Medical Genetics and Cancer

INTRODUCTION Approximately 12,000 genetic diseases afflict people This is probably an underestimate Many of these are the direct result of a mutation in one gene Genes also play roles in the development of Diseases that have a complex pattern of inheritance May involve multiple genes E.g., Diabetes, asthma, mental illness Unraveling the complexities of these diseases will be a challenge for some time to come Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

Observations of Human Diseases For traits and diseases, geneticists want to know the relative contributions from genetics and environment Geneticists cannot conduct human crosses to elucidate the genetic basis for diseases Instead, they must rely on analyses of families that already exist Several observations are consistent with the idea that a disease is caused, at least in part, by genes Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

Pedigree Analysis The pattern of inheritance of monogenic disorders, can be deduced by analyzing human pedigrees To use this method, a geneticist must obtain data from large pedigrees with many affected individuals Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

A family pedigree of Tay-Sachs disease

A family pedigree of Huntington disease

The inheritance pattern of hemophilia A in the royal families of Europe

Genetic screening refers to population-wide genetic testing Genetic testing refers to the use of tests to discover if an individual carries a genetic abnormality Genetic screening refers to population-wide genetic testing Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

Single gene mutations can also be examined at the level of the gene In many cases, single-gene mutation that affect proteins, can be examined at the protein level Biochemical assays may be available for enzymes Single gene mutations can also be examined at the level of the gene - Sequencing previously identified the mutant gene using molecular techniques A common class of human genetic abnormality is the change in chromosome number Most of these result in spontaneous abortions However, about 1 in 200 live births are aneuploid or have unbalanced chromosomal alterations Chromosomal abnormalities can be detected with a karyotype Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

In the U.S., genetic screening for certain disorders has become common medical practice For example Pregnant women over 35 years of age are screened routinely to see if they are carriers of chromosomal abnormalities Rates of such defects increase with the age of the mother Widespread screening for phenylketonuria Genetic testing has also been conducted on specific population in which a genetic disease is prevalent Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

Another issue is privacy Genetic testing and screening are medical practices with many social and ethical dimensions Do people want to know if they have a mutant gene Especially unclear if there is no known treatment May do more harm than good Another issue is privacy Could employers or insurance companies discriminate against someone with a positive genetic test In this century we will become more aware of our genetic makeup and the causes of genetic diseases It will be necessary therefore, to establish guidelines for the uses of genetic testing This may be easier said than done! Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

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

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

Progression of cellular growth leading to cancer

Certain Viruses Can Cause Cancer A few viruses are known to cause cancer in plants, animals and humans Many of these viruses can also infect lab-grown cells and convert them into malignant cells Most cancer-causing viruses are not very potent at inducing cancer 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

Proto-Oncogenes Can Be Converted into Oncogenes A proto-oncogene is a normal cellular gene that can incur a mutation to become an oncogene How this occurs is a fundamental issue in cancer biology By studying proto-oncogenes, researchers have found that this occurs in four main ways: 1. Missense mutations 2. Gene amplifications 3. Chromosomal translocations 4. Viral integration Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

Missense mutations can convert proto-oncogenes into oncogenes Experimentally, chemical carcinogens have been shown to cause these missense mutations and thereby lead to cancer Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

Many human cancers are associated with the amplification of particular oncogenes Amplification of N-myc in neuroblastom and erbB-2 in breast carcinoma Specific types of chromosomal translocations have been identified in certain types of tumors chronic myelogenous leukemia was correlated with the presence of a shortened chromosome 22 This was called this the Philadelphia chromosome after the city where it was discovered The cause is not a deletion; Rather a translocation between chromosomes 9 and 22 This puts the proto-oncogene abl under the control of the bcr promoter, which is active in white blood cells, leading to leukemia Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

An oncogene that encodes an abnormal fusion protein A proto-oncogene An oncogene that encodes an abnormal fusion protein 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

There are two types of retinoblastoma 1. Inherited, which occurs in the first few years of life 2. Noninherited, which occurs later in life Alfred Knudson proposed a “two-hit” model for retinoblastoma Retinoblastoma requires two mutation to occur 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

Since Knudson’s original hypothesis in 1971, molecular studies have confirmed the “two-hit” hypothesis The rb gene (for retinoblastoma) is on the long arm of chromosome 13 Most individuals have two normal copies of this gene 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 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

The p53 Gene: The Master Tumor-Suppressor Gene The p53 gene was the second tumor-suppressor gene discovered 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

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

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

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

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

Karyotype from a cancer cell (right) show fusions of chromosomes, duplications and deletions Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

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

Inherited Forms of Cancers Predisposition for developing cancer is often the result of being heterozygous for one of these genes Cancer results from loss of the normal copy This is known as loss of heterozygosity (LOH) Tends to be inherited in a dominant fashion Can result from point mutation in normal allele Can also occur if chromosome carrying good copy is lost Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display

Heterozygous for BRCA-1 mutation, affected Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. , Homozygous normal Heterozygous for BRCA-1 mutation, affected , Heterozygous for BRCA-1 mutation, unaffected Normal cell Cancer cell BRCA-1 BRCA-1 BRCA-1 BRCA-1 (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 (a) Pedigree for familial breast cancer (b) Development of cancer at the cellular level Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display