Inherited Basis:

It is important to recognize that most of the mutation described above arise in a somatic cell and are not transmitted to the patient’s offspring. Nevertheless, some human families are genetically prone to cancer.  One group of cancer patients, exemplified by xeroderma pigmentosum (XP) and the hereditary non-polyposis colon cancer (HNPCC) families, have defects ion DNA repair enzymes (See. Figure 1.7) so that they accumulate mutations at faster rate. More commonly, individuals in cancer-prone families inherit of a mutation in a particular oncogene, essentially reducing the number of additional mutations a cell from that person requires to become neoplastic. The two-hit model explains why even in theses cancer-prone families Tumours may require many years to develop. The inherited oncogene may be particularly relevant for a certain cell type, predisposing to a particular form of tumor (e.g. N-Ras and neurological Tumours), or be able to deregulate growth in a variety of different cell types (e.g. p53 mtations in Li-Fraumeni families which are particularly prone to early-onset leukaemias, sarcomas, and breast and brain malignancies). 

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DAVIDSON’S

Principles and Practice of Medicine

Eighteenth Edition

Multistep Carcinogenesis:

The cell’s complex self-regulating machinery means that more then one mutation is often required to produce a malignant, metastasising tumor, such as a carcinoma, derived from epithelial cells. For example, if a cell mutates to produce a growth factor to which it already expresses the receptor (paracrine stimulation), that cell will replicate more frequently but will still be subject to cell cycle checkpoints to promote DNA integrity in its progeny. If an additional mutation overriding a cell cycle checkpoint occurs, that cell and its progeny may go on to accumulate further mutations, some of which may allow it to replicate an unlimited number of times by synthesis of telomerase, or to separate from its matrix and cellular attachments without undergoing apoptosis. As deregulated growth continues, cancer cells become increasingly unable to differentiate, fail to respond to local signals as in the normal tissue, and cease to ensure appropriate chromosomal segregation pre-division, generating the classical malignant pathological appearances of disorganised growth, variable levels of differentiation, and polyploidy. This sequence is illustrated for colon carcinomas in figure 1.18.

Since DNA mutation occur so infrequently, only an occasional cell will go on to acquire a further mutation, but this will be transmitted to the progeny of that cell which, due to their faster replication rates, are likely to constitute an increasing fraction of the tumor. It is likely that the morphological premalignant appearances of cancers reflect the underlying number of mutation, particularly as pathological evidence of increased malignancy can be seen arising within premalignant lesions.

Tumor Suppressors and the two-hit model of tumorigenesis

Tumor Suppressor genes tend to encode proteins whose normal function is to inhibit the cell cycle or to induce apoptosis to prevent transmission of uncorrectable DNA defects. Direct inhibitors of the cell cycle include pRB, illustrated in figure 1.15. Other tumor suppressor genes encode components of inhibitory growth factor-signaling pathways, particularly those of transforming growth factor (TGF)-β and its associated cytoplasmic signaling molecules such as Smad2 and Smad4 (which is the DPC4 ‘deleted in pancreatic carcinoma’ gene). As noted in the previous section, neurofibromin encodes as Ras inhibitor which is mutated in neurofibromatosis. APC, the gene mutated in familial adenomatous  polyposis and 60% of sporadic colon  adenomas and carcinomas, is bought to operate as an oncogene by rendering cells less susceptible to apoptosis. P53, a key tumor suppressor gene, normally uses both mechanisms to override other signals which would otherwise stimulate cell proliferation; details of P53 activity are highlighted in figure 1.16. The importance fo P53 is illustrated by the fact that it is inactivated in over 50% of human tumors, including breast and colon carcinomas, and childhood leukaemias.

When an oncogene results from a mutation reducing the activity of a tumor suppressor, a single mutation usually is insufficient to generate oncogenic activity unless an additional mutation in activities the second copy of the gene. This ‘two-hit’ model of tumorigenesis, developed by Knudson, is illustrated in figure 1.17. If, on the other hand, an oncogene results from over activity of a proto-oncogene, a mutation in only one of the two copies may be sufficient to promote tumorigenesis. This is also true in an important exception to the two-hit rule, in the case of the tumor suppressor gene P53, since mutation in only one allele may be sufficient to result in a biological effect. This reflects the operation of the protein as a tetramer, so abnormalities in any one of the subunits may derange its function.  

  

Cancer

CANCER:

Cancer arises because certain cells within a given tissue escape from normal growth controls, replicate more frequently, and migrate to sites distant from the parent tissue where further uncontrolled replication occurs. Such escape is facilitated by the accumulation of mutations within a cancerous cell as a result of the innate and environmental carcinogens to which cellular DNA is subjected. If errors generated in coding DNA are not repaired, these will be transmitted to the daughter strands as the cell divides. Clearly, mutations will arise more rapidly if external mutagenic stimuli are increased, or if the cell is defective in DNA repair systems.

ONCOGENES:

This term refers to a gene which has been mutated to facilitate neoplastic growth. The normal function of such genes may be the synthesis of factors involved in growth control, the cell cycle or apoptosis. Oncogenes can be broadly divided into two groups, according to whether their oncogenic effect results from overactivity of a ‘proto-oncogene’ or the loss of a ‘tumour suppressor’ function.   

Proto-Oncogene:

The majority of known oncogenes are components of signal transduction pathways in which mutations or the presence of increased copies of a gene result in overactivity, mimicking persistent growth factor stimulation. These include genes encoding receptors (e.g. erbB in breast carcinoma), cytoplasmic signalling moieties such as K-ras, and transcription factors such as c-myc (important in gastrointestinal tumours and leukaemias). A recently described class encode mitotic spindle binding proteins; mutation in these genes promote premature exit from anaphase, leading to incorrect chromosome segregation to daughter cells, and anaploidy. In animals, a number of tumours are caused by retroviruses which carry activated oncogenes, but to date this has not been shown to be a common mechanism in human cancer. Nevertheless, several human cancers are undoubtedly caused by infectious agents. Important examples include human papillomavirus E7 (which inappropriately phosphorylates pRB), leading to cervical carcinoma; herpesvirus 8 (which encodes a cyclin that drives the host cell through the G1-S checkpoint); and Epstein-Barr virus, responsible for Burkitt’s lymphoma and nasopharyngeal carcinoma.   

By: DAVIDSON’S

      Principles and Practice of Medicine

      Eighteenth Edition