Advanced human cancers usually contain a multitude of genetic changes, and often epigenetic alterations. In human cancers, it is rarely possible to determine, at which stage of tumor progression they were acquired. Most data, however, suggest that they gradually accumulate during tumor progression (^13.3). A gradual accumulation of multiple genetic changes would explain why most cancers appear at older age (Figure 2.10) and would fit with epidemiological data suggesting 4 to 5 essential 'hits' to be necessary for cancer development. The genes affected by such crucial mutations are likely oncogenes and tumor suppressor genes. Indeed, advanced human carcinomas typically contain mutations in several genes of both types. Genetic and epigenetic changes in further genes may modulate the tumor phenotype. Most genetic changes are the result of somatic mutations, but an inherited predisposition to cancer can be caused by one crucial mutation passed on in the germ-line, with further mutations occuring somatically.
Alternatively, inherited predisposition to cancer can be due to germ-line mutations in DNA repair genes or 'caretaker' genes. These defects appear to favor cancer development by increasing the probability of crucial mutations in oncogenes and tumor suppressor genes, but are associated with additional mutations that are more or less important for tumor progression. For instance, cancers with defects in DNA mismatch repair contain a large number of mutations, some in oncogenes and
tumor suppressor genes, but others in irrelevant microsatellite repeats (^13.4).
So, tumors arising on that background exhibit a 'mutator phenotype'. Depending on the type of defect, a mutator phenotype can manifest as an increase in point mutations or as various kinds of chromosomal instability.
The multitude of genetic alterations observed in many advanced human cancers suggests that they have developed a sort of 'mutator phenotype', leading to an increased rate of point mutations, to chromosomal instability, or even to frequent epigenetic alterations. While the existence of genomic instability in advanced cancers seems evident, an interesting question is whether it is required for their development. In other words, can the accumulation of genetic alterations required for an advanced cancer be achieved by random mutations at a normal rate, or does it require the establishment of a 'mutator phenotype' at some stage of progression? This is a hotly debated question with ramifications for tumor therapy as well as tumor prevention.
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Retroviruses like the paradigmatic Rous Sarcoma Virus cause cancers in animals. They carry specific 'oncogenes' which are similar to cellular genes. Their investigation has led to the identification of important cellular oncogenes in human cancers (^4.1). However, only a rare retrovirus, HTLV1, appears to act in a comparable manner in humans (^Box 4.1).
Instead, several DNA viruses are implicated in human cancers, in a more or less causative manner. The strongest case can be made against human papilloma viruses (HPV) which are thought to initiate cervical and other carcinomas (^Box 5.1). Some strains of HPV express proteins which inhibit cellular proteins that control cell proliferation and genomic integrity, i.e. tumor suppressors.
Different proteins with the same function (^Fig. 5.10) are encoded by the DNA genomes of other viruses that can infect humans. This raises the question whether they too can cause human cancer. Adenoviruses encode the E1A and E1B proteins. They cause cancers in some animals and cold-like diseases in man. Nevertheless, it is generally agreed that they are not tumorigenic in man, likely because of efficient elimination by the immune system. The E1A and E1B proteins are thought to partially suppress cellular reactions to the viral infection, but are apparently not strong enough to cause transformation. Adenoviruses may, however, be exploited for cancer therapy (^22.6).
There is not as much agreement on the role of papovavirus in human cancers. The best characterized member of the family is a monkey virus, simian virus 40 (SV40), which is a potent tumor virus in rodents. It may have infected humans and has been found in brain tumors and mesotheliomas. Doubtless, its large T-antigen is capable of immortalizing cultured human cells (^7.4). The family members endemic in humans are the JC and BK viruses. They are present in many healthy humans and accordingly their genomes are found in some cancers, e.g. of the brain and the urinary tract. Their causative role is, however, debated.
In contrast, two members of the herpes virus family are accepted as co-carcinogens for human cancers. HHV8 (or KHSV) is a crucial agent in the development of Kaposi sarcoma, which most often arises in the context of immunodeficiency caused by the retrovirus HIV (^Box 8.1). Epstein Barr Virus (EBV) is best known for its role as a co-carcinogen in Burkitt lymphoma (^10.3), but is very likely also involved in further malignancies including nasopharyngeal carcinoma and certain Hodgkin and non-Hodgkin lymphomas. It appears to act mainly by suppressing apoptosis (^7.2) of lymphoid cells.
Finally, the hepatitis virus B (HBV) can be understood as an intermediate between a DNA virus and a retrovirus. It is certainly a co-carcinogenic agent in a substantial fraction of human liver cancers (^16.3). It causes cancer by a mixture of direct effects of viral proteins and indirect effects resulting from chronic inflammation elicited by the viral infection. The same can be said of the RNA hepatitis C virus (HCV), which causes another substantial fraction of human liver cancers (—>16.1).
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