1. Chapter 8
Cancer Genetics

2. Introduction
Chromosomal changes in cancer cells were recognized early in the 20th century, and it was later found that environmental agents that cause cancer are also mutagenic.
Families at high risk for specific cancers were recognized.
All this suggested that genetic change might underlie the pathogenesis of malignancy, a hypothesis that has been overwhelmingly confirmed in recent years.

3. Introduction
It now is recognized that a tumour arises as a clonal growth, originating from genetic change in a single cell.
The properties referred to as malignancy represent phenotypic features due to the accumulation of changes in multiple genes.
The identification of such genes, referred to as tumour suppressor genes and oncogenes, has led to major advances in understanding cancer biology.

4. Cancer Is A Genetic Disorder
Four lines of evidence demonstrate that cancer is a genetic disease:
the observation of chromosomal anomalies in cancer,
the existence of families in which risk of cancer is transmitted as a genetic trait,
the fact that carcinogens also tend to be mutagens, and
the occurrence of individuals with DNA repair deficiency syndromes who are at increased risk of cancer.

8. Tumour Suppressor Genes
The first inroads into the molecular genetics of cancer involved the study of a rare childhood cancer, retinoblastoma.
Retinoblastoma affects ganglion cells in the eye during early childhood.
Both hereditary and non-hereditary forms exist, but both are due to disturbances in the same gene, called Rb, which functions as a tumor suppressor gene.

9. Two-hit hypothesis
Alfred Knudson proposed a model in which retinoblastoma formation requires the occurrence of two separate mutation events in a retinal cell lineage.
Individuals with hereditary retinoblastoma have inherited one of these mutations, and therefore all their retinal cells carry the mutation.
Only one additional event needs to occur to produce a tumor.
In contrast, sporadic retinoblastoma occurs only when two independent mutational events occur in the same cell lineage.
This would be expected to be much rarer, and so age at onset is later and tumors are invariably unilateral.
Knudson’s hypothesis has come to be called the two-hit hypothesis. It has been the cornerstone for understanding hereditary predisposition to malignancy.

14. Oncogenes
The discovery of the first oncogene was based on work that began long before DNA was known to be the genetic material.
Peyton Rous, working at the Rockefeller Institute for Medical Research in New York in 1909, began a series of experiments that started with a chicken that had a lump on its leg. The lump was a soft-tissue sarcoma.
When Rous ground up some of this tumour and injected it into other chickens, they too developed sarcomas.
The active agent was identified as a virus – in fact, a retrovirus – and was called Rous sarcoma virus.
Decades later, it was found that of the four genes in this virus, one, referred to as src, is responsible for the transforming properties.
When src is lost or mutated, the virus is no longer oncogenic.

15. Routes to Oncogene Activation
Incorporation into a virus or insertion of a retrovirus adjacent to a proto-oncogene.
Gene amplification, wherein a block of DNA, including an oncogene and some neighbouring genes, is replicated tens or hundreds of times in the cell.
Chromosome rearrangement.
Mutations in gene that lead to an altered protein that causes transformation of the cell.

20. The Normal Role of Tumour Suppressor Genes and Oncogenes
Dominant proto-oncogenes sort into four classes of molecules, all of which are involved in the control of cell differentiation and proliferation: growth factors, membrane receptors, membrane associated proteins, and transcription factors.

21. Normal Role of Tumour Suppressor Genes
The Rb protein binds to and inhibits action of E2F proteins that are involved in control of transcription of proteins required to initiate DNA synthesis.
Phosphorylation of Rb disinhibits E2F, leading to onset of the S phase.
Loss of Rb therefore removes this control point, leading to rapid transit from G1 to S.
Some tumor viruses effect the same outcome by producing proteins that bind to, and interfere with the ability of Rb to inhibit, E2F proteins.

22. Normal Role of Tumour Suppressor Genes
The TP53 gene is mutated in a wide variety of tumor types and is involved in a familial cancer syndrome, Li–Fraumeni syndrome.
Like Rb, the p53 protein is involved in the regulation of the cell cycle, causing the cell to pause before DNA synthesis to repair DNA damage, or to undergo apoptosis (programmed cell death) if the damage is irreparable.
Loss of p53 activity would allow cells to proceed through division without repairing DNA damage, and thus increase the likelihood of survival of cells with genetic alterations that may contribute to malignancy.

23. Normal Role of Tumour Suppressor Genes
A different type of genetic defect has been found to underlie the syndrome of hereditary nonpolyposis colon cancer (HNPCC) (MIM ).
A hallmark of these tumors is the occurrence of a phenomenon of microsatellite instability, meaning that simple sequence repetitive DNA elements show excessive size variability due to inaccurate replication.
This has been attributed to loss of activity of any of six genes involved in repair of mismatched bases in DNA: MSH2, MLH1, PMS1, PMS2, and GTBP (also called MSH6).
These function as tumor suppressor genes, in that individuals with HNPCC are heterozygous for a mutation in any one of these genes, but the tumor cells are homozygous for a mutation in one of the genes.
Loss of activity leads to a hypermutable state, in which mutations accumulate in other dominant or recessive oncogenes, leading to tumor progression.

25. Epigenetics and MicroRNAs in Cancer
Epigenetic changes appear to act in cancer through at least three distinct mechanisms.
Firstly, cancer genomes tend to have a general hypomethylation of DNA, which becomes more pronounced as the tumour progresses toward more malignant behaviour. This may result in expression of some genes that are normally not expressed, including imprinted genes.

26. Epigenetics and MicroRNAs in Cancer
The second epigenetic change is hypermethylation of the promoter regions of some tumor suppressor genes.
This leads to reduced expression of these genes in the absence of mutation. Tumor-specific patterns of hypermethylation have been implicated in inactivation of genes such as Rb, mismatch repair genes, and BRCA1, among others. The mechanisms of hypermethylation are not known.
The third mechanism is hypermethylation of genes that encode microRNAs, leading to reduced expression of specific microRNAs and consequent aberrant gene regulation.

27. The Molecular Basis of Oncogenesis
Multistep process.
Accumulation of mutations over time.
Transformation of cells.
Selection of cells that divide and grow rapidly.

30. New Treatments for Cancer
Conventional modes of treatment are designed to kill all dividing cells.
Side effects result from killing of non tumour cells, and treatment failures are due to failure to kill all tumour cells.
Sometimes the tumour cells that survive develop drug resistance and may be more aggressive than their predecessors.

31. New Treatments for Cancer
Research in cancer therapy therefore is directed toward the development of agents that are more selective for tumor cells.
Approaches include inhibition of tumor blood supply, taking advantage of cell surface markers that are unique to tumor cells, or developing means of altering the activity of genes involved in oncogenesis.