II. Inherited risk of cancer.

III. Tumor suppressor genes.

Terms

Notes p. 334, paragraph 5, last line: This phrasing is misleading. Retinoblastoma arises later in general if two mutations are required, but "later" still means early childhood. p. 349, Summary, No. 1: Misleading. Cancer per se is very rarely present at birth. However, there are a number of genotypes for which the risk of eventual development of cancer is 100%, provided something else doesn't get you first.

I. Tumors are abnormal growth of tissue. Most involve somatic cells.

A. Cancers are tumors that are malignant.
1. They can undergo metastasis, i.e. cells can detach from the primary tumor and form secondary tumors at remote sites.

2. They can invade other tissues.

B. Benign tumors do not spread to other tissues nor are they invasive.
1. Benign tumors cause problems, if any, by increasing in size until they interfere with neighboring organs.

2. Some benign tumors can evolve into malignant tumors, a process sometimes referred to as transformation.

C. Some additional characteristics of cancers are:
1. They are clonal, i.e. all the cells of a cancer, including metastases, are descendants of a single cell. This was first demonstrated by the observation that in females heterozygous for X-linked traits, only one of the two X chromosomes is expressed in a tumor.

2. They are not subject to the normal regulation or restraints on growth.

3. Over time, cancer cells evolve from a slow-growing form to more aggressive growth. This happens through a series of stepwise changes, each representing a new clonal population.

D. Several factors are known to increase the risk of cancer.
1. Ionizing radiation and ultraviolet light.

2. Certain chemicals.

3. Certain rare viruses, such as Rous sarcoma virus in chickens and mouse mammary tumor virus.

4. In some families, heredity is important.

E. The basic defect in cancer is impairment of the systems that regulate cell cycles.

A. Overall, the risk of cancer developing in a first-degree relative of a cancer patient is slightly elevated over the general population, on the order of 3-5%.

B. Cancer clusters in some families at a much higher rate. In some of these, simple Mendelian dominant inheritance is obvious. Examples include:

1. Multiple polyposis of the colon (APC, adenomatous polyposis coli). The colon and often other areas of the intestinal tract have hundreds to thousands of polyps, with inevitable transformation of one or more into a malignant state. The APC gene has been mapped to 5q21. Expression of the mutant alleles associated with multiple polyps is dominant, the polyps usually appearing at 10 to 20 years of age.

2. Retinoblastoma is a malignant tumor that develops from embryonic cells in the retina (retinoblasts) in young children. After several years of age, retinoblasts are no longer present and the risk of developing new retinoblastomas virtually disappears. In many instances, the risk of retinoblastoma is transmitted as an autosomal dominant trait, although penetrance is less than 100%. The RB locus is at 13q14. Nonfamilial (isolated) cases of retinoblastoma also occur.

3. Two major breast cancer genes have now been isolated. BRCA1 on chromosome 17 carries a high risk of breast and ovarian cancer. BRCA2 on chromosome 13 carries a high risk of breast (but not ovarian) cancer. The risk of breast cancer in males is also increased with mutations in BRCA2.

C. Several autosomal recessive disorders are associated with high risk of developing cancer. Examples are xeroderma pigmentosum and Bloom syndrome, both of which, in addition to other problems, have a 100% risk of skin cancer. These conditions involve defects in DNA repair. Hereditary nonpolyposis cancer of the colon (HNPCC), which also involves a defect in DNA repair, is inherited as an autosomal dominant trait.

A. In 1971, Knudson proposed that retinoblastoma develops when the RB gene becomes homozygous mutant (defective) in a retinoblast cell. In familial cases, one of the mutant alleles is transmitted in the pedigree, and one additional somatic mutation must occur. In isolated (nonfamilial) cases, the zygote starts with two normal alleles, but two mutations arise independently in a retinoblast. In the latter case, since the two mutations both occur in somatic cells, the risk of retinoblastoma is not transmitted to offspring.

B. In retinoblastoma and in most other dominantly inherited cancers, the presence of one normal allele is sufficient to suppress development of cancer. This suppression is lost when both alleles become nonfunctional. Therefore, when the locus is functioning normally, tumors do not develop.

C. In general, the function of tumor suppressor genes is to regulate the cell cycle. The product of the RB locus, a protein designated RB, regulates progression from G1 into S. When RB is in its unphosphorylated form, progression does not occur. When RB is inactivated by phosphorylation in a normal cell, the transition from G1 to S occurs and the cell eventually divides. The state of phosphorylation of RB is controlled by a complex network of other regulatory proteins. If functional RB is missing because of mutation, cells divide continuously.

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