biology of neoplasia

Chapter 22 Molecular biology of neoplasia

What genetic changes occur during the development of neoplasia?

How can knowledge of genetic changes enhance clinical care?

The development of neoplasms is associated with the gradual accumulation of genetic mutations within the neoplastic cells. Some mutations have no discernable effect while others can lead to serious neoplastic or non-neoplastic diseases. Changes to the genetic material may be substitution or loss of a single DNA nucleotide, a small series of nucleotides or part or the whole of a chromosome (Fig. 3.22.1). Even a single nucleotide substitution can result in gross damage (Fig. 3.22.2). Sometimes a germline (i.e. inherited) genetic mutation is already present within the non-neoplastic cells and this can accelerate the process of neoplastic transformation (Ch. 33). Study of the mutations occurring within neoplastic cell populations can provide an insight into neoplastic transformation and the development into malignancy. Mutations important in the initiation and progression of neoplasia tend to occur within genes whose products are involved in the regulation of cellular growth and differentiation (i.e. the process of maturation from primitive but multipotential stem cells to fully functional and specialized cells).

Fig. 3.22.1 Types of change to genetic material.

Fig. 3.22.2 Consequences of mutations.

Genetic mutations and neoplasia

Cells within neoplasms usually contain mutations within multiple genes, most commonly tumour suppressor genes or oncogenes. Mutations spontaneously occur within DNA at a low but significant rate, for example owing to imperfect DNA replication during preparation for cell division. DNA may also accumulate mutations at a higher rate (e.g. in the presence of ionizing radiation). However, many mutations are recognized and corrected by complex intracellular processes, thereby limiting their potentially harmful effects.

Tumour suppressor gene describes a gene whose normal function is essential for the prevention of neoplasia development (Table 3.22.1). Although each normal cell contains two copies of each of these genes, only one correctly functioning gene is required to prevent neoplasia development. Certain inherited cancer syndromes are characterized by the inheritance of one non-functioning copy of a particular tumour suppressor gene, with mutation of the second copy occurring at the site of tumour development. Knudson was the first to describe this process as the ‘two-hit hypothesis’, initially in the context of retinoblastoma (a malignant tumour of the retina). Patients with a family history of retinoblastoma (and therefore inheriting a mutation within one copy of the retinoblastoma tumour suppressor gene) developed tumours at a younger age, and more commonly bilaterally, than those without an apparent inherited predisposition. This observation was consistent with the hypothesis that inheritance of one mutated gene was associated with a greater risk of neoplasia since prevention of neoplasia was dependent upon the correct functioning of a single copy of the gene.

Table 3.22.1 Tumour suppressor genes

Gene	Function	Clinical manifestation^a
p53	Prevention of cells containing genetic mutations from progressing to mitosis; promotion of apoptosis of these affected cells	Li-Fraumeni syndrome (multiple cancers, especially carcinomas and sarcomas)
hMLH-1, hMSH-2	Repair of genetic mutations	Hereditary non-polyposis colorectal cancer syndrome (especially of proximal colon; endometrial cancer)
RB1	Regulation of the cell cycle	Retinoblastoma, osteosarcoma
APC	Uncertain	Familial adenomatous polyposis
BRCA-1	Growth control	Breast and ovarian cancer
BRCA-2	Uncertain	Breast cancer