Introduction - Why do we need a course of Cancer
Genetics?
Cancer is still one of the major causes for mortality and morbidity in industrialized countries.
The study of hereditary cancer has been playing an important role in the enormous progress
that has been made in the understanding of the neoplastic process, not only of its hereditary
syndromes, but also of the sporadic disease, so frequent throughout the general population.
What do we mean by Cancer Genetics?
Cancer genetics is a broad concept and refers to a number of different disciplines including:
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Molecular pathology,
Tumor biology,
Molecular genetics,
Cytogenetics,
Epidemiology, and
many others
Cancer as a genetic disease:
Genetic disorders have been traditionally grouped into two classes:
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Monogenic diseases – a germline mutation at a single gene directly resulting in a
morbid phenotype.
Multigenic (complex) diseases - multiple genes and environmental factors interacting in
a very complex way to give rise to the disease phenotype.
Sporadic cancer is a complex multigenic disease susceptibility to which is determined by the
interaction of genetic and environmental modifying factors. In hereditary cancer, the features
of a monogenic disease transmitted in an autosomal dominant fashion are recognizable.
Genes involved in cancer:
There are three categories of genes that may be involved in the causation of cancer:
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Oncogenes - which are mainly dominant, growth stimulating genes
Tumor suppressor genes - recessive, growth inhibitory genes
A third category - modifying genes - genes of a very broad spectrum of functions,
alleles of which can modify the individual predisposition to cancer.
Classification:
From a genetic point of view, cancer can be divided into two broad categories: sporadic and
hereditary.
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In sporadic tumors, mutations that trigger tumorigenesis occur in somatic cells.
Additionally, specific alleles of modifiyng genes are likely to confer specific degrees of
susceptibility to sporadic cancer on an individual basis.
In hereditary forms, a mutation is present in the germline that is associated with an
inherited increased predisposition toward developing cancer.
Importantly, cancer always occurs as a multistep genetic process and is never caused by a
single gene mutation. From this point of view, the inherited germline mutation is just the first
of several mutations which underlie tumor initiation, progression and metastasis.
Hereditary Cancer:
For (almost) every cancer type there is a corresponding hereditary condition. However, for
most types of cancer, hereditary forms are extremely rare when compared to sporadic ones. In
colorectal cancer, for instance, hereditary colorectal cancer represents 2-3% of the cases,
while the vast majority are sporadic ones.
The main features of hereditary cancer are:
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early onset (cancer is generally a disease of the elderly, with a late onset, but in the
hereditary cancer it usually affects younger individuals).
high risk of multiple primary tumors (e.g. bilateral tumors of retinoblastoma or Wilm’s
tumor, multiple polyps in FAP). One should remember that the tumor suppressor genes
that cause hereditary cancer are usually expressed in a broad spectrum of tissues.
Therefore, even though one organ-specific tumor type may be prominent, e.g.
colorectal cancer in familial polyposis, many other tissues are at high-risk for cancer.
A paradigm for hereditary Cancer: Retinoblastoma
Retinoblastoma is a relatively rare tumor that originates in the retina and has an incidence of
about 1:20.000. Familial retinoblastoma usually displays a very early onset, usually from birth
up to the 6th - 7th year of age.
Retinoblastoma can be classified into two forms;
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sporadic retinoblastoma is always unilateral, and represents about 60% of the cases
familial retinoblastoma is transmitted in an autosomal dominant fashion and is
responsible for about 40% of the cases. Out of these, approx. 80% are bilateral (a very
important feature of hereditary cancers), 15% are unilateral, and 5% are totally
asymptomatic (although they carry the germline mutation, these individuals do not
develop the disease). Patients with familial retinoblastoma are at a high risk for a broad
spectrum of other primary tumors.
The "two hit" hypothesis:
Based on the epidemiology of retinoblastoma, ALFRED KNUDSON in 1971 developed the "two
hit hypothesis", which is a very fundamental concept in cancer genetics. KNUDSON
hypothesized that the gene responsible for retinoblastoma (RB) was a tumor suppressor gene,
i.e. a growth inhibitory gene. Wild type expression of the RB counteracts tumor formation.
Because Rb is a growth-inhibitory gene, both copies of this gene need to be inactivated within
a single cell to release that cell from its growth inhibitory effects. Considering that the rate at
which somatic mutations occur in a mammalian cell is extremely rare (10 -6 to 10-7), the
occurrence of two independent somatic mutations at both alleles of the same gene is likely to
represent a very rare event (10-12 to 10-14).
In a normal retinal cell, the first somatic mutation ("hit") at the RB tumor suppressor gene will
not affect the cellular phenotype (because of the recessive nature of its growth inhibitory
function) and only a second "hit" at the remaining wild type allele will trigger the tumorigenic
process. Hence, the first mutation is recessive at the cellular level, although the clinical
condition follows an autosomal dominant mode of inheritance.
In familial retinoblastoma, the first RB gene mutation is inherited through the germline, and is
therefore present in every somatic cell. This means that only one additional mutation is
required to trigger the tumorigenic process. This explains many clinical and epidemiological
differences between sporadic and inherited retinoblastoma.
Minimal genetic requirements for cancer
For a cell to develop into a tumor, three minimal requirements must be fulfilled:
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The very first mutation must provide the cell with a selective advantage. This is a
very old but still fundamental concept: cancer is an evolutionary process and “selection
is the driving force behind tumor growth. A raised mutation rate may make
tumorigenesis faster, but is not necessary for tumorigenesis to occur” (from Tomlinson
& Bodmer, Nature Medicine 5:11, 1999).
Secondly, several mutations at multiple genes are required. This raises an apparent
contradiction: given the low endogenous mutation rate in a cell, it would be
theoretically impossible to accumulate so many mutations within one cell during the
life-span of an individual.
The third requirement is genetic instability: a cell must become genetically instable to
allow mutations at multiple genes. Genetic instability is usually caused by defects in
DNA repair and/or in chromosomal stability.
Selection vs Hypermutability
“.....the current focus on genomic instability in cancer is misplaced simply because a raised
mutation rate does not itself cause a tumor to grow” (from Tomlinson & Bodmer, Nature
Medicine 5:11, 1999).
An increased mutation rate does not in itself provide a selective advantage to the cell. A cell
with an increased mutation rate is more likely to undergo programmed cell death (apoptosis)
than to develop into a tumor.
Gatekeepers and Caretakers
The isolation, characterization and functional analysis of a large number of tumor suppressor
genes has allowed Kinzler and Vogelstein (Nature 386:761, 1997) to propose a new
subdivision of this vast gene family in two categories, namely gatekeepers and caretakers. The
definitions here below have been slightly adapted by this author and do not entirely reflect the
definition reported in the original publication.
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Gatekeepers are cancer susceptibility gene that controls cellular proliferation or any
other cellular function which, when inactivated, is directly selected upon thus triggering
clonal expansion and tumor formation.
Caretakers function to maintain the integrity of the genome. Caretakers are genes
involved in preventing genomic or genetic instability. A defect in a caretaker is not likely
to provide a selective advantage but rather leads to mutation of other gatekeepers.
Indeed, we are finding now that caretakers which can initiate tumorigenesis do, in fact,
provide a selective advantage to the cell through other functions that are not directly
related to the repair function (e.g. inactivation of one of the mismatch repair genes
responsible for HNPCC confers resistance to apoptosis).
Multistep Model
Inactivation of a gatekeeper will directly lead to clonal expansion because of the selective
advantage provided by the loss of its function. Hence, two hits at one gene will trigger
tumorigenesis in the gatekeeper model. In contrast, in case of caretaker genes, one germline
and three somatic mutations are required to initiate cancer: the first two hits at the caretaker
gene will account for its inactivation and the acquisition of genetic instability. In both models,
additional mutations at oncogenes and tumor suppressor genes are necessary to promote
tumor progression (example: the adenoma-carcinoma sequence in colorectal cancer). Also, a
high degree of genetic instability will result in a high degree of genetic damage that is difficult
for a cell to cope with. This will lead to apoptosis and cell death. Again, Kinzler and Vogelstein
postulated the "just enough" genetic instability model (Cahill DP, Kinzler KW, Vogelstein B,
Lengauer C. Genetic instability and darwinian selection in tumors. Trends Cell Biol 9:12 M5760, 1999).
Genetic Instability
Genetic instabillity is a “conditio sine qua non” for cancer to progress as multiple mutations at
multiple genes are needed and wild type mutation rates will simply not allow a sufficient
number of mutations to occur. Moreover, a high degree of genetic instability will result in a
high degree of genetic damage that is difficult for a cell to cope with. This will lead to apoptosis
and cell death. .
Hence, a compromise must be found between the two extremes: again, Kinzler and Vogelstein
postulated the "just enough" genetic instability model (Cahill DP, Kinzler KW, Vogelstein B,
Lengauer C. Genetic instability and darwinian selection in tumors. Trends Cell Biol 9:12 M5760, 1999). If there is too much genetic instability, the affected cells will undergo apoptosis
(programmed cell death). If there is too little instability, not enough mutations will accumulate
to lead to cancer. Only a mutation rate between the two extremes is compatible with tumor
progression.
However, in view of recent findings on the multi-functional nature of many tumor suppressor
genes and in particular of the APC gene and the DNA mismatch repair genes (Fodde et al.
Mutations in the APC gene cause chromosomal instability. Nat Cell Biol, 2001 in press; and
Rick Fishel, personal communications) the definition of gatekeeper and caretaker may need to
be revisited.