Genetic and Epigenetic Drivers and Controllers
Current dogma has it that cancer is a genetic disease, by which is meant that an irreversible change in a gene or genes within somatic cells, or in its/their control, has created and will maintain growth of both the primary, and any secondary neoplasms. Genes can by altered by duplications or deletions in whole or parts of chromosomes, by mutations in individual genes, by silencing of normal gene expression by epigenetic events in the environment and by aberrant signalling which up-, or down-regulate gene expression.
For several decades in the latter part of the last century dogma had it that * 6 mutations in key genes was both necessary and sufficient to cause cancer. This has always seemed unlikely to the present author: which six?; how much can the cluster differ by type of cancer/tissue of origin?; how variable is the cluster by aetiology?; how variable will the pattern be within and between individuals?; given the additional mutations which comprise what we call “tumour progression” and the outgrowth of new clones, which of these are significant or just noise? Added to all of this, we are currently learning a good deal about the epigenetics of cancer, a process whereby during embryogenesis and throughout life, methylation of DNA or modification of histone proteins can silence particular genes (Fig. 1.1).
Studies of individual patients, of case-series and Genome Wide Association Studies (GWAS) of large populations produce long lists of affected genes, their frequencies in different types of cancer and racial/ethnic groups, but the associations remain statistical concepts: there may well be some common final pathways in malignant transformation and in many subsequent behaviours, but the genesis of a neoplasm may be specific to—even unique—for every patient. We should regard every neoplasm as an unique biological event in an unique host! Each patient’s metabolism and immune response will be different. The current fashion for personalised care properly takes cognisance of this.
Fig. 1.1 Epigenetic mechanisms, DNA methylation and cancer. With permission from the “National Institutes of Health”. http://commonfund.nih.gov/epigenomics/figure.aspx
A huge effort is being made sequencing all of the common, and not-so-common cancers. Recent data release from the International Cancer Genome Project (https:// icgc.org/), (http://www.genome.gov/17516564) and, the Cancer Genome Atlas in the USA and several Collaborators including the Wellcome Trust Sanger Institute (https://www.sanger.ac.uk/research/projects/cancergenome/) describes 50 collaborative projects with neoplasms taken from 18 primary cancer sites in 12,232 donors, revealing 9,871,477 simple somatic mutations in a total of 57,526 mutated genes. How many of the genetic changes in malignancy are effect rather than cause? Structural and functional changes in genes increase in number and type with the phenomenon of “tumour progression” (vide infra): every malignant cell can contain a different set of genetic aberrations; most might be regarded as epiphenomena; many are not compatible with cell viability let alone cell division; functions which are fundamental to the continued presence of stemness? Such epiphenomena may be important in key aspects of behaviour, including increase in the mass of a “tumour”; cell mobility and infiltration; propensity to metastasis, abnormal secretion, e.g., but whilst “correction” of such a malfunction may have clinical benefit, cure remains impossible whilst the host—the patient—lives unless every cell with the ability to be itself immortal is killed or permanently suppressed.
Fig. 1.2 Hallmarks of cancer and therapeutic targets (reproduced with permission from Cell 144, March 4, 2011; p. 647)