GENETIC BASIS OF CANCER Cancer is a disease characterized by uncontrolled cell division It is a genetic disease at the cellular level More than 100 kinds of human cancers are known These are classified according to the type of cell that has become cancerous Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

Cancer characteristics 1. Most cancers originate in a single cell In this regard, a cancerous growth can be considered to be clonal 2. At the cellular and genetic levels, cancer is usually a multistep process It begins with a precancerous genetic change (i.e., a benign growth) Following additional genetic changes, it progresses to cancerous cell growth 3. Once a cellular growth has become malignant, the cells are invasive (i.e., they can invade healthy tissues) They are also metastatic (i.e., they can migrate to other parts of the body) Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

~ 1 million Americans are diagnosed with cancer each year About 500,000 will die from the disease 5-10% of cancers are due to inherited predisposition 90-95% are not A small subset of these is the result of spontaneous mutations and viruses However, at least 80% of cancers are related to exposure to mutagens These alter the structure and expression of genes An environmental agent that causes cancer is termed a carcinogen Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

The M checkpoint is monitored by proteins that can sense if a chromosome is not correctly attached to the spindle apparatus Both the G1 and G2 checkpoints involve proteins that can sense DNA damage G1 checkpoint (DNA damage) G2 checkpoint (Cell size) M checkpoint (Spindle assembly)

The M checkpoint is monitored by proteins that can sense if a chromosome is not correctly attached to the spindle apparatus Both the G1 and G2 checkpoints involve proteins that can sense DNA damage

Control of Cell Cycle Cell cycle checkpoints are control mechanisms that ensure the fidelity of cell division in eukaryotic cells. These checkpoints verify whether the processes at each phase of the cell cycle have been accurately completed before progression to the next phase. function of many checkpoints is to assess DNA damage, which is detected by sensor mechanisms – function of Checkpoint proteins

Proteins with a role in Cancer Checkpoint proteins prevent division of cells that may have incurred DNA damage Provides a mechanism to stop accumulation of genetic abnormalities that could produce cancer A second class of proteins involved with genome maintenance consists of DNA repair enzymes

~ 1 million Americans are diagnosed with cancer each year About 500,000 will die from the disease 5-10% of cancers are due to inherited predisposition 90-95% are not A small subset of these is the result of spontaneous mutations and viruses However, at least 80% of cancers are related to exposure to mutagens These alter the structure and expression of genes An environmental agent that causes cancer is termed a carcinogen Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

Genetic Changes leading to Cancer Some genes affect growth directly, others may enable metastasis which allows expansion to new locations, giving the cells a growth advantage Estimated that 300 different genes may play a role in development of human cancer over 1% of our genes Chromosomal abnormalities are often associated with cancer Missing chromosomes may have carried tumor suppressor Duplicated chromosomes may overexpress proto-oncogenes Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

Two major classes of cancer causing genes Oncogenes - Proto-oncogenes are genes that normally help cells grow. When a proto-oncogene mutates (changes) or there are too many copies of it, it becomes a "bad" gene that can become permanently turned on or activated when it is not supposed to be. When this happens, the cell grows out of control, which can lead to cancer. This bad gene is called an oncogene. Tumor Suppressor genes - Tumor suppressor genes are normal genes that slow down cell division, repair DNA mistakes, or tell cells when to die (a process known as apoptosis or programmed cell death). When tumor suppressor genes don't work properly, cells can grow out of control, which can lead to cancer.

Expression becomes abnormally active proto-oncogenes are normal cellular genes that can be mutated into an oncogene. Expression becomes abnormally active This can occur in three ways: 1. The oncogene may be overexpressed This yields too much of the encoded protein 2. The oncogene may produce an aberrant protein Mutations that alter the amino acid sequence of a cell cycle protein, keep the cell division signaling pathway turned on 3. The oncogene may be expressed in a cell type where it is not normally expressed Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

The function of tumor-suppressor genes can be lost in three main ways: 1. A mutation in the tumor-suppressor gene itself The promoter could be inactivated An early stop codon could be introduced in the coding sequence 2. DNA methylation The methylation of CpG islands near the promoters of tumor-suppressor genes, inhibits transcription 3. Aneuploidy Chromosome loss may contribute to the progression of cancer if the lost chromosome carries one or more tumor-suppressor genes Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

Some tumor-suppressor genes encode proteins that function in the sensing of genome integrity genome maintenance refers to the mechanisms that prevent mutations or prevent mutant cells from surviving or dividing These proteins can detect abnormalities such as DNA breaks and improperly segregated chromosomes Many of these proteins are called checkpoint proteins They check the integrity of the genome and prevent cells from progressing past a certain point of the cell cycle if there is damage Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

Roles of Tumor-Suppressor Genes During the past three decades, researchers have identified many tumor-suppressor genes Some encode proteins that have direct effects on the regulation of cell division Others play a role in the proper maintenance of the genome Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

The p53 Gene: The Master Tumor-Suppressor Gene About 50% of all human cancers are associated with defects in the p53 gene A primary role for the p53 protein is to determine if a cell has incurred DNA damage If so, p53 will promote three types of cellular pathways to prevent the division of cells with damaged DNA Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

Central role of p53 in preventing the proliferation of cancer cells In multi-cellular organisms, individual cells which have undergone irreparable DNA damage will go through programmed cell death Central role of p53 in preventing the proliferation of cancer cells

Inherited Forms of Cancers As mentioned earlier, about 5% to 10% of all cancers involve germ-line mutations People who have inherited such mutations have a predisposition to develop cancer Genetic testing exists for certain types of cancer Familial adenomatous polyposis Most inherited forms of cancer involve a defect in tumor-suppressor genes Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

Tumor-Suppressor Genes and Their Effects on Cell Division Tumor-suppressor genes prevent the proliferation of cancer cells If they are inactivated by mutation, it becomes more likely that cancer will occur The first identification of a human tumor-suppressor gene involved studies of retinoblastoma A tumor of the retina of the eye Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

retinoblastoma

Most individuals have two normal copies of this gene related to retinoblastoma Persons with hereditary retinoblastoma have inherited one functionally defective copy In nontumorous cells of the body, they have one normal copy and one defective copy of rb In retinal tumor cells, the normal rb gene has also suffered the second hit, rendering it defective People with the inherited form have already received one mutation from one of their parents It is not unlikely that a second mutation occurs in one of the retinal cells at an early age, leading to disease People with the noninherited form, must have two mutations in the same retinal cell to cause the disease Two rare events are much less likely to occur than a single event Therefore, the noninherited form occurs much later in life, and only rarely Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

( Development of cancer at the cellular level (Inherited mutation) Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. , l , Normal cell Cancer cell BRCA-1 BRCA-1 BRCA-1 BRCA-1 ( Development of cancer at the cellular level (Inherited mutation) (Occurs in a somatic cell) (Inherited mutation) Heterozygote – cell has one functional copy of BRCA-1 Loss of heterozygosity – cell has zero functional copies of BRCA-1 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display