between the human genome and its environment is primarily mediated by the epigenetic modification of DNA (CpG dinucleotide) methylation - an evolutionary masterstroke that can reversibly transform local gene regions from being highly stable to highly unstable. In this sense we regard sporadic age-related cancer as representing a human 'price paid' for maintaining germline evolutionary plasticity, a paradigm which we have termed programmed genetic instability. At present we are directly testing this hypothesis by experimentally creating novel 'cancer-proof' (i.e., mutation-resistant) tumour suppressor genes via synonymous substitution of CpG-variable sequences within the coding region of the critical pro-apoptotic anticancer gatekeeper gene TP53.

Selected Publications

Epstein RJ. A periodic table for cancer. Future Oncology 2015 (in press)

Blackburn J, Ng R, Roden D, Wu J, Epstein RJ. Damage-inducible intragenic demethylation of an alternative intronic promoter in TP53-wildtype but not mutant human cells and tumors.  Proc AACR (Washington DC) 2014

Quah XM, Conway RM, Madigan MC, Epstein RJ. Emerging strategies for therapeutic targeting of the tumour microenvironment. Cancer Forum 2014; 38: 133-37

Epstein RJ. The unpluggable in pursuit of the undruggable: tackling the dark matter of the cancer therapeutics universe. Frontiers Oncol 2013; 3: 304- PMID 24377088

Zhao Y, Epstein RJ. Conserved nonsense-prone CpG sites in apoptosis-regulatory genes: conditional stop signs on the road to cell death. Evol Bioinform. 2013; 9:275-83.

Epstein RJ. Has discovery-based cancer research been a bust? Clin Transl Oncol. 2013; 15(11):865-70.

Zhao Y, Epstein RJ. Unexpected functional similarities between gatekeeper tumour suppressor genes and proto-oncogenes revealed by systems biology. J Hum Genet. 2011; 56(5):369-76.

Tang CS, Epstein RJ. Adaptive Evolution Hotspots at the GC-Extremes of the Human Genome: Evidence for Two Functionally Distinct Pathways of Positive Selection. Adv Bioinformatics. 2010:856825.

Epstein RJ. Digitization and its discontents: future shock in predictive oncology. Semin Oncol. 2010; 37(1):60-4.

Xiong J, Epstein RJ. Growth inhibition of human cancer cells by 5-aza-2'-deoxycytidine does not correlate with its effects on INK4a/ARF expression or initial promoter methylation status. Mol Cancer Ther. 2009; 8(4):779-85.

Epstein RJ, Zhao Y. The threat that dare not speak its name: human extinction. Perspect Biol Med. 2009; 52(1):116-25.

Zhao Y, Epstein RJ. Programmed genetic instability: a tumor-permissive mechanism for maintaining the evolvability of higher species through methylation-dependent mutation of DNA repair genes in the male germ line. Mol Biol Evol. 2008; 25(8):1737-49.

Tang CS, Epstein RJ. A structural split in the human genome. PLoS One. 2007; 11;2(7):e603

Tang CS, Zhao YZ, Smith DK, Epstein RJ. Intron length and accelerated 3' gene evolution. Genomics. 2006; 88(6):682-9

Epstein RJ, Zhao Y. Racial differences in lung cancer. N Engl J Med. 2006; 354(18):1951-3

Lin K, Tan SB, Kolatkar PR, Epstein RJ. Nonrandom intragenic variations in patterns of codon bias implicate a sequential interplay between transitional genetic drift and functional amino acid selection. J Mol Evol. 2003; 57(5):538-45

Huang GC, Hobbs S, Walton M, Epstein RJ. Dominant negative knockout of p53 abolishes ErbB2-dependent apoptosis and permits growth acceleration in human breast cancer cells. Br J Cancer. 2002; 86(7):1104-9

Epstein RJ, Lin K, Tan TW. A functional significance for codon third bases. Gene. 2000; 245(2):291-8

More Garvan Publications

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