Epigenetic modification and cancer: mark or stamp? (BRCA/fallopian tube....)

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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