Cancer Genetics and Genomics

• Genetic basis of cancer
• Cancer in families
• Familial occurrence of cancer
• Sporadic cancer
• Cytogenetic changes in cancer
• Cancer and the environment

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Chapter 9

Lecture structure

Genetic Basis of Cancer

Regardless of whether a cancer occurs sporadically in an individual, as a result of somatic mutation, or repeatedly in many individuals in a family as a hereditary trait, cancer is a genetic disease.

• Genes in which mutations cause cancer are referred to as driver genes, and the cancer causing mutations in these genes are driver mutations.
• Driver genes fall into two distinct categories: activated oncogenes and tumor suppressor genes (TSGs).
• An activated oncogene is a mutant allele of a proto-oncogene, a class of normal cellular protein-coding genes that promotes growth and survival of cells. Oncogenes facilitate malignant transformation by stimulating proliferation or inhibiting apoptosis.

Oncogenes encode proteins such as the following:

• Proteins in signaling pathways for cell proliferation
• Transcription factors that control the expression of growth promoting genes
• Inhibitors of programmed cell death machinery
• A TSG is a gene in which loss of function through mutation or epigenomic silencing directly removes normal regulatory controls on cell growth or leads indirectly to such losses through an increased mutation rate or aberrant gene expression. TSGs encode proteins involved in many aspects of cellular function, including maintenance of correct chromosome number and structure, DNA repair proteins, proteins involved in regulating the cell cycle, cellular proliferation, or contact inhibition, just to name a few examples.

• Tumor initiation can be caused by different types of genetic alterations.

These include mutations such as the following:

• Activating or gain-of-function mutations, including gene amplification, point mutations, and promoter mutations, that turn one allele of a proto-oncogene into an oncogene
• Ectopic and heterochronic mutations of protooncogenes
• Chromosome translocations that cause misexpression of genes or create chimeric genes encoding proteins with novel functional properties
• Loss of function of both alleles, or a dominant negative mutation of one allele, of TSGs

• Tumor progression occurs as a result of accumulating additional genetic damage, through mutations or epigenetic silencing, of driver genes that encode the machinery that repairs damaged DNA and maintains cytogenetic normality. A further consequence of genetic damage is altered expression of genes that promote vascularization and the spread of the tumor through local invasion and distant metastasis.

Cellular Heterogeneity within Individual Tumors

• The accumulation of driver gene mutations does not occur synchronously, in lockstep, in every cell of a tumor.
• To the contrary, cancer evolves along multiple lineages within a tumor, as chance mutational and epigenetic events in different cells activate protooncogenes and cripple the machinery for maintaining genome integrity, leading to more genetic changes in a vicious cycle of more mutations and worsening growth control.
• The lineages that experience an enhancement of growth, survival, invasion, and distant spread will come to predominate as the cancer evolves and progresses.
• In this way, the original clone of neoplastic cells evolves and gives rise to multiple sublineages, each carrying a set of mutations and epigenomic alterations that are different from but overlap with what is carried in other sublineages.

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• The profile of mutations and epigenomic changes can differ between the primary and its metastases, between different metastases, and even between the cells of the original tumor or within a single metastasis.

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Stages in the evolution of cancer

Cancer in Families

• Many forms of cancer have a higher incidence in relatives of patients than in the general population.
• In some cases, this increased incidence is due primarily to inheritance of a single mutant gene with high penetrance.
• These mutations result in hereditary cancer syndromes following mendelian patterns of inheritance.
• Among these syndromes, we currently know of approximately 100 different genes in which deleterious mutations increase the risk for cancer many-fold higher than in the general population.

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• There are also many dozens of additional genetic disorders that are not usually considered to be hereditary cancer syndromes and yet include some increased predisposition to cancer (for example, the ten- to twenty-fold increased lifetime risk for leukemia in Down syndrome).

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• These clear examples notwithstanding, it is important to emphasize that not all families with an apparently increased incidence of cancer can be explained by known mendelian or clearly recognized genetic disorders.

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• These families likely represent the effects of both shared environment and one or more genetic variants that increase susceptibility and are therefore classified as multifactorial, with complex inheritance.

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• Although individuals with a hereditary cancer syndrome represent probably less than 5% of all patients with cancer, identification of a genetic basis for their disease has great importance both for clinical management of these families and for understanding cancer in general.
• First, the relatives of individuals with strong hereditary predispositions, which are most often due to mutations in a single gene, can be offered testing and counseling to provide appropriate reassurance or more intensive monitoring and therapy, depending on the results of testing.

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• Second, as is the case with many common diseases, understanding the hereditary forms of the disease provides crucial insights into disease mechanisms that go far beyond the rare hereditary forms themselves.

Activated Oncogenes in Hereditary Cancer Syndromes�Multiple Endocrine Adenomatosis, Type 2

• The type A variant of multiple endocrine adenomatosis, type 2 (MEN2) is an autosomal dominant disorder characterized by a high incidence of medullary carcinoma of the thyroid that is often but not always associated with pheochromocytoma, benign parathyroid adenomas, or both.
• The mutations responsible for MEN2 are in the RET gene.
• Individuals who inherit an activating mutation in RET have a greater than 60% chance of developing a particular type of thyroid carcinoma (medullary), although more sensitive tests, such as blood tests for thyrocalcitonin or urinary catecholamines synthesized by pheochromocytomas, are abnormal in well above 90% of heterozygotes for MEN2.

• RET encodes a cell-surface protein that contains an extracellular domain that can bind signaling molecules and a cytoplasmic tyrosine kinase domain.
• Tyrosine phosphorylation initiates a signaling cascade of changes in protein-protein and DNA-protein interactions and in the enzymatic activity of many proteins.

• The mutations in RET that cause MEN2A increase its kinase activity even in the absence of its ligand (a state referred to as constitutive activation).

The Two-Hit Theory of Tumor Suppressor Gene Inactivation in Cancer

• Whereas the proteins encoded by proto-oncogenes promote cancer when activated or overexpressed, mutations in TSGs contribute to malignancy by a different mechanism, the loss of function of both alleles of the gene.
• The existence of TSG mutations leading to cancer was proposed to explain why certain tumors can occur in either hereditary or sporadic forms.
• It was suggested that the hereditary form of the childhood cancer retinoblastoma might be initiated when a cell in a person heterozygous for a germline mutation in the retinoblastoma TSG, required to prevent the development of the cancer, undergoes a second, somatic event that inactivates the other retinoblastoma gene allele.
• As a consequence of this second somatic event, the cell loses function of both alleles, giving rise to a tumor.

• In the sporadic form of retinoblastoma, both alleles are also inactivated from two somatic events occurring in the same cell.
• This so-called two-hit model is now widely accepted as the explanation for many hereditary cancers.

Selected Tumor Suppressor Genes

Comparison of mendelian and sporadic forms of cancers such as retinoblastoma and familial polyposis of the colon.

Tumor Suppressor Genes (TSG) in Autosomal Dominant Cancer Syndromes

• Retinoblastoma
• Retinoblastoma is the prototype of diseases caused by mutation in a TSG and is a rare malignant tumor of the retina in infants, with an incidence of approximately 1 in 20,000 births.
• Diagnosis of a retinoblastoma must usually be followed by removal of the affected eye, although smaller tumors, diagnosed at an early stage, can be treated by local therapy so that vision can be preserved.

Retinoblastoma in a young girl, showing as a white reflex in the affected left eye when light reflects directly off the tumor surface.

• Approximately 40% of cases of retinoblastoma are of the heritable form, in which the child inherits one mutant allele at the retinoblastoma locus (RB1) through the germline from either a heterozygous parent or, more rarely, from a parent with germline mosaicism for an RB1 mutation.
• In these children, retinal cells, which like all the other cells of the body are already carrying one inherited defective RB1 allele, suffer a somatic mutation or other alteration in the remaining normal allele, leading to loss of both copies of the RB1 gene and initiating development of a tumor in each of those cells.
• The disorder appears to be inherited as a dominant trait because the large number of primordial retinoblasts and their rapid rate of proliferation make it very likely that a somatic mutation will occur as a second hit in one or more of the more than 10⁶ retinoblasts already carrying an inherited RB1 mutation.

• Because the chance of a second hit is so great, it occurs frequently in more than one cell, and thus heterozygotes for the disorder often have tumors arising at multiple sites, such as multifocal tumors in one eye, in both eyes (bilateral retinoblastoma), or in both eyes, as well as in the pineal gland (referred to as “trilateral” retinoblastoma).
• It is worth emphasizing, however, that the occurrence of a second hit is a matter of chance and does not occur 100% of the time; the penetrance of retinoblastoma therefore, although greater than 90%, is not complete.
• The other 60% of cases of retinoblastoma are sporadic; in these cases, both RB1 alleles in a single retinal cell have been mutated or inactivated independently by chance, and the child does not carry an RB1 mutation inherited through the germline.

• Because two hits in the same cell is a statistically rare event, there is usually only a single clonal tumor, and the retinoblastoma is found at one location (unifocal) in one eye only.
• Unilateral tumor is no guarantee that the child does not have the heritable form of retinoblastoma, however, because 15% of patients with the heritable type develop a tumor in only one eye.
• Another difference between hereditary and sporadic tumors is that the average age at onset of the sporadic form is in early childhood, later than in infants with the heritable form, reflecting the longer time needed on average for two mutations, rather than one, to occur.
• In a small percentage of patients with retinoblastoma, the mutation responsible is a cytogenetically detectable deletion or translocation of the portion of chromosome 13 that contains the RB1 gene. Such chromosomal changes, if they also disrupt genes adjacent to RB1, may lead to dysmorphic features in addition to retinoblastoma.

Nature of the Second Hit

• Typically, for retinoblastoma as well as for the other hereditary cancer syndromes, the first hit is an inherited mutation, that is, a change in the DNA sequence.
• The second hit, however, can be caused by a variety of genetic, epigenetic, or genomic mechanisms; although it is most often a somatic mutation, loss of function without mutation, such as occurs with epigenetic silencing, has also been observed in some cancer cells.
• The common theme is loss of function of RB1.
• The RB1 gene product, p110 Rb1, is a phosphoprotein that normally regulates entry of the cell into the S phase of the cell cycle.
• Thus loss of the RB1 gene and/or absence of the normal RB1 gene product (by whatever mechanism) deprives cells of an important checkpoint and allows uncontrolled proliferation.

Loss of Heterozygosity (LOH)

• Individuals with retinoblastoma who were heterozygous at polymorphic loci flanking the RB1 locus in normal tissues had tumors that contained alleles from only one of their two chromosome 13 homologues, revealing a loss of heterozygosity (LOH) in tumor DNA in and around the RB1 locus.
• Furthermore, in familial cases, the retained chromosome 13 markers were the ones inherited from the affected parent, that is, the chromosome with the abnormal RB1 allele.
• Thus, in these cases, LOH represents the second hit of the remaining allele.
• LOH may occur by interstitial deletion, but there are other mechanisms as well, such as mitotic recombination or monosomy 13 due to nondisjunction.
• LOH is the most common mutational mechanism by which the function of the remaining normal RB1 allele is disrupted in heterozygotes.

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• LOH is a feature of tumors in a number of cancers, both heritable and sporadic, and is often considered evidence for the existence of a TSG in the region of LOH.

Chromosomal mechanisms that could lead to loss of heterozygosity

• Familial Breast Cancer due to Mutations in BRCA1 and BRCA2

• Breast cancer is common. Among all cases of this disease, a small proportion (≈3% to 5%) appears to be due to a highly penetrant dominantly inherited mendelian predisposition that increases the risk for female breast cancer fourfold to sevenfold over the 12% lifetime risk observed in the general female population.

• Features characteristic of hereditary breast cancer:
• multiple affected individuals in a family,
• earlier age at onset,
• frequent multifocal, bilateral disease or second independent primary breast tumor, and
• second primary cancers in other tissues such as ovary and prostate.

• The two genes responsible for the majority of all hereditary breast cancers are BRCA1 and BRCA2.
• Together, these two TSGs account for approximately one half and one third, respectively, of autosomal dominant familial breast cancer.
• Numerous mutant alleles of both genes have now been catalogued.
• Mutations in BRCA1 and BRCA2 are also associated with a significant increase in the risk for ovarian and fallopian duct cancer in female heterozygotes.
• Moreover, mutations in BRCA2 and, to a lesser extent, BRCA1, also account for 10% to 20% of all male breast cancer and increase the risk for male breast cancer ten to sixtyfold over the 0.1% lifetime risk observed among males in the general population.

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Lifetime Cancer Risks in Carriers of BRCA1 or BRCA2 Mutations Compared to the General Population �

• As might be expected for any TSG, tumor tissue from heterozygotes for BRCA1 and BRCA2 mutations frequently demonstrates LOH with loss of the normal allele.

• The discrepancy between the penetrance of mutant alleles in families with multiple occurrences of breast cancer and the penetrance seen in women identified by population screening and not by family history suggests that other genetic or environmental factors must play a role in the ultimate penetrance of BRCA1 and BRCA2 mutations in women heterozygous for these mutations.
• In addition to mutations in BRCA1 and BRCA2, mutations in other genes can also cause autosomal dominantly inherited breast cancer syndromes, albeit less commonly.
• These syndromes, which include:
• Li-Fraumeni
• Peutz-Jeghers
• These syndromes, demonstrate lifetime breast cancer risks that approach those seen in carriers of BRCA1 or BRCA2 mutations, as well as risks for other forms of cancer such as sarcomas, brain tumors, and carcinomas of the stomach, thyroid, and small intestine.

Penetrance of BRCA1 and BRCA2 Mutations

• Cowden syndrome
• Hereditary diffuse gastric cancer

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• Clinicians faced with a family with multiple affected individuals with breast cancer often look for distinguishing signs in the patient and in the family history to help guide the choice of which genes to analyze.
• However, the rapid decline in the cost of gene or even genome-wide sequencing has allowed the development of gene panels in which a dozen or more candidate genes can be accurately and simultaneously tested for mutations, often at a cost that is equivalent or even less than what was charged previously to analyze just one or two genes.

• Hereditary Colon Cancer

• Colorectal cancer, a malignancy of the epithelial cells of the colon and rectum, is responsible for approximately 10% to 15% of all cancer.
• Most cases are sporadic, but a small proportion of colon cancer cases are familial, among which are two autosomal dominant conditions:
• Familial adenomatous polyposis (FAP) and
• Lynch syndrome (LS), along with their variants.

Familial Adenomatous Polyposis (FAP)

• FAP and its subvariant, Gardner syndrome, together have an incidence of approximately 1 per 10,000.
• Because this disorder is inherited as an autosomal dominant trait, relatives of affected persons must be examined periodically by colonoscopy.
• FAP is caused by loss-of-function mutations in a TSG known as the APC gene (so-named because the condition used to be called adenomatous polyposis coli).

Lynch Syndrome (LS)

• Approximately 2% to 4% of cases of colon cancer are attributable to LS.
• LS is characterized by autosomal dominant inheritance of colon cancer in association with a small number of adenomatous polyps that begin during early adulthood.
• LS results from loss-of-function mutations in one of four distinct but related DNA repair genes (MLH1, MSH2, MSH6, and PMS2) that encode mismatch repair proteins.
• Like the BRCA1 and BRCA2 genes, the LS mismatch repair genes are TSGs involved in maintaining the integrity of the genome.

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• At the cellular level, the most striking phenotype of cells lacking mismatch repair proteins is an enormous increase in both point mutations and mutations occurring during replication of simple DNA repeats, such as a segment containing a string of the same base, for example (A)n, or a microsatellite, such as (TG)n.

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• Such instability, referred to as the microsatellite instability-positive (MSI+) phenotype, occurs at two orders of magnitude higher frequency in cells lacking both copies of a mismatch repair gene.

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• The MSI+ phenotype is easily seen in DNA as three, four, or even more alleles of a microsatellite polymorphism in a single individual's tumor DNA.
• It is estimated that cells lacking both copies of a mismatch repair gene may carry 100,000 mutations within simple repeats throughout the genome.

Gel electrophoresis of a different microsatellite polymorphic marker in normal (N) and tumor (T) sample from a patient with a mutation in MSH2 and microsatellite instability.

Mutations in Tumor Suppressor Genes Causing Autosomal Recessive Pediatric Cancer Syndromes

• Mutations in the LS mismatch repair genes are frequent enough in the population for there to be rare individuals with two germline mutations in one of the LS genes.
• Although much rarer than autosomal dominant forms of LS just discussed, this condition, known as constitutional mismatch repair  (CMMRD)  syndrome, results in a markedly elevated risk for many cancers during childhood, including colorectal and small bowel cancer, as well as some cancers not associated with LS, such as leukemia in infancy and various types of brain tumors in childhood.
• Several other well-known autosomal recessive disorders, including xeroderma pigmentosum, ataxia-telangiectasia, Fanconi anemia, and Bloom syndrome, are also due to loss of function of proteins required for normal DNA repair or replication.

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• Patients with these rare conditions have a high frequency of chromosome and gene mutations and, as a result, a markedly increased risk for various types of cancer, particularly leukemia or, in the case of xeroderma pigmentosum, skin cancers in sun-exposed areas.
• Although these syndromes are rare autosomal recessive disorders, heterozygotes for these gene defects are much more common and appear to be at increased risk for malignant neoplasia.
• For example, Fanconi anemia, in which homozygotes have a number of congenital anomalies, bone marrow failure, leukemia, and squamous cell carcinoma of the head and neck, is a chromosome instability syndrome resulting from mutations of at least 18 different loci involved in DNA and chromosome repair.
• In the aggregate, Fanconi anemia has a population frequency of approximately 1 to 5 per million, which translates to a carrier frequency of approximately 1 to 2 per 500.
• One of these Fanconi anemia loci turns out to be the known hereditary cancer gene BRCA2.

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Testing for Germline Mutations Causing Hereditary Cancer

BRCA1 and BRCA2 Testing (breast cancer)

• Identification of a germline mutation in BRCA1 or BRCA2 in a patient with breast cancer is of obvious importance for genetic counseling and cancer risk management for the patient's children, siblings, and other relatives, who may or may not be at increased risk.
• Such testing is, of course, also important for the patient's own management.
• For instance, in addition to removal of the cancer, a woman found to carry a BRCA1 mutation might also choose to have a prophylactic mastectomy on the unaffected breast or a bilateral oophorectomy simultaneously. Finding a mutation in the proband or a first-degree relative would also allow mutation-specific testing in the rest of the family.
• As the cost of sequencing falls, and large gene panels of breast cancer susceptibility genes, including BRCA1 and BRCA2, can now be analyzed for less than it cost previously to sequence just BRCA1 and BRCA2 alone.

Colorectal Cancer Germline Mutation Testing

For LS, clinical factors such as the presence of multiple polyps, an early age at onset (before the age of 50 years), the location of the tumor in more proximal portions of the colon, the presence of a second tumor or history of colorectal cancer, a family history of colorectal or other cancers (particularly endometrial cancer), and cancer in relatives younger than 50 years of age, all boost the probability that a patient with colon cancer is carrying a mutation in a mismatch repair gene.

• Molecular studies of the tumor tissue, to look for evidence of the MSI+ phenotype or evidence of absent MSH2 and/or MSH6 protein by antibody staining in the tumor, also increase the probability that an individual patient with colorectal cancer carries a germline mismatch repair mutation.

For FAP, the presence of hundreds of adenomatous polyps developing at an early age, multiple sebaceous adenomas, or the extracolonic signs of Gardner syndrome are sufficient to trigger germline testing for an APC mutation.

Familial Occurrence of Cancer

• Cancer can show increased incidence in families without fitting a clear-cut mendelian pattern. For example, it is estimated that as many as 20% of all breast cancer cases occurring in families that lack a clear, highly penetrant mendelian disorder nonetheless have a significant genetic contribution, as revealed by twin and family studies.
• The observed increase in cancer risk when relatives are affected may be due to mutations in a single gene but with penetrance that is sufficiently reduced to obscure any mendelian inheritance pattern.
• For example, in breast cancer, mutations in a gene such as PALB2 can increase lifetime risk for breast cancer to approximately 25% by age 55 and approximately 40% by age 85.
• A lack of obvious breast cancer risk in men with PALB2 mutations further obscures the inheritance pattern, although there is a significant increased risk for pancreatic cancer in men with these reduced penetrance alleles.

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• The bulk of familial cancer is, however, likely to be a complex disorder caused by both genetic and shared environmental factors.
• The degree of complex familial cancer risk can be assessed by epidemiological studies that compare how often the disease occurs in relatives versus the general population.
• This increased risk has been observed in individuals whose first-degree relatives (parent or sibling) are affected by a wide variety of different cancers, with an even greater increase in incidence when an individual's parent and sibling are both affected.
• For example, population-based epidemiological studies have shown that approximately 5% of all individuals in North America and Western Europe will develop colorectal cancer in their lifetime, but the lifetime risk for colorectal cancer is increased twofold to threefold over the average population risk if one first-degree relative is affected.
• In agreement with the likely complex inheritance of cancers, genome-wide association studies have identified more than 150 mostly common variants associated with a variety of cancers.

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Sporadic Cancer

• Previously, we introduced the concept of activation of oncogenes by a variety of mutational mechanisms.
• Here, we explore these mechanisms and their effects in greater detail, particularly in the context of sporadic cancers.
• Activation of Oncogenes by Point Mutation
• Activation of Oncogenes by Chromosome Translocation
• Telomerase as an Oncogene
• Loss of Tumor Suppressor Gene in Sporadic Cancer

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Activation of Oncogenes by Point Mutation

• One of the first activated oncogenes discovered was a mutant RAS gene derived from a bladder carcinoma cell line. Remarkably, the activated oncogene and its normal counterpart proto-oncogene differed at only a single nucleotide.
• The alteration led to synthesis of an abnormal Ras protein that was able to signal continuously, thus stimulating cell division and changing it into a tumor.
• To date, nearly 50 human proto-oncogenes have been identified as driver mutations in sporadic cancer.
• Only a few of these proto-oncogenes have also been found to be inherited in a hereditary cancer syndrome.

Activation of Oncogenes by Chromosome Translocation

• In some instances, a proto-oncogene is activated by a subchromosomal mutation, typically a translocation.
• More than 40 oncogenic chromosome translocations have been described to date, primarily in sporadic leukemias and lymphomas but also in a few rare connective tissue sarcomas.
• Although originally detected only by cytogenetic analysis, such chromosome alterations can be detected now by whole-genome sequence analysis, even using cell-free DNA in plasma samples from cancer patients.
• In some cases, translocation breakpoints lie within the introns of two genes, thereby form a chimeric gene that encodes an abnormal protein with novel oncogenic properties.

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Activation of Oncogenes by Chromosome Translocation

• The best-known example is the translocation between chromosomes 9 and 22, the so-called Philadelphia chromosome that is seen in chronic myelogenous leukemia (CML).
• The translocation moves the protooncogene ABL1, a tyrosine kinase, from its normal position on chromosome 9q to a gene of unknown function, BCR, on chromosome 22q.
• The translocation results in the synthesis of a novel, chimeric protein, BCR-ABL1, containing a portion of the normal Abl protein with increased tyrosine kinase activity.
• New, highly effective drug therapies for CML, such as imatinib, have been developed, based on inhibition of this tyrosine kinase activity.

The Philadelphia chromosome translocation, t(9;22)(q34;q11)

Telomerase as an Oncogene

• Another type of oncogene is the gene-encoding telomerase, a reverse transcriptase that is required to synthesize the hexamer repeat, TTAGGG, a component of telomeres at the ends of chromosomes.
• As cells differentiate, telomerase activity declines in all somatic tissues.
• In many tumors, telomerase expression persists, allowing tumor cells to proliferate indefinitely.
• In some cases, telomerase activity results from chromosome or genome mutations that directly upregulate the telomerase gene; in others, telomerase may be only one of many genes whose expression is altered by a transforming oncogene, such as MYC.

Loss of Tumor Suppressor Gene in Sporadic Cancer�TP53 in Sporadic Cancers

• Although Li-Fraumeni syndrome, caused by a dominantly inherited germline mutation in the TP53 gene, is a rare familial syndrome, somatic mutation causing a loss of function of both alleles of TP53 is one of the most common genetic alterations seen in sporadic cancer.
• Mutations of TP53, deletion of the segment of chromosome 17p that includes TP53, or loss of the entire chromosome 17 is frequently and repeatedly seen in a wide range of sporadic cancers.
• These include breast, ovarian, bladder, cervical, esophageal, colorectal, skin, and lung carcinomas; glioblastoma of the brain; osteogenic sarcoma; and hepatocellular carcinoma.

Cytogenetic Changes in Cancer�Aneuploidy and Aneusomy

• Cytogenetic changes are hallmarks of cancer, whether sporadic or familial, particularly in later and more malignant or invasive stages of tumor development.
• When CML, with the 9;22 Philadelphia chromosome, evolves from the typically indolent chronic phase to a severe, life-threatening blast crisis, there may be several additional cytogenetic abnormalities, including numerical or structural changes.
• A vast array of chromosomal abnormalities are seen in most solid tumors.
• Cytogenetic abnormalities found repeatedly in a specific type of cancer are likely to be driver chromosome mutations involved in the initiation or progression of the malignant neoplasm.

Gene Amplification�

• Is a cytogenetic aberration seen in many cancers, in which many additional copies of a segment of the genome are present in the cell.
• Amplified segments of DNA are readily detected by comparative genome hybridization or whole-genome sequencing and appear as two types of cytogenetic change in routine chromosome analysis:
• double minutes (very small accessory chromosomes) and
• homogeneously staining regions that do not band normally and contain multiple, amplified copies of a particular DNA segment.

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Targeted Cancer Therapy

• Until recently, most nonsurgical cancer treatment relied on cytotoxic agents, such as chemotherapeutic agents or radiation, designed to preferentially kill tumor cells while attempting to spare normal tissues.
• Despite tremendous successes in curing such diseases as childhood acute lymphocytic leukemia and Hodgkin lymphoma, most cancer patients in whom complete removal of the tumor with surgery is no longer possible receive remission, not cure, of their disease, usually at the cost of substantial toxicity from cytotoxic agents.
• The discovery of specific driver genes and their mutations in cancers has opened a new avenue for precisely targeted, less toxic treatments.
• Activated oncogenes are tempting targets for cancer therapy through direct blockade of their aberrant function.
• This can include blocking an activated cell surface receptor by monoclonal antibodies, or targeted inhibition of intracellular constitutive kinase activity with drugs designed to specifically inhibit their enzymatic activities.

�Cancer Treatments Targeted to Specific Activated Driver Oncogenes

Cancer and the Environment

• Although the theme of this chapter emphasizes the genetic basis of cancer, there is no contradiction in considering the role of environment in carcinogenesis.
• By environment, we include exposure to a wide variety of different types of agents—food, natural and artificial radiation, chemicals, even which viruses and bacteria are colonizing the gut.
• The risk for cancer shows significant variation among different populations and even within the same population in different environments.
• For example, gastric cancer is almost three times as common among Japanese in Japan as among Japanese living in Hawaii or Los Angeles.