VHL gene on chromosome 3p, the protein product degrading hydroxylated hypoxia inducible factor-1α,

nearly 80% of cases are familial.39 Unlike most autosomal dominant disorders, VHL disease subscribes

to the Knudson “two-hit hypothesis” with mutation of both VHL alleles necessary for tumor or cyst

formation.38

Environmental Risk Factors

Although the cause of most human cancers remains unidentified, the causal association between

carcinogenesis and exposure to environmental risk factors is significant. The first known documented

link between cancer and exposure to a carcinogen was documented in the treatises of the English

surgeon Percivall Pott.40 In 1775, Pott documented the high incidence of scrotal cancer among chimney

sweeps secondary to soot lodging in scrotal skin. Subsequent preventive measures aimed at increasing

bathing and use of protective clothing led to a dramatic decline in the incidence of scrotal cancer. It was

not until the 20th century that the active carcinogens in soot were shown to be polycyclic aromatic

hydrocarbons.41 Table 14-5 lists the most common carcinogens associated with human cancers.

Table 14-5 Preventable Exposures Associated with Human Solid Organ Cancers

Tobacco and Cancer

Tobacco use is associated with more cancer-related deaths worldwide than any other environmental risk

factor. There are now 19 cancers for which causal evidence exists between cancer formation and

cigarette smoking: lung, oral cavity, nasopharynx, nasal cavity, larynx, esophagus, liver, stomach,

colorectum, pancreas, kidney, ureter, urinary bladder, cervix, ovary, and bone marrow. Three cancers

have known causality with smokeless tobacco use: oral cavity, esophagus, and pancreas.42 Table 14-6

details the relative risks by cancer site of tobacco smoking.

The causative carcinogens in tobacco products are broad and heterogeneous. In fact, the International

Agency for Research on Cancer (IARC) working group has identified 72 carcinogens contained in

cigarette smoke linked to cancer development.43 The underlying pathophysiology for smoking-related

cancer is organ specific but likely dependent on the oxidative damage caused by the carcinogens

producing free oxygen radicals and redox cycling.44

Viral Risk Factors

Nearly 15% of cancers or 1.3 million cancer cases worldwide can be attributed to viral infection.45 The

search for human tumor viruses is accentuated by a long appreciation of viral-linked cancers in birds

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and rodents. Peyton Rous in 1911 demonstrated spindle cell sarcomas could be readily transmitted from

diseased to healthy chickens using tumor cell infiltrates.46 This observation led to the identification of

the Rous sarcoma virus (RSV), a member of the Retroviridae family, as causative agent responsible for

Rous’ original observation decades earlier.46

The lack of convincing animal models confirming epidemiologic studies coupled with the lack of

oncogene expression by human tumor–associated viruses has delayed recognition of virus-induced

human cancers. Using both epidemiology and molecular biology analysis, six viruses are established as

causative agents of cancer (Table 14-7). Hepatitis B and C viruses (HBV and HCV), HPV, and the human

herpes virus 8 (HHV-8) (Kaposi sarcoma-associated herpes virus) will be discussed in further detail.

Table 14-6 Cancer Sites Associated with Tobacco Smoking by Relative Risk

According to the International Agency for Research on Cancer

Working Groups

Table 14-7 Human Tumor–Associated Viruses

Hepatitis B and Hepatitis C Viruses

HBV and HCV are hepatotropic viruses causing both acute and chronic viral hepatitis and are

responsible for nearly 90% of hepatocellular carcinoma (HCC) cases diagnosed worldwide.47 HBV, a

member of the Hepadnaviridae family, is a circular double-stranded DNA that incorporates into the

cellular DNA of hepatocytes at random sites. Although the exact mechanism for induction of HBVrelated HCC remains unknown due to the long latency period between viral infection and cancer

appearance it is postulated to occur through either (1) induction of chronic liver cell injury leading to

random chromosomal and genetic injury or (2) expression of X protein from the incorporated HBV

activating the mitogen-activated protein kinase, c-jun N-terminal kinase, protein kinase C,

phosphatidylinositol 3-kinase, protein kinase B, and JAK/STAT pathways.48–51

HCV is a single-stranded RNA virus from the Flaviviridae family, unique as the only human tumor virus

utilizing RNA as genetic material. Responsible for the vast majority of HCC cases within the United

States, HCV has six known genotypes and has a latency period from infection to HCC formation

typically more than two decades. The actual pathophysiologic mechanism for HCV-related HCC

development is unknown but like HBV-related HCC is thought to occur secondary to creating a state of

chronic inflammation and regeneration within the liver parenchyma at the hepatocyte level.52,53

With the development of a HBV vaccine in the late 1970s the incidence of HBV-related HCC has

decreased worldwide. Although there is no commercially available HCV vaccines, since 2010 there are

orally bioavailable drugs that dramatically decrease the HCV viral load. However, it is unclear whether

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HCV treatment will impact HCC incidence rates as many patients have already progressed to cirrhosis

prior to actual HCV diagnosis.

Human Papilloma Virus

HPV is a nonenveloped double-stranded DNA tumor virus that is responsible for a variety of epithelial

disorders ranging from benign to malignant. Although consisting of over 100 known variants, HPV-16

and HPV-18 are designated high risk for tumor induction and are responsible for over 70% of known

cervical and anal cancers.54,55 The molecular pathogenesis of HPV-related cancers is better understood

than other viral-associated cancers and occurs following HPV infection of keratinocytes at the basal

epithelial layer of the stratified squamous epithelium. Upon HPV integration into host DNA, two viral

genes, E6 and E7, are expressed and their products bind to a p53 tumor suppressor gene (E6) and/or

retinoblastoma suppressor protein (E7) to deregulate cell growth and inhibit apoptosis leading to the

accumulation of mutations and the development of cancers following a length latency period.56,57 The

recent development of quadrivalent and bivalent HPV vaccines is expected to have a significant impact

on the development of HPV and subsequent cervical and anal cancer incidence.58

Human Herpes Virus 8

HHV-8, also known as Kaposi sarcoma-associated herpes virus, is a double-stranded DNA virus from the

Herpesviridae family associated with the development of Kaposi sarcoma, primary effusion lymphoma,

and multicentric Castleman disease. HHV-8 has a latent and lytic phase persisting in B-lymphocytes.

During the latent phase HHV-8 evades the host immune system and has only minimal expression of gene

products. However, in the lytic phase innumerable viral proteins are produced including viral G

protein–coupled receptor, K1, v-cyclin, and v-Bcl-2 that modulates cell growth, induces vascular

endothelial growth factor (VEGF) expression, and inhibits apoptosis, respectively, leading to induction

of cancer.59,60

Dietary Risk Factors and Obesity

3 Dietary factors are thought to account for nearly 30% of cancer cases in developed countries, making

dietary factors second only to tobacco use as the most preventable cause of cancer.61 The contribution

of diet to cancer risk in developing countries is considerably lower, most estimates indicate a 20%

causal rate.62 Attaining definitive evidence to confirm or refute effects of specific dietary factors on

cancer incidence is oftentimes difficult with causal associations relying on migration patterns of

immigrants. Migration studies have demonstrated that the incidence of many cancers change as much as

5- to 10-fold among immigrants over time, approaching that of the host country. The age at migration

appears linked to cancer development among first-generation immigrants, suggesting that the

susceptibility to environmental carcinogenic influences varies with age by cancer type.63–65 Table 14-10

lists cancer sites with causal associations with dietary factors.

Obesity

The most important impact of diet on the risk of cancer is mediated through body weight. The IARC

working group on weight control and physical activity estimates in developed countries a body mass

index over 25 kg/m2 accounts for approximately 39% of endometrial, 25% of kidney, 11% of colon, 9%

of postmenopausal breast cancer, and 5% of total cancer incidence.66

The mechanisms linking obesity and cancer development are largely unknown but likely

multifactorial. An example of a causal association between cancer and obesity is in postmenopausal

breast cancer. A weight gain of 10 kg or more is associated with a significant increase in breast cancer

incidence among women who have never used hormone replacement therapy.67 This is likely secondary

to large increases in endogenous estrogen levels, also leading to increased incidence of endometrial

cancer.68 The mechanism for obesity-related nonbreast or nonendometrial cancers remains unclear and

is under clinical investigation.

Table 14-8 Human Cancers Associated with Dietary Factors and Nutrition

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Cell Cycle

Control of the cell division cycle is central for governing when the cell should progress to DNA synthesis

and proliferation versus growth arrest, DNA repair, or apoptosis. Cell division proceeds through a welldefined series of stages with tightly regulated and balanced processes dependent on oncogene and

tumor suppressor gene expression (Fig. 14-4). When cells leave quiescence (G0

), they enter a first gap

phase (G1

) where an explosion of growth factors and macromolecules is transcribed and translated

allowing cells to divide but not lose overall size. Toward the end of G1

, cells reach a restriction point

governed by cell cycle checkpoint genes where thereafter they are now committed to division. It is at

this restriction point where DNA repair or programmed cell death (apoptosis) occurs and where

phosphorylation of the tumor suppressor product, RB protein, allows entry into the S phase. During the

S phase, DNA is synthesized and progression to second gap phase (G2

) follows. Within the middle of the

G2 phase yet another restriction point or cell cycle checkpoint occurs prior to cell entry into mitosis

(M), the actual cell division phase.69

Proto-oncogenes code for proteins that send signals to the cell nucleus promoting cell division,

especially at the G1–S and G2–M transition points. Oncogenes are altered versions of proto-oncogenes

also coding for signaling proteins but in a continuous fashion leading to incontrollable cell division and

thus, tumor development. The conversion of proto-oncogenes into oncogenes occurs through three basic

methods: (1) a mutation within a proto-oncogene producing an increase in protein activity (seen in the

conversion of the Ras proto-oncogene), (2) an increase in the amount of protein within the cell resulting

in amplified expression (i.e., c-MYC proto-oncogene), and (3) a chromosomal translocation where fusion

proteins are produced or protein expression is altered (i.e., Philadelphia chromosome, BCR/ABL).70

Tumor suppressor genes also play a crucial role in the cell division cycle serving as a brake for

division in response to DNA damage. The tumor suppressor genes, p53 and RB, play a critical role in

maintaining the checkpoint at the G1–S transition point.71,72 Homozygous loss of p53 is found in 65% of

colon cancers, 30% to 50% of breast cancers, and 50% of lung cancers. In addition, p53 germline

mutations are associated with Li–Fraumeni syndrome, an autosomal dominant disorder associated with

sarcomas, breast cancer, leukemia, and adrenal gland cancers.73

Cancer Immunology

The fundamental tenet of the immune surveillance hypothesis, postulated by Thomas and Burnet nearly

five decades ago, is that the underlying function of the immune system is to survey the human body,

recognize and then eliminate tumors based on tumor antigen expression.74,75 Well documented in

nonhuman animal models, the role of the immune system as a surveillance and treatment response in

human malignancies is debatable and is best supported by tangential clinical evidence. In humans,

cancer incidence rates correlate to advancing age presumably due to increased cell division and error

rates in chromosomal replication over time that the immune system simply cannot overcome.

A corollary to the immune surveillance hypothesis is that immunodeficient individuals have an

increased rate of cancer development.76 Epidemiologic studies of patients with heritable

immunodeficiencies demonstrate mixed results for this hypothesis. Incidence rates of traditional

noncommon cancers including Kaposi sarcoma and lymphoblastic lymphoma have demonstrated

increased frequency in heritable immunodeficiencies.77 However, common epithelial-based cancers,

including lung, colorectal, and breast, have similar incidence rates as the general population.77 The

initial epidemiologic studies were conducted at a time when patients with heritable immunodeficient

disorders rarely lived past 30 years of age, so it is difficult to ascertain whether subtle changes in

incidence seen in the more common epithelial cancers are more obvious as patients age. A similar

phenomenon is seen in acquired immunodeficiencies, including acquired immunodeficient syndrome

(AIDS), where uncommon cancers such as Kaposi sarcoma and non-Hodgkin lymphoma and not

epithelial-based tumors remain the most common AIDS-related cancers.78 As HIV-positive individuals

are living longer due to more efficacious antiretroviral treatments, common epithelial cancers as well as

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cancers secondary to viral coinfectivity, with hepatitis viruses and/or HPV have increased in

incidence.79,80

Figure 14-4. Mammalian cell cycle. Rb, a tumor suppressor gene, is complexed to E2F and is thereby unable to enter from G1

to S

phases. Upon signaling from the checkpoint genes, CDK4, 6, and cyclin D, Rb is phosphorylated allowing passage into S phase.

Another cohort, with an acquired immunodeficiency, demonstrating increased incidence rates of

common and noncommon cancers are patients receiving immunosuppressive drugs following

transplantation. A recent study examining cancer incidence in patients following heart and/or lung

transplantation receiving immunosuppression therapy demonstrated a sevenfold increased incidence of

cancer compared to the general population, with leukemia and lymphoma being the most prevalent.81

Additionally, nearly a 200-fold increase in basal and squamous cell carcinomas is demonstrated

following renal transplantation, secondary to immunosuppression and UV radiation damage.82

Tumors differ fundamentally from their normal cell counterparts through the production of tumor

antigens, thereby allowing the immune system to differentiate self versus nonself. Tumor antigens are

generated by the tumor cell and have historically been broken into two groups, tumor-specific antigens

and tumor-associated antigens.76 Tumor-specific antigens are molecules, typically proteins produced by

the tumor secondary to a mutation of a proto-oncogene or tumor suppressor gene. Tumor-associated

antigens are proteins produced following gene mutations unrelated to tumor formation. Due to lack of

specificity between the two historical terms, tumor antigens are more accurately classified according to

mutation of normal self-proteins, overexpression or aberrant expression of normal self-proteins,

glycoproteins, or glycolipids, and formation of protein products of oncogenes or oncoviruses.76

The innate immune system response to tumors can be divided into two general compartments: a set of

barriers and cell activity.83 The barriers are comprised of mechanical factors including the skin and

mucous membrane, chemical factors including high gastric acidity, and biologic barriers including

commensal microbes. Natural killer cells, macrophages, and dendritic cells comprise the cellular

component of the innate immune system response.

Natural killer cells constitute the primary innate immune cell type responsible for killing nonmajor

histocompatibility complex (MHC) expressing cancer cells. Many tumors lose MHC class I molecules

during malignant transformation while continuing to express ligands such as MICA and MICB that

constitutively bind NK receptors, including NKG2D, inducing tumor cell apoptosis through perforin and

granzyme release.84 Macrophages can efficiently eliminate apoptotic tumor cells through the release of

lysosomal enzymes, reactive oxygen intermediaries, and nitric oxide. Dendritic cells link the innate

immune system to the adaptive immune system. Residing in specific tissues according to dendritic cell

lineage, dendritic cells phagocytize tumor antigens and carry the proteins to draining lymph tissue

presenting to tumor-specific T cells. Depending on the state of dendritic cell maturity caused by

costimulatory molecule signaling, either a state of anergy/tolerization (immature) or activation

(mature) of tumor-specific T cells and the adaptive immune system response occur.76

Evidence supporting activation of the adaptive immune system response in mouse tumor cell models

is well documented. However, its role in human malignancies is not as clearly defined due to the

heterogeneity of the tumor microenvironment and the obvious lack of immunodeficient human models.

Nevertheless, compelling clinical data supports the hypothesis that an adaptive immune system response

serves as a mechanism for tumor cell death in humans. Tumor infiltrating lymphocytes (TILs) including

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