Epigenetic modification and cancer: mark or stamp?
Abstract
Hypotheses are built upon data, but
data require hypotheses before they can be understood. The development
of the ‘two-hit’
hypothesis of carcinogenesis was a key event in
cancer genetics because it provided a testable model of how tumours
develop.
In this commentary on ‘Promoter hypermethylation
patterns in Fallopian tube epithelium of BRCA1 and BRCA2 germline mutation carriers’ by Bijron et al. published in the February 2012 issue of Endocrine-Related Cancer, the need for new grammar and some new hypotheses in epigenetics is discussed. Meanwhile, data suggesting an important role
of epigenetic modification in the cause, progression and treatment of cancer continues to accumulate............
Introduction
In hereditary tumours, the first hit
occurs in the germ line, whereas in non-hereditary tumours, the first
hit occurs in the
cell from which the tumour arises. The second
hits are always somatic, and can inactivate the second allele in various
different
ways. The development of the ‘two-hit’
hypothesis of carcinogenesis was a key event in cancer genetics because
it provided
a testable model of how tumours develop (Knudson 1971, 1978). Although there have been extensions and revisions to the basic model (Tomlinson et al. 2001), the essential elements of the basic hypothesis remain intact, 40 years on. In the original ‘test case’ of RB-1 mutations in retinoblastoma, these events were physical alterations in the structure of the chromosome or gene (Cavenee et al. 1983), and the perception was such that physical changes put a ‘stamp’ on the tumour that could be detected by examination of
genomic DNA.............
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