The Biology of Cancer and Its Relationship to Disparities in Cancer Occurrence and Outcomes Part 1


Cancer is a group of diseases in which cells have developed the ability to invade into surrounding tissues and potentially metastasize to distant sites (Kessenbrock, Plaks, & Werb, 2010; Talmadge & Fidler, 2010). There are many different types of cancer, but they all occur as a consequence of acquired mistakes in the DNA, including epigenetic changes (Hoeijmakers, 2009). The DNA provides the master plan for all organisms in which four nucleotide bases (guanine, cytosine, adenine, and thymine) occur in specific arrangements and spell out the exact instructions required to create a particular organism with its own unique traits. The coding contained in the DNA is responsible for the formation and function of the complete spectrum of different cells and organs, as well as the biologic changes that occur as we age. The changes in the DNA that lead to cancer alter critical cellular processes that govern cell behavior, leading to cells that can invade and move to places where they do not belong (Markowitz & Bertagnolli, 2009; Michor, Iwasa, Vogelstein, Lengauer, & Nowak, 2005; Vogelstein & Kinzler, 2004). The different types of cancer reflect the different types of cells that undergo changes in their programming as a consequence of the alterations in the DNA (Aranda, Nolan, & Muthuswamy, 2008; Asselin-Labat et al., 2008; Lindvall, Bu, Williams, & Li, 2007; Lukacs et al., 2008; Mishra, Glod, & Banerjee, 2009). For example, kidney cancer occurs when the DNA in kidney cells changes to allow cells to invade and metastasize (Valladares Ayerbes et al., 2008), whereas breast cancer occurs when breast cells develop critical changes in their DNA (Lindvall et al., 2007; Turner & Grose, 2010). The types of mistakes that lead to cancer create additional subtypes of cancer. For example, breast cancer with amplification of the HER-2/neu gene is different from breast cancer that over expresses the estrogen receptor (Charafe-Jauffret et al., 2005; Livasy et al., 2006). Thus, cancer is hundreds of different diseases, and knowledge of the shared and unique features of the different types of cancer is leading to more effective strategies for prevention, early detection, and treatment.

To understand why some people get cancer and others do not, it is important to understand that people are protected against cancer by many biologic processes designed to ensure that the more than 3 billion nucleotides in the DNA are properly copied each time a cell divides (Bartek & Lukas, 2007; de Bruin & Wittenberg, 2009; Talos & Moll, 2010). Both genetic and environmental factors affect the likelihood that mistakes will occur, and both contribute to disparities in cancer occurrence and outcome in various populations.

There are many different types of errors that can occur when DNA is replicated, and when they are not corrected, the changes are usually detrimental to the cell, but occasionally they give a growth advantage. While nearly all cells have the same DNA, different types of cells use distinct portions of the DNA for defining cellular characteristics and behavior, and making proteins that address each cell’s specific needs. Access to distinct portions of the DNA code are regulated through a process called epigenetics, in which the ability to read the DNA code is changed without changing the DNA sequence, and epigenetic changes can also contribute to cancer (Clark, 2007; Omura & Goggins, 2009; Weidman, Dolinoy, Murphy, & Jirtle, 2007). Most cancers also contain alterations in the DNA sequence. Simple substitutions of nucleotides can lead to mutations that alter proteins or change regulatory regions in the DNA (Lee et al., 2010; Salk, Fox, & Loeb, 2010). Sometimes changes involve large portions of DNA, including duplications, deletions, inversions, or movement of DNA to distant regions (called translocations); these changes often affect hundreds of genes simultaneously (Argos et al., 2008; Dreyling et al., 1995; Grushko et al., 2002; Murnane, 2010; Nussenzweig & Nussenzweig, 2010; Turner & Grose, 2010). Changes in DNA that are detrimental to the cells usually are eliminated, whereas changes that give cells a growth and survival advantage can rapidly be propagated and set the stage for the development of cancer.

The development of cancer generally requires multiple changes in the DNA, and cells that undergo many divisions are at increased risk for cancer, especially if they are exposed to carcinogenic agents that induce DNA damage (Rajaraman, Guernsey, Rajaraman, & Rajaraman, 2006). The likelihood of multiple mistakes happening within a single cell increases over time and with multiple cell divisions. Thus, the overall risk of cancer increases with age and is more likely to occur in cells that are programmed to undergo frequent replacement, such as skin cells or cells lining the colon (Hoeijmakers, 2009). There can be more than 1,000 mutations and other genetic mistakes within some cancers (Kwei, Kung, Salari, Holcomb, & Pollack, 2010; Lee et al., 2010), indicating that many biologic processes are likely to be altered and making simple fixes difficult. Cancer cells continue to evolve and acquire additional changes in their DNA (Kwei et al., 2010; Negrini, Gorgoulis, & Halazonetis, 2010; Talos & Moll, 2010). As new variants arise, those that offer survival advantage become more prevalent in the population. The ongoing evolution of tumors can lead to resistance to treatment and clinical relapses, even when the original cancer shows a complete clinical response.

Despite the huge number of changes in DNA that have been identified in some cancers, critical changes converge on a limited number of biologic processes. Pathways that are commonly involved include those that allow replication of damaged DNA, those that promote cellular replication, those that inhibit programmed cell death, those that immortalize cells, and those that stimulate environments favorable for tumor cell growth (Kessenbrock et al., 2010; Tammela & Alitalo, 2010; Turner & Grose, 2010).


The incidence and outcome of cancer differ in various segments of the U.S. population, with socioeconomic status, race/ethnicity, residence, gender, and sexual orientation all having an impact (American Cancer Society, 2010). Data from the Surveillance, Epidemiology, and End Results (SEER) program show that African Americans have the highest incidence and mortality rates of cancer compared to other racial and ethnic groups within the United States. The mortality rate for African American males is 34% higher than among Caucasian males; African American females display a 17% higher mortality rate when compared to Caucasian females. The causes of the increased mortality depend on the type of cancer and involve differences in tumor biology, timeliness of diagnosis, approach to cancer management, and presence of coexisting diseases. Hispanics, Asians/Pacific Islanders, and American Indians/Alaska Natives in the United States have lower i ncidence rates when compared to Caucasians and African Americans for the most common cancer types. In contrast, Asians/Pacific Islanders display the highest incidence and mortality rates for liver and stomach cancers, cancers that are initiated by infectious agents that are more prevalent in Asia than in the United States, suggesting that immigrants from these areas might be contributing to the higher incidence (Kimura, 2000; Tsai & Chung, 2010). To understand and correct the disparities that exist, it is important to incorporate our evolving knowledge of the complex biologic processes that are affected by various forms of cancer into the analysis of the disparities that exist.


While cancer is due to acquired mistakes in the DNA, the likelihood of acquiring these changes can be affected by inherited factors in the DNA. It is currently estimated that more than 90% of cancers are sporadic and are not due to an inherited susceptibility, whereas 5%-10% of cancers are linked to an inherited susceptibility. The prevalence of some of the inherited factors differs in various populations, thereby contributing to some cancer disparities (Markowitz & Bertagnolli, 2009; Petrucelli, Daly, & Feldman, 2010; Rebbeck, Halbert, & Sankar, 2006). For those who have inherited a defective copy of a gene that increases cancer risk, the development of cancer is still dependent on acquiring additional changes in the DNA, with various environmental factors affecting the likelihood that cancer-causing changes will occur.

Some inherited cancer-susceptibility genes confer risk for many forms of cancer, whereas others confer risk for only a specific type of cancer (Markowitz & Bertagnolli, 2009; Petrucelli et al., 2010; Rebbeck et al., 2006). Inherited defects in the BRCA1 and BRCA2 genes increase risk for both breast and ovarian cancers (about 80% lifetime risk in some carriers), whereas they confer a much smaller risk of developing other cancers, including pancreatic cancer (Petrucelli et al., 2010). The BRCA1 and BRCA2 proteins play a role in DNA repair, and when the proteins are defective, damaged DNA is more likely to persist and accumulate multiple changes that can culminate in cancer (Kwei et al., 2010; Olopade, Grushko, Nanda, & Huo, 2008; Powell & Kachnic, 2008; Zhang & Powell, 2005). Inherited mutations in the BRCA genes are found most often in people of Ashkenazi Jewish decent, but they may also contribute to breast cancer in young African American women, as will be discussed later in the topic.

Some people inherit defective forms of one of the enzymes in the DNA mismatch repair system, and this predisposes to hereditary nonpolyposis colorectal cancer (Lynch syndrome), with endometrial cancer and ovarian cancer also occurring at increased frequency (Hampel et al., 2005). Many other genes that predispose to cancer have been identified, but most of the inherited cancer syndromes are relatively rare, and thus do not play a large role in overall disparities in the occurrence and outcome of cancer in various populations.


Tumorigenesis is a multistage process that usually happens over many years, making it difficult to pinpoint the specific environmental agents responsible for the multiple changes that lead to cancer. Broadly defined, environmental factors include all external forces that act upon an organism, including dietary factors, infectious agents, sunlight, occupational exposures, pollutants, and all other agents encountered throughout a lifetime, some of which might increase risk for cancer (Chameides, 2010; Clavel, 2007; Monforton, 2006; Robinson, 2002; Tominaga, 1999; Weidman et al., 2007; Zhao, Shi, Castranova, & Ding, 2009). Exposure to carcinogens at a young age is generally more problematic than for older individuals, due to the higher rate of cell division in younger people who are growing and due to the many years over which additional mistakes can accumulate (Barton et al., 2005). Some environmental factors increase the risk of cancer by directly inducing DNA damage, whereas others increase the likelihood that a cell with damaged DNA will survive, proliferate, and go on to develop more damage that leads to cancer.

Cancer clusters that are associated with specific occupations, specific geographic sites, and/or use of specific products have played an important role in identifying carcinogenic agents. For example, boys who served as chimney sweeps in the 18th century were observed to develop scrotal cancer, an otherwise rare form of cancer that was triggered by some of the chemicals in the soot that came in contact with their tissues (Cherniack, 1992; Hall, 1998). In the late 19th century, epidemiologic studies identified an excessive occurrence of bladder cancer among workers in the aniline dye industry. Since that time, multiple studies have firmly established that the risk of bladder cancer increases with exposure to a variety of industrial chemicals known to have carcinogenic effects, including naphthylamine, methylene dianiline, and toluidine (Golka, Wiese, Assennato, & Bolt, 2004). Ship workers and others exposed to asbestos fibers are at increased risk of mesothelioma and of lung cancer, with the inflammation triggered by the fibers playing a large role in tumor development many years after the exposure (Gibbs & Berry, 2008; Maeda et al., 2010). The Environmental Protection Agency, the Consumer Product Safety Commission, the Occupational Safety and Health Administration, and other federal and state groups have enacted regulations to limit exposure to many carcinogenic substances. These regulations reduce risk, but exposures to carcinogens continue to occur, with some occupations and geographic areas posing greater risk than others, and with lower socioeconomic groups proportionally having greater exposures (Steenland, Burnett, Lalich, Ward, & Hurrell, 2003).


Some chemicals that are present in tobacco are carcinogenic, and the risk that they pose increases with exposure (Secretan et al., 2009). Some people also inherit an increased risk to becoming addicted to nicotine and hence are at increased risk of heavy smoking, which thereby increases their cancer risk (Stevens et al., 2008). There are multiple genes that affect the likelihood that someone will become addicted, and the role of these in racial differences in tobacco use and dependence is only starting to be explored (Sherva et al., 2010). In addition, some people inherit genes that modulate their risk of cancer through differences in their ability to metabolize and clear carcinogens, through differences in their ability to recognize and repair damaged DNA, and through other mechanisms (Weisberg, Tran, Christensen, Sibani, & Rozen, 1998; Wu et al., 2002). The tissues that are most at risk for damage from the carcinogens in cigarettes are those within the respiratory track, mouth, and upper digestive tract, which are exposed to the chemicals in smoke. Some chemicals in smoke get absorbed and are excreted through the kidneys and bladder, which contributes to an increased risk of kidney and bladder cancer in smokers (Green et al., 2000; Lodovici & Bigagli, 2009). Most smokers start as teenagers; the incidence of lung cancer, however, peaks after age 60, which indicates that it often takes a long time for carcinogenic agents to cause damage to the DNA that is sufficient to cause cancer. Quitting smoking reduces but does not eliminate risk, because some of the damage that has occurred is permanent, and these cells remain at increased risk for acquiring additional changes in the DNA (Ebbert et al., 2003). Some agents enhance the carcinogenic nature of tobacco. For example, the combination of heavy tobacco and alcohol poses a greater risk of developing cancers of the oral cavity and esophagus than either agent alone (Scully & Bedi, 2000; Secretan et al., 2009). The mechanisms responsible for these combined effects are not known and are being investigated. The combination of asbestos and tobacco leads to a much higher risk of lung cancer than either agent alone.Some of the cancers that are induced by tobacco can also occur in nonsmokers. Sometimes, these tumors are linked to secondhand smoke, but some of them have molecular features that indicate that distinct mechanisms are involved in their initiation. For example, while most head and neck cancer in the United States is due to heavy use of tobacco and alcohol, an increasing number are due to infection with human papillomavirus (HPV) (Settle et al., 2009). Many cases of lung cancer in nonsmokers have molecular features that differ dramatically from lung cancer in smokers, pointing to distinct mechanisms involved in their development.

Dietary Factors

Dietary factors can either increase or decrease the risk of cancer through a variety of different mechanisms (Ahn et al., 2007; Carpenter, Yu, & London, 2009; Huxley et al., 2009). People with diets that are low in fruits and vegetables are at increased risk for cancer, yet people who consume high amounts of fruits and vegetables do not appear to be at less risk for cancer than those who consume moderate amounts. Very low consumption of fruits and vegetables can lead to vitamin deficiencies, including folate, vitamin B6, vitamin B12, and vitamin A, and these can increase mutation rates (Ames, 1999). Several randomized studies indicate that supplementation with micronutrients is often not sufficient to reduce risk, and may increase risk in some situations (Goodman, Alberts, & Meyskens, 2008). For example, deficiencies in beta-carotene (a precursor to vitamin A) have been associated with an increased risk of cancer in people exposed to the carcinogens in tobacco, but randomized trials in high-risk populations have shown that supplementation with beta-carotene increased rather than decreased cancer incidence and cancer mortality among smokers (Bardia et al., 2008). The form in which a micronutrient is delivered can also make a difference. Vitamin C from dietary sources, but not from supplements, is associated with a reduced risk of oral premalignant lesions (Maserejian, Giovannucci, Rosner, & Joshipura, 2007). Consumers are often led to believe that such supplements are safe and effective, but many do not help, and some may be causing harm.

Some studies show that the manner in which the food is prepared plays an important role in the increased risk that is linked to consumption of some foods. For example, grilling of red meats at high temperatures can generate heterocyclic amine carcinogens that would be absent or at lower levels with meat prepared in different manners (Alaejos, Gonzalez, & Afonso, 2008; Cross & Sinha, 2004). This is thought to contribute to some of the increased risk of cancer in people who consume large quantities of red meat. Smoking and salt preservation are thought to contribute to the high rate of stomach cancer in Japan, especially when the bacteria Helicobacter pylori (HP) is present (Kimura, 2000). A diet high in fresh fruits and vegetables reduces the risk of stomach cancer in people with HP who consume high quantities of salted and pickled foods, illustrating the complexity of how diet affects cancer risk.

While some methods of food preservation are associated with increased risk of cancer, foods that are free of preservatives are not always better than those that have preservatives, especially if the food is at risk for contamination with microorganisms. Several fungi that grow on grains produce potent carcinogens, with fumonisen and aflatoxin increasing the risk of liver cancer (Larsen, 2010; Moore, 2009; Murphy et al., 1996; Preston & Williams, 2005). Levels of these toxins are carefully monitored and regulated in the United States, but are often found in the food supplies of developing nations, especially those with poor storage facilities. Susceptibility to carcinogens found in food can be modified by many dietary factors. For example, the chlorophyll found in green plants reduces absorption of aflatoxin, thereby offering some protection from this potent carcinogen (Preston & Williams, 2005).

Some advocacy groups have raised concern that milk products, especially those from cows that receive bovine growth factor, increase the risk of breast cancer. Bovine growth hormone is biologically inactive in humans, and data from multiple epidemiologic studies as well as laboratory studies do not show that dairy products increase risk of breast cancer (Parodi, 2005).


There is an increased rate of some forms of cancer in individuals who are obese (Ahn et al., 2007; Brown & Simpson, 2010; Calle, Rodriguez, WalkerThurmond, & Thun, 2003; van Kruijsdijk, van der Wall, & Visseren, 2009). There are multiple biologic changes that can occur during obesity, including insulin resistance, elevated levels of circulating cellular growth factors, elevated levels of estrogen, and increased inflammation (van Kruijsdijk et al., 2009).    These may be working with carcinogens, viruses, and other factors to increase the risk of DNA damage, thereby enhancing the risk of tumor development. Fat also serves as a reservoir for certain types of chemicals, some of which are carcinogenic.

The multiple changes in DNA that lead to cancer generally occur over many years, and thus it is likely that the age at which someone becomes obese and the duration of the obesity both have an impact on cancer risk. Some ethnic and racial groups are at increased risk of obesity, with genetic, cultural, and environmental factors all contributing to variations in its prevalence. Dieting reverses obesity in only a small fraction of people who attempt it, and studies that have looked at the consequences of weight loss in large populations did not show a reduction in mortality, most likely because some of the weight loss was triggered by disease processes rather than by individual choice (Bamia et al., 2010; Dixon, 2010; Eckel, 2008; Nanri et al., 2010).    Nonsurgical methods for planned weight loss have been disappointing, with a low percentage of subjects achieving and sustaining the desired weight, but subjects often show improvement in cholesterol and markers of inflammation, providing evidence of probable clinical benefit (Dansinger, Gleason, Griffith, Selker, & Schaefer, 2005; Eckel, 2008; Franco et al., 2007; Rapp et al., 2008; Sacks et al., 2009). One 10-year prospective interventional study showed that bariatric surgery on morbidly obese patients in Sweden led to major sustained weight loss, with a modest reduction in cancer rates in women but not men (Sjostrom et al., 2009). Thus, while obesity may increase the risk of cancer, weight loss in adults is disappointing in its ability to reduce risk. Ideally, efforts should be focused on preventing obesity to reduce short- and long-term health effects, including cancer.


The immune system is designed to respond to infection or injury, and in most cases it protects the host, but it can sometimes contribute to tumor formation and propagation (Grivennikov, Greten, & Karin, 2010; Sgambato & Cittadini, 2010; Wang & DuBois, 2008). This occurs in part because cells of the immune system are designed to attach and kill foreign organisms, but they can also damage normal cells when inflammation is prolonged. The duration of inflammation is linked to the risk of cancer, with the site of the inflammation being linked to where cancer occurs. The inflammation can be in response to inflammatory diseases, such as ulcerative colitis, which increases the risk of colon cancer (Markowitz & Bertagnolli, 2009). Prolonged stomach acid reflux can lead to chronic irritation of the esophagus that causes cellular changes recognized as Barrett’s esophagus, a premalignant condition in which inflammation plays an important role in the subsequent development of esophageal cancer (Edelstein, Farrow, Bronner, Rosen, & Vaughan, 2007; Sharma, 2009a, 2009b). Particle irritation, as occurs with asbestos, triggers an inflammatory response that plays an important role in the development of mesothelioma and lung cancer (Antonescu-Turcu & Schapira, 2010; Heintz, Janssen-Heininger, & Mossman, 2010; Maeda et al., 2010). Prolonged infection, as occurs with some viral, bacterial, or parasitic infections, also plays an important role in the development of some forms of cancer (Heintz et al., 2010; Maeda et al., 2010).

Infectious Agents

Some reports estimate that 20%-30% of human cancers are initiated by an infectious agent, with specific viruses, bacteria, and parasites serving as carcinogens (Morris, Young, & Dawson, 2008). Some viruses directly contribute to human cancers by bringing genetic materials into cells that permanently alter cellular programming, thereby increasing the likelihood that cells will acquire additional changes that sometimes result in cancer (Morris et al., 2008). Tumorigenic viruses that directly alter cellular programming as an early event in tumor development include HPV, Epstein-Barr virus (EBV), the Kaposi’s sarcoma herpesvirus (KSHV), hepatitis B, human T cell leukemia virus, and Merkel cell carcinoma polyoma virus (Carbone, Cesarman, Spina, Gloghini, & Schulz, 2009; Chang et al., 1994; Feng, Shuda, Chang, & Moore, 2008; Kalland, Ke, & Oyan, 2009; Klass & Offermann, 2005; Morris et al., 2008; Ruprecht, Mayer, Sauter, Roemer, & Mueller-Lantzsch, 2008). The inflammatory response that accompanies chronic infection can also lead to some forms of cancer, as occurs with HP and schistosomiasis (Kimura, 2000; Mostafa, Sheweita, & O’Connor, 1999). HP is a bacterium that contributes to the development of most cases of stomach cancer (Perrin, Ruskin, & Niwa, 2010), and the parasite schistosomiasis causes bladder cancer in parts of the world where infection is common (Mostafa et al., 1999). Infections that suppress immune function, including the human immunodeficiency virus (HIV), also contribute to tumorigenesis by reducing the ability of the immune system to suppress or kill tumorigenic viruses and developing tumors (Carbone et al., 2009; Crum-Cianflone et al., 2009). The importance of recognizing the role of infectious agents in tumorigenesis relates to the potential for preventing or clearing the infectious agent, thereby reducing cancer risk.

The likelihood that someone will develop a cancer as a consequence of an infectious agent is affected by place of birth, racial or ethnic background, sexual orientation, socioeconomic status, access to state-of-the-art health care and other factors. For example, hepatitis B is a vaccine-preventable disease that is endemic to certain parts of Asia and Africa (Lee & Lee, 2007; Tsai & Chung, 2010). Women who are carriers can transmit the virus to their newborn offspring, and the virus is also transmitted sexually or through contact with infected blood. People who develop chronic active hepatitis as a consequence of hepatitis B infection are at increased risk for hepatocellular cancer, with most tumors arising after 30 years or more of infection, since tumor development remains dependent on the acquisition of additional changes in the DNA. The risk of hepatitis B infection can be reduced through vaccination, screening of blood products to ensure that the products are free of the virus, using sterile needles for injections and infusions, and educating the public on how to reduce the risk of sexually transmitted diseases. When someone is found to be a chronic carrier and has chronic active hepatitis, treatments are available that clear infection in a high percentage of carriers. These measures are disparately used to prevent and control infection within various populations within the United States, and many of them are not available in poor countries.

In addition to differences in prevalence of infection with tumorigenic agents in different populations, there are differences in exposure to agents that serve as co-carcinogens. For example, nearly 100% of cervical cancers and anal cancers are initiated by HPV, but only a subset of people who are infected with tumorigenic strains of HPV go on to develop cancer (Longworth & Laimins, 2004; Settle et al., 2009; Stanley, Pett, & Coleman, 2007; Woodman, Collins, & Young, 2007). Both smoking and obesity increase the likelihood that someone with HPV infection will go on to develop cervical cancer (Rieck & Fiander, 2006). Screening through the use of Pap smears detects HPV-induced premalignant and malignant changes that can be treated before they become advanced, but the use of these methods and the use of vaccination against HPV is not consistent across various populations.

Infection with HIV increases the risk for cancer, with the greatest risk from cancers linked to tumorigenic viruses such as HPV, EBV, and KSHV (Carbone et al., 2009; Crum-Cianflone et al., 2009). HIV infection increases the risk for the development of Kaposi’s sarcoma 20,000-80,000-fold, with people who acquired HIV through homosexual activity at greater risk than those who acquired HIV through intravenous drug use. Not all people infected with HIV are at equal risk for the development of cancer, in part because lifestyle factors affect the risk of co-infection with HPV and KSHV, and they also affect exposure to co-carcinogens.

Next post:

Previous post: