CANCER GENETICS - Pat J. Morin, Jeffrey M. Trent, Francis S. Collins, Bert Vogelstein

CANCER IS A GENETIC DISEASE

Cancer arises through a series of somatic alterations in DNA that results in unrestrained cellular proliferation. Most of these alterations involve actual sequence changes in DNA (i.e., mutations). They may arise as a consequence of random replication errors, exposure to carcinogens (e.g., radiation), or faulty DNA repair processes. While most cancers arise sporadically, familial clustering of cancers occurs in certain families who carry a germline mutation in a cancer gene.

HISTORIC PERSPECTIVE

The concept of cancer genetics is relatively new. The idea that cancer progression is driven by sequential somatic mutations in specific genes has only gained general acceptance in the last 25 years. Before the advent of the microscope, cancer was believed to be composed of aggregates of mucus or other noncellular matter. By the middle of the nineteenth century, it became clear that tumors were masses of cells and that these cells arose from the normal cells of the tissue in which the cancer originated. However, the molecular basis for the uncontrolled proliferation of cancer cells was to remain a mystery for another century. During that time, a number of theories for the origin of cancer were postulated. The great biochemist Otto Warburg proposed the combustion theory of cancer, which stipulated that cancer was due to abnormal oxygen metabolism: while normal cells required oxygen, cancer cells could survive in its absence. In addition, some believed that all cancers were caused by viruses, and that cancer was in fact a contagious disease.

In the end, observations of cancer occurring in chimney sweeps, studies of x-rays, and the overwhelming data demonstrating cigarette smoke as a causative agent in lung cancer, together with Ames's work on chemical mutagenesis, were sufficient to convince many that cancer originated through changes in DNA1. Although the viral theory of cancer did not prove to be generally accurate, the study of retroviruses led to the discovery of the first human oncogenes in the mid to late 1970s. Soon after, the study of families with genetic predisposition to cancer was instrumental in the discovery of tumor suppressor genes. The field that studies the type of mutations, as well as the consequence of these mutations in tumor cells, is now known as cancer genetics.

THE CLONAL ORIGIN AND MULTISTEP NATURE OF CANCER

Nearly all cancers originate from a single cell; this clonal origin is a critical discriminating feature between neoplasia and hyperplasia. Multiple cumulative mutational events are invariably required for the progression from normal to fully malignant phenotype. The process can be seen as Darwinian microevolution in which, at each successive step, the mutated cells gain a growth advantage resulting in an increased representation relative to their neighbors (Fig. 68-1). It is believed that five to ten accumulated mutations are necessary for a cell to progress from the normal to the fully malignant phenotype.

We are beginning to understand the precise nature of the genetic alterations responsible for some malignancies and to get a sense of the order in which they occur. The best studied example is colon cancer, in which analyses of DNA1 from tissues extending from normal colon epithelium through adenoma to carcinoma have identified some of the genes mutated in the process (Fig. 68-2). Similar progression models are being elucidated for other malignancies.

GENERAL CLASSES OF CANCER GENES

There are two major classes of cancer genes. The first class comprises genes that directly affect cell growth either positively (oncogenes) or negatively (tumor suppressor genes). These genes exert their effects on tumor growth through their ability to control cell division (cell birth) or cell death (apoptosis). Oncogenes are tightly regulated in normal cells. In cancer cells, oncogenes acquire mutations that relieve this control and lead to increased activity of the gene product. This mutational event typically occurs in a single allele of the oncogene and acts in a dominant fashion. In contrast, the normal function of tumor suppressor genes is to restrain cell growth and this function is lost in cancer. Because of the diploid nature of mammalian cells, both alleles must be inactivated to completely lose the function of a tumor suppressor gene, leading to a recessive mechanism at the cellular level. From these ideas and studies on the inherited form of retinoblastoma, Knudson and others formulated the two-hit hypothesis, which in its modern version states that both copies of a tumor suppressor gene must be inactivated in cancer.

The second class of cancer genes, the caretakers, do not directly affect cell growth but rather affect the ability of the cell to maintain the integrity of its genome. Cells with deficiency in these genes have an increased rate of mutations in all the genes, including oncogenes and tumor suppressor genes. This "mutator" phenotype was first hypothesized by Loeb to explain how the multiple mutational events required for tumorigenesis can occur in the lifetime of an individual. A mutation phenotype has now been observed in cancer at both the nucleotide sequence and chromosomal levels.

MECHANISMS OF TUMOR SUPPRESSOR INACTIVATION

The two major types of somatic lesions observed in tumor suppressor genes during tumor development are point mutations and large deletions. Point mutations in the coding region of tumor suppressor genes will frequently lead to truncated protein products or otherwise nonfunctional proteins. Similarly, deletions lead to the loss of a functional product and sometimes encompass the entire gene or even the entire chromosome arm, leading to loss of heterozygosity (LOH) in the tumor DNA1 compared to the corresponding normal tissue DNA (Fig. 68-3). LOH in tumor DNA is considered a hallmark for the presence of a tumor suppressor gene at a particular locus and LOH studies have been useful in the positional cloning of many tumor suppressor genes. Gene silencing, which occurs in conjunction with hypermethylation of the promoter, is another mechanism of tumor suppressor gene inactivation.

FAMILIAL CANCER SYNDROMES

A small fraction of the cancers occur in patients with a genetic predisposition. In these families, the affected individuals have a predisposing loss-of-function mutation in one allele of a tumor suppressor gene or caretaker gene. The tumors in these patients show a loss of the remaining normal allele as a result of somatic events (point mutations or deletions), in agreement with the Knudson hypothesis (Fig. 68-3). Thus, most cells of an individual with an inherited loss-of-function mutation in a tumor suppressor gene are functionally normal and only the rare cells that develop a mutation in the remaining normal allele will exhibit uncontrolled growth. The normal function of tumor suppressors is to restrain growth, to promote differentiation (gatekeeper genes), or to preserve genome integrity (caretaker genes).

Roughly 100 syndromes of familial cancer have been reported, although many are rare. The majority are inherited as autosomal dominant traits although some of those associated with DNA1 repair abnormalities (xeroderma pigmentosum, Fanconi's anemia, ataxia telangiectasia) are autosomal recessive. Table 68-1 shows a number of cancer predisposition syndromes and the responsible genes. The current paradigm states that the genes mutated in familial syndromes can also be targets for somatic mutations in sporadic (noninherited) tumors. The study of cancer syndromes has thus provided invaluable insights into the mechanisms of progression for many tumor types. This section examines the case of inherited colon cancer in detail, but the same general lessons can be applied to all the cancer syndromes listed in Table 68-1.

Familial adenomatous polyposis (FAP) is a dominantly inherited colon cancer syndrome due to germline mutations in the adenomatous polyposis coli (APC) tumor suppressor gene on chromosome 5. Patients with this syndrome develop hundreds to thousands of adenomas in the colon. Each of these adenomas has lost the normal remaining allele of APC but has not yet accumulated the required additional mutations to generate fully malignant cells (Fig. 68-2). However, out of these thousands of benign adenomas, several will invariably acquire further abnormalities and a subset will even develop into fully malignant cancers. APC is thus considered to be a gatekeeper for colon tumorigenesis; Fig. 68-4 shows germline and somatic mutations found in the APC gene. The function of the APC protein is still not completely understood but likely provides differentiation and apoptotic cues to colonic cells as they migrate up the crypts. Defects in this process may lead to abnormal accumulation of cells that should normally undergo apoptosis and slough off.

In contrast to FAP2, patients with hereditary nonpolyposis colon cancer (HNPCC or Lynch syndrome) do not develop multiple polyposis but instead develop only one or a small number of adenomas that rapidly progress to cancer. HNPCC is commonly defined by family history, with at least three individuals over at least two generations developing colon or endometrial cancer, and with at least one individual diagnosed before the age of 50. Most HNPCC is due to mutations in one of four DNA1 mismatch repair genes (Table 68-1), which are components of a repair system that is normally responsible for correcting errors in freshly replicated DNA. Germline mutations in MSH2 and MLH1 account for more than 60% of HNPCC cases, while mutations in MSH6 and PMS2 are much less frequent. When a somatic mutation inactivates the remaining wild-type allele of a mismatch repair gene, the cell develops a hypermutable phenotype characterized by profound genomic instability, especially for the short repeated sequences called microsatellites. This microsatellite instability (MIN) favors the development of cancer by increasing the rate of mutations in many genes, including oncogenes and tumor suppressor genes (Fig. 68-2). These genes can thus be considered caretakers. Figure 68-5 shows an example of the instability in allele sizes for dinucleotide repeats in the cancers of HNPCC patients.

While most autosomal dominant inherited cancer syndromes are due to mutations in tumor suppressor genes (Table 68-1), there are a few interesting exceptions. Multiple endocrine neoplasia type II, a dominant disorder characterized by pituitary adenomas, medullary carcinoma of the thyroid, and (in some pedigrees) pheochromocytoma, is due to gain-of-function mutations in the protooncogene RET on chromosome 10. Similarly, gain-of-function mutations in the tyrosine kinase domain of the MET oncogene lead to hereditary papillary renal carcinoma. Interestingly, loss-of-function mutations in the RET gene cause a completely different disease, Hirschsprung's disease [aganglionic megacolon (Chaps. 279 and 330)].

Although the Mendelian forms of cancer described above have taught us much about the mechanisms of growth control, most forms of cancer do not follow simple patterns of inheritance. In many instances (e.g., lung cancer), a strong environmental contribution is at work. Even in such circumstances, however, some individuals may be more genetically susceptible to developing cancer, given the appropriate exposure, due to the presence of modifier alleles.

GENETIC TESTING FOR FAMILIAL CANCER

The discovery of cancer susceptibility genes raises the possibility of DNA1 testing to predict the risk of cancer in individuals of affected families. An algorithm for cancer risk assessment and decision-making in high-risk families using genetic testing is shown in Fig. 68-6. Once a mutation is discovered in a family, subsequent testing of asymptomatic family members can be crucial in patient management. A negative gene test in these individuals can prevent years of anxiety in the knowledge that their cancer risk is no higher than that of the general population. On the other hand, a positive test may lead to alteration of clinical management, such as increased frequency of cancer screening and, when feasible and appropriate, prophylactic surgery. Potential negative consequences of a positive test result include psychological distress (anxiety, depression) and discrimination (insurance, employment). Testing should therefore not be conducted without counseling before and after disclosure of the test result. In addition, the decision to test should depend on whether effective interventions exist for the particular type of cancer to be tested. Despite these caveats, genetic cancer testing for some cancer syndromes already appears to have greater benefits than risks and many companies now offer testing for various genes associated with the predisposition to breast cancer (BRCA1 and BRCA2), melanoma (p16INK4), and colon cancer (APC3 and the HNPCC4 genes).

Because of the inherent problems of genetic testing such as cost, specificity, and sensitivity, it is not yet appropriate to offer these tests to the general population. However, testing may be appropriate in some subpopulations with a known increased risk, even without a defined family history. For example, two mutations in the breast cancer susceptibility gene BRCA1, 185delAG and 5382insC, exhibit a sufficiently high frequency in the Ashkenazi Jewish population that genetic testing of an individual of this ethnic group may be warranted.

It is important that genetic test results be communicated to families by trained genetic counselors. To ensure that the families clearly understand its advantages and disadvantages and the impact it may have on their management and psyche, genetic testing should never be done before counseling. Significant expertise is needed to communicate the results of genetic testing to families. For example, one common mistake is to misinterpret the result of negative genetic tests. For many cancer predisposition genes, the sensitivity of genetic testing is only 70% or less (i.e., of 100 kindreds tested, disease-causing mutations can be identified in only 70). Therefore, such testing should in general begin with an affected member of the kindred (the youngest family member still alive who has had the cancer of interest). If a mutation is not identified in this individual, then the test should be reported as noninformative (Fig. 68-6) rather than negative (because it is possible that the mutation in this individual is not detectable by standard genetic assays for purely technical reasons). On the other hand, if a mutation can be identified in this individual, then testing of other family members can be performed, and the sensitivity of such subsequent tests will be 100% (because the mutation in the family is in this case known to be detectable by the assay methods used).

ONCOGENES IN HUMAN CANCER

Oncogenes of the kind found in human cancers were initially discovered through their presence in the genome of retroviruses capable of causing cancers in chickens, mice, and rats. The cellular homologues of these viral genes are often targets of mutation or aberrant regulation in human cancer. Whereas many oncogenes were discovered because of their presence in retroviruses, other oncogenes, particularly those involved in translocations characteristic of particular leukemias and lymphomas, were isolated through genomic approaches. Investigators cloned the sequences surrounding the chromosomal translocations observed cytogenetically and then deduced the nature of the genes that were the targets of these translocations (see below). Some of these were oncogenes known from retroviruses [like ABL, involved in chronic myelogenous leukemia (CML)], while others were new (like BCL2, involved in B cell lymphoma). In the normal cellular environment, protooncogenes have crucial roles in cell proliferation and differentiation. Table 68-2 is a partial list of oncogenes known to be involved in human cancer.

The normal growth and differentiation of cells is controlled by growth factors, which bind to receptors on the surface of the cell. The signals generated by the membrane receptors are transmitted inside the cells through signaling cascades involving kinases, G proteins, and other regulatory proteins. Ultimately, these signals affect the activity of transcription factors in the nucleus, which regulate the expression of genes crucial in cell proliferation, cell differentiation, and cell death. Oncogene products have been found to function at critical steps in these pathways (Chap. 69), and inappropriate activation of these pathways can lead to tumorigenesis.

MECHANISMS OF ONCOGENE ACTIVATION

Mechanisms that upregulate (or activate) cellular oncogenes fall into three broad categories: point mutation, DNA1 amplification, and chromosomal rearrangement.

Point Mutation  Point mutation is a common mechanism of oncogene activation. For example, mutations in one of the RAS genes (HRAS, KRAS, or NRAS) are present in up to 85% of pancreatic cancers and 50% of colon cancers but are relatively uncommon in other cancer types. Remarkably — and in contrast to the diversity of mutations found in tumor suppressor genes (Fig. 68-4) — most of the activated RAS genes contain point mutations in codons 12, 13, or 61 (which convey resistance to GAP, a protein that interacts with RAS and inactivates it through substitution of the GTP cofactor with GDP). The restricted pattern of mutation compared to tumor suppressor genes reflects the fact that gain-of-function mutations of oncogenes are more difficult to attain than simple inactivation. Indeed, inactivation of a gene can be attained through the introduction of a stop codon anywhere in the coding sequence, whereas activations require precise substitutions at residues that normally downregulate the activity of the encoded protein. The specificity of oncogene mutations provides specific diagnostic opportunities, as it is much simpler to find mutations at specified positions than it is when mutations can be scattered throughout the gene (as in tumor suppressor genes).

DNA Amplification  The second mechanism for activation of oncogenes is DNA1 sequence amplification, leading to overexpression of the gene product. This increase in DNA copy number may cause cytologically recognizable chromosome alterations referred to as homogeneous staining regions (HSRs), if integrated within chromosomes or double minutes (dmins), if extrachromosomal in nature. The recognition of DNA amplification is accomplished through various cytogenetic techniques such as comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH), which allow the visualization of chromosomal aberrations using fluorescent dyes. With these techniques, the entire genome can be surveyed for gains and losses of DNA sequences, thus pinpointing chromosomal regions likely to contain genes important in the development or progression of cancer. Noncytogenetic, molecular techniques for identifying amplifications have more recently become available.

Numerous genes have been reported to be amplified in cancer. Several genes, including NMYC and LMYC, were identified through their presence within the amplified DNA1 sequences of a tumor and had homology to known oncogenes. Because the region amplified often extends to hundreds of thousands of base pairs, more than one oncogene may be amplified in some cancers (particularly sarcomas). Genes simultaneously amplified in many cases include MDM2, GLI, CDK4, and SAS. Demonstration of amplification of a cellular gene is often a predictor of poor prognosis. For example, ERBB2/HER2 and NMYC are often amplified in aggressive breast cancers and neuroblastoma, respectively.

Chromosomal Rearrangement  Chromosomal alterations provide important clues to the genetic changes in cancer. The chromosomal alterations in human solid tumors such as carcinomas are heterogeneous and complex and likely reflect selection for the loss of tumor suppressor genes on the involved chromosome. In contrast, the chromosome alterations in liquid tumors (leukemias and lymphomas) are often simple translocations, i.e., reciprocal transfers of chromosome arms from one chromosome to another. Consequently, many detailed and informative chromosome analyses have been performed on hematopoietic cancers. The breakpoints of recurring chromosome abnormalities usually occur at the site of cellular oncogenes. Table 68-3 lists representative examples of recurring chromosome alterations in malignancy and the associated gene(s) rearranged or deregulated by the chromosomal rearrangement. Translocations are particularly common in lymphoid tumors, probably because these cell types normally rearrange their DNA1 to generate antigen receptors. Indeed, antigen receptor genes are commonly involved in the translocations, implying that an imperfect regulation of receptor gene rearrangement may be involved in the pathogenesis. An example is Burkitt's lymphoma, a B cell tumor characterized by a reciprocal translocation between chromosomes 8 and 14. Molecular analysis of Burkitt's lymphomas demonstrated that the breakpoints occurred within or near the MYC locus on chromosome 8 and within the immunoglobulin heavy chain locus on chromosome 14, resulting in the transcriptional activation of MYC. Enhancer activation by translocation, although not universal, appears to play an important role in malignant progression. In addition to transcription factors and signal transduction molecules, translocation may result in the overexpression of cell cycle regulatory proteins such as cyclins and of proteins that regulate cell death such as bcl-2.

The first reproducible chromosome abnormality detected in human malignancy was the Philadelphia chromosome detected in CML5. This cytogenetic abnormality is generated by reciprocal translocation involving the ABL oncogene, a tyrosine kinase on chromosome 9, being placed in proximity to the BCR (breakpoint cluster region) on chromosome 22. Figure 68-7 illustrates the generation of the translocation and its protein product. The consequence of expression of the BCR-ABL gene product is the activation of signal transduction pathways leading to cell growth independent of normal external signals. Interestingly, a compound (gleevec) that specifically blocks the activity of BCR-ABL was synthesized and shown to exhibit remarkable efficacy with little toxicity in patients with CML. Knowledge of genetic alterations in cancer can lead to mechanism-based design and development of a new generation of cancer drugs.

CHROMOSOMAL INSTABILITY IN SOLID TUMORS

Solid tumors are generally highly aneuploid, containing an abnormal number of chromosomes; these chromosomes also exhibit structural alterations such as translocations, deletions, and amplifications. Again, colon cancer has proven to be a particularly useful model for the study of chromosomal instability (CIN). As described above, some familial cases are characterized by the presence of MIN6. Interestingly, MIN and CIN appear to be mutually exclusive in colon cancer, suggesting that they represent alternative mechanisms for the generation of a mutator phenotype in this cancer (Fig. 68-2). Other cancer types rarely exhibit MIN but almost always exhibit CIN. Normal cells possess several cell cycle checkpoints, often defined as quality control requirements that have to be met before subsequent events are allowed to take place. The spindle checkpoint, which ensures proper chromosome attachment to the mitotic spindle before allowing the sister chromatid to separate, has been shown to be deficient in certain cancers. The genes that, when mutated, may cause CIN have in general not yet been identified, although a few candidates mutated in a small number of tumors have been discovered. The identification of the cause of CIN in tumors will likely be a formidable task, considering that several hundred genes are thought to control the mitotic checkpoint and other cellular processes assuring proper chromosome segregation. Regardless of the mechanisms underlying CIN, the measurement of the number of chromosomal alterations present in tumors is now possible with both cytogenetic and molecular techniques, and several studies have shown that this information can be useful for prognostic purposes.

VIRUSES IN HUMAN CANCER

Certain human malignancies are associated with viruses. Examples include Burkitt's lymphoma (Epstein-Barr virus), hepatocellular carcinoma (hepatitis virus), cervical cancer [human papillomavirus (HPV)], and T cell leukemia (retroviruses). The mechanisms of action of these viruses are varied but always involve activation of growth-promoting pathways or inhibition of tumor suppressor products in the infected cells. For example, HPV proteins E6 and E7 bind and inactivate cellular tumor suppressors p53 and pRB, respectively. Viruses are not sufficient for cancer development but constitute one alteration in the multistep process of cancer.

EPIGENETIC REGULATION OF GENE EXPRESSION IN CANCER

An epigenetic modification refers to a change in the genome, heritable by cell progeny, that does not involve a change in the DNA1 sequence. The inactivation of the second X chromosome in female cells is an example of an epigenetic mechanism that prevents gene expression from the inactivated chromosome. During embryologic development, regions of chromosomes from one parent are silenced and gene expression proceeds from the chromosome of the other parent. For most genes, expression occurs from both alleles or randomly from one allele or the other. The preferential expression of a particular gene exclusively from the allele contributed by one parent is called parental imprinting and is thought to be regulated by covalent modifications of chromatin protein and DNA (particularly methylation) of the silenced llele.

The role of epigenetic control mechanisms in the development of human cancer is unclear. However, a general decrease in the level of DNA1 methylation has been noted as a common change in cancer. In addition, numerous genes, including some tumor suppressor genes, appear to become hypermethylated and silenced during tumorigenesis. VHL and p16INK4 are well-studied examples of tumor suppressor genes that are silenced through methylation in human cancers. Overall, epigenetic mechanisms may be responsible for reprogramming the expression of a large number of genes in cancer and, together with the mutation of specific genes, are likely to be crucial in the development of human malignancies.

GENE EXPRESSION PROFILING IN CANCER

The tumorigenesis process, driven by alterations in tumor suppressors, oncogenes, and epigenetic regulation, is accompanied by changes in gene expression. The advent of powerful new techniques such as microarrays and serial analysis of gene expression (SAGE) has allowed the study of gene expression in neoplastic cells on a scale never before accomplished. Indeed, it is now possible to identify expression levels of thousands of genes expressed in normal and cancer tissues. Figure 68-8 shows a typical cDNA array experiment examining gene expression in cancer. This global knowledge of gene expression allows the identification of differentially expressed genes and, in principle, the understanding of the complex molecular circuitry regulating normal and neoplastic behaviors. Such studies have led to molecular profiling of tumors, which has suggested general methods for distinguishing tumors of various biologic behaviors (molecular classification), elucidating pathways relevant to the development of tumors and identifying molecular targets for the detection and therapy of cancer. The first practical applications of this technology have suggested that global gene expression profiling can provide prognostic information not evident from other clinical or laboratory tests. The National Cancer Institute, in conjunction with the National Center for Biotechnology Information, has undertaken the Cancer Genome Anatomy Project (CGAP) (www.ncbi.nlm.nih.gov/ncicgap/) to collect data on gene expression in normal and malignant tissues and make it available on the Internet.

THE FUTURE

It is clear that there has been a revolution in cancer genetics in the past 20 years. Identification of cancer genes has led to a better understanding of the tumorigenesis process and has had important repercussions on all fields of biology. In spite of these spectacular advances, however, there has been little overall improvement in cancer death rates. It is hoped that, as the molecular mechanisms of cancer initiation and development continue to be elucidated, novel therapies based on pathophysiology rather than empiricism will emerge. Time will tell whether these strategies will rely on novel combinations or dosing schedules of conventional drugs or will be based on new approaches such as those involving gene therapy or immunotherapy. In addition, a better understanding of the molecular pathways and genetic alterations in cancer cells may lead to the development of sensitive strategies for early detection of cancer.

FURTHER READING

EMERY J : Common hereditary cancers and implications for primary care. Lancet 358:56, 2001

GOLUB TR et al: Molecular classification of cancer: Class discovery and class prediction by gene expression monitoring. Science 286:531, 1999

JALLEPALLI PV, LENGAUER C : Chromosome segregation and cancer: Cutting through the mystery. Nat Rev Cancer 1:109, 2001

LOEB LA : Mutator phenotype may be required for multistage carcinogenesis. Cancer Res 51:3075, 1991

MUNGER K : Disruption of oncogene/tumor suppressor networks during human carcinogenesis. Cancer Invest 20:71, 2002

STRAUSBERG RL et al: In silico analysis of cancer through the Cancer Genome Anatomy Project. Trends Cell Biol 11:S66, 2001

VOGELSTEIN B, KINZLER KW : The multistep nature of cancer. Trends Genet 9:138, 1993

YAN et al: Genetic testing — present and future. Science 289:1890, 2000

BIBLIOGRAPHY

FEARON ER, CHO KR : The molecular biology of cancer, in Principles and Practices of Medical Genetics, AE Emery, DL Rimoin (eds). New York, Churchill Livingstone, 1996

HESKETH R : The Oncogene and Tumour Suppressor Gene Facts Book, 2d ed. San Diego, Academic Press, 1997

VOGELSTEIN B, KINZLER KW : The Genetic Basis of Human Cancer, 2d ed. New York, McGraw-Hill, 2002

1deoxyribonucleic acid (DNA)

2Familial adenomatous polyposis (FAP)

3adenomatous polyposis coli (APC)

4hereditary nonpolyposis colon cancer (HNPCC

5chronic myelogenous leukemia (CML)

6microsatellite instability (MIN)

 

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HARRISON'S PRINCIPLES OF INTERNAL MEDICINE - 16th Ed. (2005)
   PART FIVE - ONCOLOGY AND HEMATOLOGY
      Section 1 - Neoplastic Disorders
          68. CANCER GENETICS - Pat J. Morin, Jeffrey M. Trent, Francis S. Collins, Bert Vogelstein
            CANCER IS A GENETIC DISEASE