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One widely held opinion is that cancer is a genetic disease that arises from an accumulation of genomic alterations that leads to the selection of cells with increasingly aggressive behavior. These alterations may lead either to a gain of function by oncogenes or to a loss of function by tumor-suppressor genes. These acquired gene alterations are termed somatic mutations to distinguish them from germline mutations that are inherited from parents and transmitted to offspring. Somatic mutations in a cancer genome may consist of several classes of DNA sequence changes. These include substitutions of one base by another; insertions or deletions of small or large segments of DNA; rearrangements, in which the DNA sequence has been broken and then rejoined to another DNA segment; copy number losses that may result in complete absence of a DNA sequence and copy number gains from the two copies present in the normal diploid genome.
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Somatic mutations in a cancer cell genome have accumulated over the lifetime of the patient (Fig. 10-9).37 DNA in normal cells is continuously damaged by internal and external mutagens. Most of this damage is repaired; however, a small fraction may remain as fixed mutations. Mutation rates increase in the presence of substantial exogenous mutagenic exposures, such as tobacco carcinogens or various forms of radiation, including ultraviolet light. These exposures are associated with increased rates of lung and skin cancer, respectively, and somatic mutations within such cancers often exhibit the distinctive mutational signatures known to be associated with the mutagen.38 The rates of somatic mutations are also increased in several rare inherited diseases, such as Fanconi anemia, ataxia telangiectasia, and xeroderma pigmentosum, which are associated with increased risks of cancer.39,40 The rest of the somatic mutations in a cancer cell have been acquired after the cancer cell already shows phenotypic evidence of neoplastic change. Whether the somatic mutation rate is always higher during this part of the lineage is controversial. This is clearly the case for some cancers. For instance, colorectal and endometrial cancers with defective DNA mismatch repair due to abnormalities in genes such as MLH1 and MSH2, exhibit increased rates of single nucleotide changes and small insertions/deletions atpolynucleotide tract.41 These tumor types are often referred to as “mutator phenotypes.”
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To date about 300 genes that have been reported to be mutated and causally implicated in cancer development.42 Ninety percent of cancer genes show somatic mutations in cancer, 20% show germline mutations, and 10% show both. The most common class of genomic alterations among the known cancer genes is a chromosomaltranslocation that creates a chimeric gene. Many more cancer genes have been found in leukemias, lymphomas, and sarcomas than in other types of cancer; and these genes are usually altered by chromosomal translocation. The most common cancer genes are protein kinases. Several domains that are involved in DNA binding and transcriptional regulation are also common in proteins encoded by cancer genes. Somatic mutations in a cancer genome may be classified according to its consequences for cancer development. “Driver” mutations confer a growth advantage to the cells carrying them and have been positively selected during the evolution of the cancer. The remainder of mutations are “bystanders” or “passengers” that do not confer growth advantage. It is likely that most somatic mutations are passenger mutations. Each tumor may have dozens to hundreds of genomic alterations, making it critical to determine which alterations are indeed drivers, and potentially better therapeutic targets.
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There are several ongoing large scale studies to characterize and catalogue genomic alterations in different cancer types, including the Cancer Genome Project at the Sanger Institute, United Kingdom, and The Cancer Genome Atlas project (TCGA). There are also increasing number of publically accessible resources, including COSMIC (http://www.sanger.ac.uk/cosmic), which curates comprehensive information on somatic mutations in human cancer.43 These resources are being utilized to determine the most common genomic alterations in common tumor types. This information is being integrated into clinical practice in many tumor types, such as lung cancer, where molecular drivers are being chosen taking into consideration in systemic therapy selection (Fig. 10-10).
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Tumor Heterogeneity and Molecular Evolution
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There is increasing recognition that tumors are heterogeneous; this represents an important challenge to utilizing genomic alterations to personalize cancer therapy (Fig. 10-11).44 First, there is significant intertumoral heterogeneity, such that patients with tumors that seem similar histologically, may differ in genomic alterations and in malignant potential.45,46,47 Second, during cancer progression, subclones frequently arise, resulting in differences in the proportion and pattern of genomic alterations between the primary tumor and the metastases or local-regional recurrences.44 Third, there may also be significant intratumoral heterogeneity, with spatially separated heterogeneous somatic mutations and chromosomal imbalances.48 Such spatial heterogeneity of subclones within the primary tumor or metastases provides an additional challenge, as it has been proposed that sequencing of a biopsy specimen or only a portion of the tumor could miss therapeutically relevant genomic alterations. The genomic alterations found in a tumor can also change under the selective pressure of a targeted therapy, adding to the challenge of implementing genomically-informed personalized therapy.
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Genes Associated with Hereditary Cancer Risk
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Most of our information on human cancer genes has been gained from hereditary cancers. In the case of hereditary cancers, the individual carries a particular germline mutation in every cell. To date, over 70 genes have been associated with hereditary cancers (Table 10-3).42 A few of these hereditary cancer genes are oncogenes, but most are tumor-suppressor genes. Although hereditary cancer syndromes are rare, somatic mutations that occur in sporadic cancer have been found to disrupt the cellular pathways altered in hereditary cancer syndromes, which suggests that these pathways are critical to normal cell growth, cell cycle, and proliferation.
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The following factors may suggest the presence of a hereditary cancer49:
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Tumor development at a much younger age than usual
Presence of bilateral disease
Presence of multiple primary malignancies
Presentation of a cancer in the less affected sex (e.g., male breast cancer)
Clustering of the same cancer type in relatives
Occurrence of cancer in association with other conditions such as mental retardation or pathognomonic skin lesions
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It is crucial that all surgeons caring for cancer patients be aware of hereditary cancer syndromes, because a patient’s genetic background has significant implications for patient counseling, planning of surgical therapy, and cancer screening and prevention. Some of the more commonly encountered hereditary cancer syndromes are discussed here.
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The retinoblastoma gene rb1 was the first tumor suppressor to be cloned. The rb1 gene product, the Rb protein, is a regulator of transcription that controls the cell cycle, differentiation, and apoptosis in normal development.50 Retinoblastoma has long been known to occur in hereditary and nonhereditary forms. Interestingly, although most children with an affected parent develop bilateral retinoblastoma, some develop unilateral retinoblastoma. Furthermore, some children with an affected parent are not affected themselves but then have an affected child, which indicates that they are rb1 mutation carriers. These findings led to the theory that a single mutation is not sufficient for tumorigenesis. Alfred Knudson hypothesized that hereditary retinoblastoma involves two mutations, of which one is germline and one somatic, whereas nonhereditary retinoblastoma is due to two somatic mutations (Fig. 10-12).51 Thus, both hereditary and nonhereditary forms of retinoblastoma involve the same number of mutations, a hypothesis known as Knudson’s “two-hit” hypothesis. A “hit” may be a point mutation, a chromosomal deletion referred to as allelic loss, or a loss of heterozygosity, or silencing of an existing gene.
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p53 and Li-Fraumeni Syndrome
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Li-Fraumeni syndrome (LFS) was first defined on the basis of observed clustering of malignancies, including early-onset breast cancer, soft tissue sarcomas, brain tumors, adrenocortical tumors, and leukemia.52 Criteria for classic LFS in an individual (the proband) include: (a) a bone or soft tissue sarcoma when younger than 45 years, (b) a first-degree relative with cancer before age 45 years, and (c) another first- or second-degree relative with either a sarcoma diagnosed at any age or any cancer diagnosed before age 45 years.53 Approximately 70% of LFS families have been shown to have germline mutations in the tumor-suppressor gene p53.54 Breast carcinoma, soft tissue sarcoma, osteosarcoma, brain tumors, adrenocortical carcinoma, Wilms’ tumor, and phyllodes tumor of the breast are strongly associated; pancreatic cancer is moderately associated; and leukemia and neuroblastoma are weakly associated with germline p53 mutations.55 Mutations of p53 have not been detected in approximately 30% of LFS families, and it is hypothesized that genetic alterations in other proteins interacting with p53 function may play a role in these families.
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Of the known genes in human cancer, p53 is the most commonly mutated. The p53 protein regulates cell-cycle progression as well as apoptotic cell death as part of stress response pathways after exposure to ionizing or ultraviolet (UV) irradiation, chemotherapy, acidosis, growth factor deprivation, or hypoxia. When cells are exposed to stressors, p53 acts as a transcription factor for genes that induce cell-cycle arrest or apoptosis. A majority of p53 mutations are found within a central DNA recognition motif and disrupt DNA binding by p53. Families with germline missense mutations in the DNA-binding domain show a more highly penetrant phenotype than families with other p53 mutations.56 Furthermore, proband cancers are linked with significantly younger age at diagnosis in patients with missense mutations in the DNA-binding domain.56
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BRCA1, BRCA2, and Hereditary Breast-Ovarian Cancer
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It is estimated that 5% to 10% of breast cancers are hereditary. Of women with early-onset breast cancer (aged 40 years or younger), nearly 10% have a germline mutation in one of the breast cancer genes BRCA1 or BRCA2.57 Mutation carriers are more prevalent among women who have a first- or second-degree relative with premenopausal breast cancer or ovarian cancer at any age. The likelihood of a BRCA mutation is higher in patients who belong to a population in which founder mutations may be prevalent, such as in the Ashkenazi Jewish population. For a female BRCA1 mutation carrier, the cumulative risks of developing breast cancer and ovarian cancer by age 70 have been estimated to be 87% and 44%, respectively.58 The cumulative risks of breast cancer and ovarian cancer by age 70 in families with BRCA2 mutation have been estimated to be 84% and 27%, respectively.59 Although male breast cancer can occur with either BRCA1 or BRCA2 mutation, the majority of families (76%) with both male and female breast cancer have mutations in BRCA2.59 Besides breast and ovarian cancer, BRCA1 and BRCA2 mutations may be associated with increased risks for several other cancers. BRCA1 mutations confer a fourfold increased risk for colon cancer and threefold increased risk for prostate cancer.58 BRCA2 mutations confer a fivefold increased risk for prostate cancer, sevenfold in men younger than 65 years.60 Furthermore, BRCA2 mutations confer a fivefold increased risk for gallbladder and bile duct cancers, fourfold increased risk for pancreatic cancer, and threefold increased risk for gastric cancer and malignant melanoma.60
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BRCA1 was the first breast cancer susceptibility gene identified and has been mapped to 17q21. BRCA2, mapped to 13q12.3, was reported shortly afterward. BRCA1 and BRCA2 encode large nuclear proteins, 208 kDa and 384 kDa, respectively, that have been implicated in processes fundamental to all cells, including DNA repair and recombination, checkpoint control of the cell cycle, and transcription.61 Although early studies suggested that the two proteins function together as a complex, subsequent data demonstrated that they have distinct functions.62,63 In fact, breast cancers arising from BRCA1 or BRCA2 mutations are different at the molecular level and have been found to have distinct gene expression profiles.64 BRCA1-associated tumors are more likely to be estrogen receptor negative, whereas BRCA2-associated tumors are more likely to be estrogen receptor positive. Currently, studies are ongoing to determine whether BRCA1 and BRCA2 status can be used to guide systemic therapy choices for breast cancer.
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APC Gene and Familial Adenomatous Polyposis
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Patients affected with familial adenomatous polyposis (FAP) characteristically develop hundreds to thousands of polyps in the colon and rectum. The polyps usually appear in adolescence and, if left untreated, progress to colorectal cancer. FAP is associated with benign extracolonic manifestations that may be useful in identifying new cases, including congenital hypertrophy of the retinal pigment epithelium, epidermoid cysts, and osteomas. In addition to colorectal cancer, patients with FAP are at risk for upper intestinal neoplasms (gastric and duodenal polyps, duodenal and periampullary cancer), hepatobiliary tumors (hepatoblastoma, pancreatic cancer, and cholangiocarcinoma), thyroid carcinomas, desmoid tumors, and medulloblastomas.
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The product of the adenomatous polyposis coli tumor-suppressor gene (APC) plays an important role in cell-cell interactions, cell adhesion, regulation of β-catenin, and maintenance of cytoskeletal microtubules. Alterations in APC lead to dysregulation of several physiologic processes that govern colonic epithelial cell homeostasis, including cell-cycle progression, migration, differentiation, and apoptosis. Mutations in the APC have been identified in FAP and in 80% of sporadic colorectal cancers.65 Furthermore, APC mutations are the earliest known genetic alterations in colorectal cancer progression, which emphasizes its importance in cancer initiation. The germline mutations in APC may arise from point mutations, insertions, or deletions that lead to a premature stop codon and a truncated, functionally inactive protein. The risk of developing specific manifestations of FAP is correlated with the position of the FAP mutations, a phenomenon referred to as genotype-phenotype correlation. For example, desmoids usually are associated with mutations between codons 1403 and 1578.66,67 Mutations in the extreme 5’ or 3’ ends of APC, or in the alternatively spliced region of exon 9, are associated with an attenuated version of FAP. Better understanding of the genotype-phenotype correlations may assist in patient counseling and therapeutic planning.
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Mismatch Repair Genes and Hereditary Nonpolyposis Colorectal Cancer
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Hereditary nonpolyposis colorectal cancer (HNPCC), also referred to as Lynch syndrome, is an autosomal dominant hereditary cancer syndrome that predisposes to a wide spectrum of cancers, including colorectal cancer without polyposis. Some have proposed that HNPCC consists of at least two syndromes: Lynch syndrome 1, which entails hereditary predisposition for colorectal cancer with early age of onset (approximately age 44 years) and an excess of synchronous and metachronous colonic cancers; and Lynch syndrome 2, featuring a similar colonic phenotype accompanied by a high risk for carcinoma of the endometrium, transitional cell carcinoma of the ureter and renal pelvis, and carcinomas of the stomach, small bowel, ovary, and pancreas.68 The diagnostic criteria for HNPCC are referred to as the Amsterdam criteria, or the 3-2-1-0 rule. The classic Amsterdam criteria were revised to include other HNPCC-related cancers (Table 10-4).69 These criteria are met when three or more family members have histologically verified, HNPCC-associated cancers (one of whom is a first-degree relative of the other two), two or more generations are involved, at least one individual was diagnosed before age 50 years, and no individuals have FAP.69
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During DNA replication, DNA polymerases may introduce single nucleotide mismatches or small insertion or deletion loops. These errors are corrected through a process referred to as mismatch repair. When mismatch repair genes are inactivated, DNA mutations in other genes that are critical to cell growth and proliferation accumulate rapidly. In HNPCC, germline mutations have been identified in several genes that play a key role in DNA nucleotide mismatch repair: hMLH1 (human mutL homologue 1), hMSH2 (human mutS homologue 2), hMSH6, and hPMS1 and hPMS2 (human postmeiotic segregation 1 and 2), of which hMLH1 and hMSH2 are the most common.70,71,72,73,74,75 The hallmark of HNPCC is microsatellite instability, which occurs on the basis of unrepaired mismatches and small insertion or deletion loops. Microsatellite instability can be tested by comparing the DNA of a patient’s tumor with DNA from adjacent normal epithelium, amplifying the DNA with polymerase chain reaction (PCR) using a standard set of markers, comparing the amplified genomic DNA sequences, and classifying the degree of microsatellite instability as high, low, or stable. Such microsatellite instability testing may help select patients who are more likely to have germline mutations.
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PTEN and Cowden Disease
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Somatic deletions or mutations in the tumor-suppressor gene PTEN (phosphatase and tensin homologue deleted on chromosome 10) have been observed in a number of glioma breast, prostate, and renal carcinoma cell lines and several primary tumor specimens.76
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PTEN encodes a 403-amino-acid protein, tyrosine phosphatase. PTEN negatively controls the PI3K signaling pathway for the regulation of cell growth and survival by dephosphorylating phosphoinositol 3,4,5-triphosphate; thus mutation of PTEN leads to constitutive activation of the PI3K/Akt signaling pathway. The “hot spot” for PTEN mutations has been identified in exon 5. Forty-three percent of CD mutations have been identified in this exon, which contains the tyrosine phosphatase core domain. This suggests that the PTEN catalytic activity is vital for its biologic function. PTEN was identified as the susceptibility gene for the autosomal dominant syndrome Cowden disease (CD) or multiple hamartoma syndrome.77 Trichilemmomas, benign tumors of the hair follicle infundibulum, and mucocutaneous papillomatosis are pathognomonic of CD. Other common features include thyroid adenomas and multinodular goiters, breast fibroadenomas, and hamartomatous GI polyps. The diagnosis of CD is made when an individual or family has a combination of pathognomonic major and/or minor criteria proposed by the International Cowden Consortium.78 CD is associated with an increased risk of breast and thyroid cancers. Breast cancer develops in 25% to 50% of affected women.78
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p16 and Hereditary Malignant Melanoma
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The gene p16, also known as INK4A, CDKN1, CDKN2A, and MTS1, is a tumor suppressor that acts by binding CDK4 and CDK6 and inhibiting the catalytic activity of the CDK4-CDK6/cyclin D complex that is required for phosphorylation of Rb and subsequent cell-cycle progression. Studies suggest that germline mutations in p16 can be found in 20% of melanoma-prone families.79 Mutations in p16 that alter its ability to inhibit the catalytic activity of the CDK4-CDK6/cyclin D complex not only increase the risk of melanoma by 75-fold but also increase the risk of pancreatic cancer by 22-fold.80 Interestingly, p16 mutations that do not appear to alter its function increase the risk of melanoma by 38-fold and do not increase the risk of pancreatic cancer.80 Genomic characterization of primary tumors has revealed that p16 is inactivated through point mutation, promoter methylation, or deletion in a significant portion of sporadic tumors, including cancers of the pancreas, esophagus, head and neck, stomach, breast, and colon, as well as melanomas.
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E-cadherin and Hereditary Diffuse Gastric Cancer
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E-cadherin is a cell adhesion molecule that plays an important role in normal architecture and function of epithelial cells. The adhesive function of E-cadherin is dependent on interaction of its cytoplasmic domain with β- and γ-catenins and may be regulated by phosphorylation of β-catenin.
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Hereditary diffuse gastric carcinoma is an autosomal dominant cancer syndrome that results from germline mutations in the E-cadherin gene, CDH1. Carriers of CDH1 mutations have a 70% to 80% chance of developing gastric cancer.81 Furthermore, mutations of CDH1 have been described in sporadic cancers of the ovary, endometrium, breast, and thyroid. However, frequent mutations have been identified in only two particular tumors: diffuse gastric carcinomas and lobular breast carcinomas. Invasive lobular breast carcinomas often show inactivating mutations in combination with a loss of heterozygosity of the wild-type CDH1 allele.82 Interestingly, in gastric carcinomas the predominant mutations are exon skipping causing in-frame deletions, whereas most mutations identified in lobular breast cancers are premature stop codons; this suggests a genotype-phenotype correlation.
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RET Proto-Oncogene and Multiple Endocrine Neoplasia Type 2
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The RET (rearranged during transfection) gene encodes for a transmembrane receptor tyrosine kinase that plays a role in proliferation, migration, and differentiation of cells derived from the neural crest. Gain-of-function mutations in the RET gene are associated with medullary thyroid carcinoma in isolation or multiple endocrine neoplasia type 2 (MEN2) syndromes. MEN2A is associated with medullary thyroid carcinoma and pheochromocytoma (in 50%) or parathyroid adenoma (in 20%), whereas MEN2B is associated with medullary thyroid carcinoma, marfanoid habitus, mucosal neuromas, and ganglioneuromatosis.83RET mutations lead to uncontrolled growth of the thyroid C cells, and in familial medullary cancer, C-cell hyperplasia progresses to bilateral, multicentric medullary thyroid cancer. Mutations in the RET gene have also been identified in half of sporadic medullary thyroid cancers.
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Genetic Modifiers of Risk
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Individuals carrying identical germline mutations vary in regard to cancer penetrance (whether cancer will develop or not) and cancer phenotype (the tissues involved). It is thought that this variability may be due to environmental influences or, if genetic, to genetic modifiers of risk. Similarly, genetic modifiers of risk also can play a role in determining whether an individual will develop cancer after exposure to carcinogens.
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The first report indicating that cancer could be caused by environmental factors was by John Hill, who in 1761 noted the association between nasal cancer and excessive use of tobacco snuff.84 Currently, approximately 60% to 90% of cancers are thought to be due to environmental factors. Any agent that can contribute to tumor formation is referred to as a carcinogen and can be a chemical, physical, or viral agent. Chemicals are classified into three groups based on how they contribute to tumor formation. The first group of chemical agents, the genotoxins, can initiate carcinogenesis by causing a mutation. The second group, the cocarcinogens, by themselves cannot cause cancer but potentiate carcinogenesis by enhancing the potency of genotoxins. The third group, tumor promoters, enhances tumor formation when given after exposure to genotoxins.
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The International Agency for Research on Cancer (IARC) maintains a registry of human carcinogens that is available through the World Wide Web (http://www.iarc.fr). The compounds are categorized into five groups based on an analysis of epidemiologic studies, animal models, and short-term mutagenesis tests. Group 1 contains what are considered to be proven human carcinogens, based on formal epidemiologic studies among workers who were exposed for long periods (several years) to the chemicals.85 Group 2A contains what are considered to be probable human carcinogens. Suggestive epidemiologic evidence exists for compounds in this group, but the data are insufficient to establish causality. There is evidence of carcinogenicity, however, from animal studies carried out under conditions relevant to human exposure. Group 2B contains what are considered to be possible carcinogens, because these substances are associated with a clear statistically and biologically significant increase in the incidence of malignant tumors in more than one animal species or strain. Group 3 agents are not classifiable, and Group 4 agents are probably not carcinogenic to humans. Selected substances that have been classified as proven carcinogens (group 1) by the IARC in an expert panel review in 2009 are listed in Table 10-5.86
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Physical carcinogenesis can occur through induction of inflammation and cell proliferation over a period of time or through exposure to physical agents that induce DNA damage. Foreign bodies can cause chronic irritation that can expose cells to carcinogenesis due to other environmental agents. In animal models, for example, subcutaneous implantation of a foreign body can lead to the development of tumors that have been attributed to chronic irritation from the foreign objects. In humans, clinical scenarios associated with chronic irritation and inflammation such as chronic nonhealing wounds, burns, and inflammatory bowel syndrome have all been associated with an increased risk of cancer. H. pylori infection is associated with gastritis and gastric cancer, and thus, its carcinogenicity may be considered physical carcinogenesis. Infection with the liver fluke Opisthorchis viverrini similarly leads to local inflammation and cholangiocarcinoma.
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The induction of lung and mesothelial cancers by asbestos fibers and nonfibrous particles such as silica are other examples of foreign body-induced physical carcinogenesis.87 Animal experiments have demonstrated that the dimensions and durability of the asbestos and other fibrous minerals are the key determinants of their carcinogenicity.88 Short fibers can be inactivated by phagocytosis, whereas long fibers (>10 μm) are cleared less effectively and are encompassed by proliferating epithelial cells. The long fibers support cell proliferation and have been shown to preferentially induce tumors. Asbestos-associated biologic effects also may be mediated through reactive oxygen and nitrogen species. Furthermore, an interaction occurs between asbestos and silica and components of cigarette smoke. Polycyclic aromatic hydrocarbons (PAHs) in cigarette smoke are metabolized by epithelial cells and form DNA adducts. If PAH is coated on asbestos, PAH uptake is increased.87 Both PAH and asbestos impair lung clearance, potentially increasing uptake further. Therefore, physical carcinogens may be synergistic with chemical carcinogens.
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Radiation is the best-known agent of physical carcinogens and is classified as ionizing radiation (X-rays, gamma rays, and alpha and beta particles) or nonionizing radiation (UV). The carcinogenic potential of ionizing radiation was recognized soon after Wilhelm Conrad Roentgen’s discovery of X-rays in 1895. Within the next 20 years, a large number of radiation-related skin cancers were reported. Long-term follow-up of survivors of the atomic bombing of Hiroshima and Nagasaki revealed that virtually all tissues exposed to radiation are at risk for cancer.
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Radiation can induce a spectrum of DNA lesions that includes damage to the nucleotide bases and cross-linking, and DNA single- and double-strand breaks (DSBs). Misrepaired DSBs are the principal lesions of importance in the induction of chromosomal abnormalities and gene mutations. DSBs in irradiated cells are repaired primarily by a nonhomologous end-joining process, which is error prone; thus, DSBs facilitate the production of chromosomal rearrangements and other large-scale changes such as chromosomal deletions. It is thought that radiation may initiate cancer by inactivating tumor-suppressor genes. Activation of oncogenes appears to play a lesser role in radiation carcinogenesis.
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Although it has been assumed that the initial genetic events induced by radiation constitute direct mutagenesis from radiation, other indirect effects may contribute to carcinogenesis. For example, radiation induces genomic instability in cells that persists for at least 30 generations after irradiation. Therefore, even if cells do not acquire mutations at initial irradiation, they remain at risk for developing new mutations for several generations. Moreover, even cells that have not been directly irradiated appear to be at risk, a phenomenon referred to as the bystander effect.
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Nonionizing UV radiation is a potent DNA-damaging agent and is known to induce skin cancer in experimental animals. Most nonmelanoma human skin cancers are thought to be induced by repeated exposure to sunlight, which leads to a series of mutations that allow the cells to escape normal growth control. Patients with inherited xeroderma pigmentosum lack one or more DNA repair pathways, which confers susceptibility to UV-induced cancers, especially on sun-exposed body parts. Patients with ataxia telangiectasia mutated syndrome also have a radiation-sensitive phenotype.
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One of the first observations that cancer may be caused by transmissible agents was by Peyton Rous in 1910 when he demonstrated that cell-free extracts from sarcomas in chickens could transmit sarcomas to other animals injected with these extracts.89 This was subsequently discovered to represent viral transmission of cancer by the Rous sarcoma virus. At present, several human viruses are known to have oncogenic properties, and several have been causally linked to human cancers (Table 10-6).85 It is estimated that 15% of all human tumors worldwide are caused by viruses.90
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Viruses may cause or increase the risk of malignancy through several mechanisms, including direct transformation, expression of oncogenes that interfere with cell-cycle checkpoints or DNA repair, expression of cytokines or other growth factors, and alteration of the immune system. Oncogenic viruses may be RNA or DNA viruses. Oncogenic RNA viruses are retroviruses and contain a reverse transcriptase. After the viral infection, the single-stranded RNA viral genome is transcribed into a double-stranded DNA copy, which is then integrated into the chromosomal DNA of the cell. Retroviral infection of the cell is permanent; thus, integrated DNA sequences remain in the host chromosome. Oncogenic transforming retroviruses carry oncogenes derived from cellular genes. These cellular genes, referred to as proto-oncogenes, usually are involved in mitogenic signaling and growth control, and include protein kinases, G proteins, growth factors, and transcription factors (Table 10-7).90
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Integration of the provirus upstream of a proto-oncogene may produce chimeric virus-cell transcripts and recombination during the next round of replication that could lead to incorporation of the cellular gene into the viral genome.90 Then again, many retroviruses do not possess oncogenes but can cause tumors in animals regardless. This occurs by integration of the provirus near a normal cellular proto-oncogene and activation of the expression of these genes by the strong promoter and enhancer sequences in the integrated viral sequence.
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Unlike the oncogenes of the RNA viruses, those of the DNA tumor viruses are viral, not cellular, in origin. These genes are required for viral replication using the host cell machinery. In permissive hosts, infection with an oncogenic DNA virus may result in a productive lytic infection, which leads to cell death and the release of newly formed viruses. In nonpermissive cells, the viral DNA can be integrated into the cellular chromosomal DNA, and some of the early viral genes can be synthesized persistently, which leads to transformation of cells to a neoplastic state. The binding of viral oncoproteins to cellular tumor-suppressor proteins p53 and Rb is fundamental to the carcinogenesis induced by most DNA viruses, although some target different cellular proteins.
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Like other types of carcinogenesis, viral carcinogenesis is a multistep process. Some retroviruses contain two cellular oncogenes, rather than one, in their genome and are more rapidly tumorigenic than single-gene transforming retroviruses, which emphasizes the cooperation between transforming genes. Furthermore, some viruses encode genes that suppress or delay apoptosis.
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Although immunocompromised individuals are at elevated risk, most patients infected with oncogenic viruses do not develop cancer. When cancer does develop, it usually occurs several years after the viral infection. It is estimated, for example, that the risk of hepatocellular carcinoma (HCC) among individuals infected with hepatitis C virus is 1% to 3% after 30 years.91 There may be synergy between various environmental factors and viruses in carcinogenesis.
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Recognition of a viral origin for some tumors has led to the pursuit of vaccination as a preventive strategy. The use of childhood hepatitis B vaccination has already translated into a decrease in liver cancer incidence in the Far East.5 Similarly, it is recognized that cervical cancer and its obligate precursors, cervical intraepithelial neoplasia grades 2 and 3, and adenocarcinoma in situ, are caused by oncogenic human papillomavirus (HPV); administration of HPV vaccine to HPV-naive women, substantially reduces the incidence of HPV16/18-related cervical precancers and cervical cancer.92 The American Cancer Society now recommends routine HPV vaccination principally for females aged 11 to 12 years, but also for females aged 13 to 18 years to ‘’catch up’’ those who missed the opportunity to be vaccinated or who need to complete the vaccination series.93