Chapter 16 – Cancer Genetics

explain Tumor Formation

As they lose their response to the normal controls, cancer cells gradually lose their regular shape and boundaries, eventually forming a distinct mass of abnormal cells—a tumor

Malignant

Tumor consisting of cells that invade other tissues

Metastasis

Cells that travel to other sites in the body, where they establish secondary tumor

Cancer arises as a result of

fundamental defects in the regulation of cell division, and its study therefore has signifi cance not only for public health but also for our basic understanding of cell biology

Some specific types of cancers tend to run in families observations hinted that genes play some role in cancer, the theory of cancer as a genetic disease had several significant problems, what are they?

• If cancer is inherited, then every cell in the body should receive the cancer-causing gene, and therefore, every cell should become cancerous. In the types of cancer that run in families, however, tumors typically appear only in certain tissues and often only when the person reaches an advanced age.

• Finally, many cancers do not run in families at all, and even in those cancers that generally do, isolated cases crop up in families with no history of the disease.

Knudson’s proposal suggested

cancer is the result of a multistep process that requires several mutations. If one or more of the required mutations are inherited, fewer additional mutations are required to produce cancer, and the cancer tends to run in families

• Knudson’s idea has been called the “two-hit hypothesis” because, in retinoblastoma, only two mutations are necessary to cause a tumor.

Cancer begins when

a single somatic cell undergoes a mutation that causes the cell to divide at an abnormally rapid rate. The cell proliferates, giving rise to a clone of cells, each of which carries the same mutation. Because the cells of the clone divide more rapidly than normal, they soon outgrow other cells. An additional somatic mutation that arises in some of the clone’s cells may further enhance the ability of those cells to proliferate, and cells carrying both mutations soon become the most common cells in the clone in a process known as clonal evolution

clonal evolution

Process by which mutations that enhance the ability of cells to proliferate predominate in a clone of cells, allowing the clone to become increasingly rapid in growth and increasingly aggressive in proliferation properties.

The rate of clonal evolution depends on

the frequency with which new mutations arise. Any genetic defect that allows more mutations to arise will accelerate cancer progression

• Mutations in genes that affect chromosome segregation may also contribute to the clonal evolution of tumors.

The role of environmental factors in cancer is suggested by

differences in the incidence of specifi c cancers throughout the world

• those that have the greatest eff ects include tobacco use, diet, obesity, alcohol, and UV radiation

The signals that regulate cell division fall into what two basic types?

• molecules that stimulate cell division

• molecules that inhibit it.

Tumor-suppressor genes

Gene that normally inhibits cell division. Recessive mutations in such genes often contribute to cancer.

Oncogenes

Dominant-acting gene that stimulates cell division, leading to the formation of tumors and contributing to cancer; arises from a mutated copy of a normal cellular gene (proto-oncogene). the first cancer-causing genes to be identified

What is meant by Tumor suppresor genes are recessive?

both alleles must be mutated before the inhibition of cell division is removed and Defects in both copies of a tumor-suppressor gene are usually required to cause cancer.

loss of heterozygosity

Inactivation or loss of the wild-type allele of a heterozygote

Haploinsufficiency

Appearance of a mutant phenotype in an individual cell or organism that is heterozygous for a normally recessive trait.

The RB protein helps

control a cell’s progression through the G1/S checkpoint by binding transcription factor E2F.

APC

• Normal function: Scaffold protein, interacts with microtubules

• Cancer in which gene is mutated: Colorectal

BRCA1

• Normal function: DNA repair, transcription factor

• Cancer in which gene is mutated: Breast and ovarian

CDKN2A

• Normal function: Regulates cell division

• Cancer in which gene is mutated: Melanoma

NF1

• Normal function: GTPase activator

• Cancer in which gene is mutated: Neurofibromatosis

p53

• Normal function: Regulates cell division, apoptosis, DNA repair,

  and other functions

• Cancer in which gene is mutated: Many types of cancer

RB

• Normal function: Regulates cell division

• Cancer in which gene is mutated: Retinoblastoma and many other cancers

Key events of the cell cycle are controlled by

cyclin-dependent kinases (CDKs) 

cyclin-dependent kinases (CDKs)

A key protein in the control of the cell cycle; combines with cyclin.

Cyclin

A key protein in the control of the cell cycle; combines with a cyclin-dependent kinase (CDK). The levels of cyclin rise and fall in the course of the cell cycle.

Apoptosis

a process of programmed cell death in which the cell’s DNA is degraded, its nucleus and cytoplasm shrink, and the cell undergoes phagocytosis by other cells without the leakage of its contents.

• The ability of a cell to initiate apoptosis in response to DNA damage, for example, depends on p53, which is inactive in many human cancers.

autophagy

proteins, cytoplasm, damaged organelles, and other cellular components are engulfed by vesicles within the cell and transported to lysosomes, where they are degraded and their components recycled.

• has been shown to suppress tumor formation under some conditions and promote tumor growth under others.

Oxygen and nutrients, which are essential to the survival and growth of tumors, are supplied by blood vessels, and the growth of new blood vessels (_______) is important to tumor progression

angiogenesis

Angiogenesis is stimulated by

growth factors and other proteins encoded by genes whose expression is carefully regulated in normal cells.

In the development of many cancers, the primary tumor gives rise to cells that spread to distant sites, producing secondary tumors. This is called ______ and is the cause of death in 90% of human cancer deaths.

metastasis

Metastasis

a complex process, requiring that cancer cells escape from the primary tumor site, evade the immune system, travel to a distant site, adhere to existing cells at the new site, and receive nutrients and growth factors necessary for sustained growth. The process requires numerous cellular changes induced by somatic mutation at a number of genes.

Epigenetic changes

alterations to chromatin structure that aff ect gene expression—are seen in many cancer cells.

These two broad lines of evidence suggest that epigenetic changes play an important role in cancer progression:

1. genes encoding proteins that are important regulators of epigenetic changes are often mutated in some types of cancer

2. genomic studies that have compared the chromatin structure of cancer cells with that of normal cells from the same individual. These studies often fi nd that the cancer cells have signifi cant alterations to their DNA methylation patterns and histone structure. Research has also demonstrated that the histone proteins in nucleosomes—the fundamental units of chromatin—are often abnormally modified in cancer cells.

   1. Modification of histone proteins, including methylation and acetylation, alters chromatin structure and aff ects whether transcription occurs

In cancer Deletions can result in

the loss of one or more tumor suppressor genes.

Inversions and translocations contribute to cancer in several ways, what are they?

• First, the chromosome breaks that accompany these mutations can lie within tumor-suppressor genes, disrupting their function and leading to cell proliferation

• Second, translocations and inversions can bring together sequences from two diff erent genes, generating a fusion protein that stimulates some aspect of the cancer process

• A third mechanism by which chromosome rearrangements can produce cancer is the transfer of a potential cancer-causing gene to a new location, where it is activated by diff erent regulatory sequences.

Human papillomavirus (HPV)

Virus associated with cervical cancer.

Many of the viruses that cause cancer in animals are _____

retroviruses

Retroviruses can cause cancer by

1. mutating or rearranging proto-oncogenes

2. inserting strong promoters near proto-oncogenes.