Understanding the Causes and Mechanisms of Cancer

Cancer is invariably caused by changes in the function of genes that regulate vital cellular processes, such as growth and proliferation and programmed cell death (apoptosis). These changes may be caused by mutations in the DNA sequence of a person's genes or by epigenetic events, in which gene expression is altered without the occurrence of DNA mutations.

NCI and its partners worldwide are striving to identify the genetic, epigenetic, and environmental factors that contribute to the development of cancer. We are also seeking to understand how genes and the environment interact to influence the cancer process. In this effort, we are developing innovative technologies and harnessing the power of bioinformatics.

Environmental Carcinogens

Identifying and characterizing the environmental causes of cancer are crucial if we are to develop effective strategies for cancer prevention and control. Two major NCI-supported efforts in this area are the International Agency for Research on Cancer's (IARC) Program on the Evaluation of Carcinogenic Risks to Humans (see below) and the Institute's long-standing partnership with Chinese health authorities to investigate the effects of occupational exposure to benzene, which is described in Benzene and Cancer: East Meets West.

Other NCI-supported international activities that focus on environmental risk factors for cancer include the following:

A collaboration involving NCI's Chernobyl Research Unit and investigators in Ukraine and Belarus to study the long-term health consequences of the Chernobyl nuclear accident
NCI's Chernobyl Research Unit (CRU) is participating in three epidemiologic studies related to the 1986 accident at the Chernobyl nuclear facility in Ukraine: 1) a study of leukemia, lymphoma, and other blood diseases among Ukrainian clean-up workers; 2) a study of thyroid cancer and other thyroid diseases among Ukrainians who were exposed as children to radiation from the Chernobyl reactor; and 3) a study of thyroid cancer and thyroid diseases among Belarusians who were exposed as children to radiation from Chernobyl. The Chernobyl facility is located about 12 kilometers south of the Ukraine-Belarus border.

The thyroid studies involve biannual thyroid gland examinations of approximately 12,000 to 13,000 individuals in each country who were exposed to radiation from the accident when they were 0 to 18 years of age and who had thyroid radiation dose measurements made in the weeks following the accident.

This program has relevance to international concerns about nuclear terrorism because the Chernobyl exposures are similar to those expected from a "dirty bomb" attack.

A U.S.-Mexico binational study of the relationship between arsenic exposure and gastrointestinal cancer
Arsenic exposure is an established risk factor for kidney, bladder, lung, and skin cancers, but the relationship between arsenic, its metabolites, and gastrointestinal cancer has received only limited attention. In this study, researchers are investigating the role of arsenic in the development of gastrointestinal cancer in two geographic areas of Sonora, Mexico that have different levels of arsenic in their drinking water supplies. Researchers from the University of Arizona, the University of Sonora, and the Technological Institute of Sonora - who are experienced in arsenic research, exposure assessment, and cancer research - are conducting the study.

A project at the University of Alberta, Canada to develop innovative, cost-effective, and reliable technology for quantifying DNA damage caused by environmental exposures, including low-level exposures
Historically, attempts to link environmental exposures to cancer have frequently relied on population surveys, which provide indirect information in the form of responses to questionnaires or personal interviews. The inherent errors associated with these kinds of assessments have long hindered the identification and quantification of important exposures. Rather than relying on these traditional methods of dose estimation and extrapolation from high-dose exposures in rodent models, researchers at the University of Alberta are developing new technology to provide sufficiently sensitive DNA damage measurements that would permit more realistic assessments of environmental risk. The technology would also be useful for measuring the DNA damage induced by anticancer agents and for studying DNA repair, which is an essential cellular defense mechanism against DNA damage and cancer development.

Genes, Infectious Agents, and Gene-Environment Interactions

Although our understanding of the causes and mechanisms of cancer initiation and progression has expanded rapidly, much remains to be learned. We now recognize that a person's susceptibility to cancer can be governed by the interaction of genetic and environmental factors. If we are to continue making progress in the prevention and treatment of cancer, it is clear we must increase our understanding of the interplay between susceptibility genes and the environment. To achieve our goal of eliminating the suffering and death due to cancer, broad collaboration of persons, organizations, and nations in this effort is crucial.

A prime example of such collaboration is the InterLymph Consortium, more formally known as the International Consortium of Investigators Working on Non-Hodgkin's Lymphoma Epidemiologic Studies. This consortium is described in InterLymph Leads Global Research in Non-Hodgkin Lymphoma. Other examples include the following:

Benzene and Cancer: East Meets West More than 15 years ago, researchers from NCI and the Chinese Center for Disease Control (CCDC), which was then called the Chinese Academy of Preventive Medicine, formed a partnership to evaluate the cancer risks associated with occupational exposure to benzene. This collaboration grew out of a Chinese national health survey that showed that benzene exposure was common in Chinese industry and that exposed workers had increased risks for leukemia and other diseases. In view of these findings, NCI and Chinese scientists decided to characterize the spectrum of diseases caused by benzene, to relate benzene exposure levels to disease risks, and to define the mechanisms of benzene carcinogenicity in humans. This partnership, one of the longest ever undertaken between American and Chinese scientists, engages NCI experts in cancer epidemiology, industrial exposure assessment, and the pathology of blood-system diseases. This is a significant Chinese public health problem that also has important implications for the United States and other countries. To date, findings from this collaboration have contributed to lowering the occupational standard for benzene exposure in China and have greatly affected the risk assessment process for environmental benzene exposure in the United States. The initial study included 75,000 benzene-exposed workers and 35,000 workers without occupational benzene exposure who were employed between 1972 and 1987 at more than 700 factories in 12 cities throughout China. Data on work history and exposure were collected, along with follow-up data on each worker to ascertain vital status, cause of death for deceased workers, and incidence of any hematopoietic or lymphoproliferative malignancy or related disorder. This study produced three key findings that were reported in a landmark paper published in 1997.1 First, significantly increased risks were found among exposed workers for developing acute non-lymphocytic leukemia (ANLL) and related myelodysplastic syndromes (MDS) and for non-Hodgkin lymphoma (NHL). Second, elevated risks for the combined grouping of ANLL/MDS and for NHL occurred at average exposures of less than 10 parts-per-million (ppm). Third, the developmental pattern of disease differed between ANLL/MDS and NHL, i.e., the former diseases were linked to more recent benzene exposure (less than 10 years before diagnosis), whereas NHL was more related to exposures that occurred 10 or more years earlier). Subsequent studies revealed the presence of leukemia-associated chromosomal aberrations in benzene-exposed workers and showed that susceptibility to the adverse health effects of benzene can vary on the basis of an individual's genetic make up. One study reported in 2004 demonstrated that the toxic effects of benzene on mature and early progenitor blood cells can occur at air levels of 1 ppm or less and suggested that these effects may be particularly evident among genetically susceptible individuals.2 These latter findings have relevance for American workers because the current occupational standard for benzene exposure, established by the U.S. Occupational Safety and Health Administration (OSHA), is 1 ppm during a 40-hour work week. 1 Hayes R, Yin S-N, Dosemeci M, Li G-L, Wacholder S, Travis L, Li C-Y, Rothman N, Hoover R, Linet M. Benzene and the dose-related incidence of hematologic neoplasms in China. Journal of the National Cancer Institute, July 16, 1997; 89(14):1065-1071. 2 Lan Q, Zhang L, Li G, Vermeulen R, Weinberg R, Dosemeci M, Rappaport S, Shen M, Alter B, Wu Y, Kopp W, Waidyanatha S, Rabkin C, Guo W, Chanock S, Hayes R, Linet M, Kim S, Yin S, Rothman N, Smith M. Hematotoxicity in workers exposed to low levels of benzene. Science, December 3, 2004; 306(5702):1774-1776.

The International Head and Neck Cancer Epidemiology (INHANCE) Consortium to address the global challenge of head and neck cancer incidence and mortality
In the year 2000, an estimated half-million cases of head and neck cancer were diagnosed worldwide and 300,000 people died of the disease. Most of these cancers can be attributed to tobacco and alcohol use, but other risk factors that may play a role include viral infection, occupational exposures, radiation exposure, dietary factors, and genetic susceptibility. In 2004, NCI and the World Health Organization (WHO) joined forces to establish the INHANCE Consortium, which is comprised of research groups that are conducting large molecular epidemiology studies of head and neck cancer. These studies should increase our understanding of the causes and mechanisms of head and neck cancer worldwide. The consortium is managed by IARC and includes investigators from the United States, France, the Czech Republic, Slovakia, Romania, Hungary, Poland, Russia, Spain, Costa Rica, Italy, Switzerland, Brazil, Argentina, Germany, the United Kingdom, Norway, Greece, Estonia, and Croatia.

A collaboration of NCI scientists and research groups in China to study the interaction of infection with Epstein-Barr virus (EBV) or hepatitis B virus (HBV) and host genetic factors in cancer development
NCI scientists and researchers from China's Institute for Viral Disease Control and Prevention, Beijing and the Wuzhou Red Cross Hospital, Guangxi Province are attempting to characterize genes associated with susceptibility or resistance to the development of nasopharyngeal carcinoma (NPC). The population in Guangxi Province has a high incidence of NPC. This population offers a unique model of this human malignancy for understanding a multistep carcinogenic process that involves a virus (EBV), environmental carcinogens (dietary and other causes), and genetic factors.

Similarly, NCI scientists have joined forces with the Department of Infectious Diseases at Peking University First Hospital, Beijing to study how outcomes of HBV exposure and infection are influenced by host genetic factors in the Chinese population. In China, more than 120 million individuals are infected with HBV. Among persons persistently infected with this virus, 10 to 30 percent will develop cirrhosis and liver cancer.

A study at the University of Cape Town, South Africa to investigate the role of the NDRG1 gene in squamous cell esophageal carcinoma
In South Africa, squamous cell esophageal cancer occurs with high frequency, causing the majority of cancer-related deaths among black males. Better understanding of the molecular events leading to the development of this cancer will allow earlier diagnosis, the development of better therapeutic strategies, and enhanced prevention of metastasis. Reduced expression of NDRG1 (N-Myc Downstream Regulated Gene 1) - which has been implicated in cell differentiation, cell proliferation, and cancer cell metastasis - has been found in poorly differentiated esophageal tumors.

A study at the Hospital General de Grand Yoff in Senegal of the epidemiology of prostate cancer among African men
Despite the knowledge that prostate cancer occurs with high frequency in men of African descent in the Americas, little information is available regarding the epidemiology of prostate cancer in native African men, even though prostate cancer seems to be prevalent in that population as well. The objective of this study is to examine the role of genes that regulate the physiological disposition of testosterone in the development of prostate cancer and to evaluate whether these genes explain, in part, ethnic differences in prostate cancer rates. An understanding of the complex interplay of genetic variability at multiple loci and of environmental agents may improve our understanding of ethnic differences in prostate cancer development and risk prediction.

Two studies conducted by IARC of the genetics of tobacco and alcohol-related cancers Even though lung and upper aerodigestive tract (UADT) cancers are predominantly
caused by tobacco and alcohol use, only a minority of heavy smokers and heavy drinkers will develop these cancers. A possible explanation for this phenomenon is that individuals vary widely in their metabolism of carcinogenic products, internal dose levels of these products and/or their metabolites, DNA repair capacity, and cell-cycle control mechanisms due to genetic factors. In separate investigations, the researchers will study the role of 45 genes that may be involved in the susceptibility to lung and UADT cancers.

A study of breast and prostate cancer risk in relation to genetic polymorphisms and gene-environment interactions that affect hormone metabolism
The goal of this study is to identify single-nucleotide polymorphisms (SNPs) and haplotypes in steroid hormone metabolizing genes, genes in the insulin-like growth factor (IGF) pathway, and genes that encode related receptor proteins. SNPs are DNA sequence variations that arise from single nucleotide (A, T, C, or G) changes. Haplotypes are sets of genes that are linked closely enough to be inherited as a unit.

Woman smoking

In the study, the investigators will have access to prospectively gathered plasma samples, genetic material, anthropometric measurements, and extensive questionnaire data on diet, physical activity, exogenous hormone use, smoking, and other lifestyle factors from over 790,000 men and women worldwide. The biological samples and other data are from the following large prospective cohorts: the American Cancer Society's Cancer Prevention Study II; Harvard University's Harvard Cohort Studies; IARC's European Prospective Investigation into Cancer and Nutrition (EPIC) Study; the University of Hawaii and the University of Southern California's Multiethnic Cohort Study; and two NCI intramural cohorts (the Prostate, Lung, Colon, and Ovarian Cancer Screening Study and the Alpha-Tocopherol, Beta-Carotene Prevention Trial).

The ultimate goal of this study is to provide the foundation for reducing the public health burden of breast and prostate cancers.

A study at the Queensland Institute of Medical Research in Australia of the molecular genetics and genetic epidemiology of cutaneous melanoma and its risk factors
Over the past few decades, the incidence of cutaneous melanoma has increased dramatically in light-skinned populations worldwide. The Australian state of Queensland has the highest incidence of cutaneous melanoma in the world, with lifetime incidences of 1 in 13 males and 1 in 16 females. Although these rates are almost five times greater than those in the United States, the shapes of the age-specific incidence curves are almost the same in the two populations, suggesting similar causal factors.

In this study, the researchers will extend several earlier large-scale investigations into the molecular genetics and genetic epidemiology of melanoma and its risk factors (in particular, nevus density and pigmentation). They will analyze DNA specimens obtained from 6,248 individuals. These analyses will include DNA sequencing and singlenucleotide polymorphism (SNP) analyses of genes in the cell-cycle control and pigmentation pathways. The researchers will look for associations of melanoma risk variables with SNPs and environmental risk factors. They will also investigate whether melanoma in childhood or adolescence can be explained solely by the same risk factors that operate in adults or whether affected children or adolescents carry rare alleles in cell cycle or pigmentation genes.

InterLymph Leads Global Research in Non-Hodgkin Lymphoma The InterLymph Consortium - more formally known as the International Consortium of Investigators Working on Non-Hodgkin Lymphoma Epidemiologic Studies - is an open scientific forum for epidemiologic research that was formed in 2001. The Consortium is comprised of international investigators who have completed or have ongoing case-control studies of non-Hodgkin lymphoma and who discuss and undertake research projects that pool data across studies or otherwise conduct collaborative research. The ultimate goal of InterLymph is to speed progress toward understanding the etiology of non-Hodgkin lymphomas. Support for the logistical needs of InterLymph is provided by NCI, the International Agency for Research on Cancer (IARC), and the United Kingdom's Leukaemia Research Fund. Some InterLymph investigators also receive grant support for research projects from NCI. Investigators from the United States, Europe, Canada, Australia, the Middle East, and Asia have participated in the Consortium. Eight InterLymph working groups develop ideas for coordinated research in the areas of diet and behavior, family studies, genotyping, immunology, infections, occupation, pathology, and sunlight. Recently reported studies investigated the relationships between cigarette smoking, alcohol consumption, and common genetic variants in immune system and inflammatory response genes and the risk of non-Hodgkin lymphoma.1,2,3 Interlymph 5th Annual Meeting Washington, D.C. March 30-April 1, 2006 1 Morton L, Hartge P, Holford T, Holly E, Chiu B, Vineis P, Stagnaro E, Willett E, Franceschi S, La Vecchia C, Hughes A, Cozen W, Davis S, Severson R, Bernstein L, Mayne S, Dee F, Cerhan J, Zheng T. Cigarette smoking and risk of non-Hodgkin lymphoma: a pooled analysis from the International Lymphoma Epidemiology Consortium (InterLymph). Cancer Epidemiology, Biomarkers & Prevention, April 2005; 14(4):925-933. 2 Morton L, Zheng T, Holford T, Holly E, Chiu B, Costantini A, Stagnaro E, Willett E, Dal Maso L, Serraino D, Chang E, Cozen W, Davis S, Severson R, Bernstein L, Mayne S, Dee F, Cerhan J, Hartge P; InterLymph Consortium. Alcohol consumption and risk of non-Hodgkin lymphoma: a pooled analysis. Lancet Oncology, July 2005; 6(7):469-476. 3 Rothman N, Skibola C, Wang S, Morgan G, Lan Q, Smith M, Spinelli J, Willett E, De Sanjose S, Cocco P, Berndt S, Brennan P, Brooks-Wilson A, Wacholder S, Becker N, Hartge P, Zheng T, Roman E, Holly E, Boffetta P, Armstrong B, Cozen W, Linet M, Bosch F, Ennas M, Holford T, Gallagher R, Rollinson S, Bracci P, Cerhan J, Whitby D, Moore P, Leaderer B, Lai A, Spink C, Davis S, Bosch R, Scarpa A, Zhang Y, Severson R, Yeager M, Chanock S, Nieters A. Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium. Lancet Oncology, January 2006; 7(1):27-38.

The International Familial Chronic Lymphocytic Leukemia (CLL) Consortium to identify inherited susceptibility genes
CLL is the most common form of leukemia among adults in the Western world. No specific environmental risk factors have been established for CLL, but epidemiologic and family studies indicate that 8 to 10 percent of CLL cases involve inherited susceptibility to the disease. Because it was recognized that no single institution could recruit a sufficient number of CLL families to achieve the goal of identifying a susceptibility gene(s), the International Familial CLL Consortium was established in 2002. Enrolling new CLL families and coordinating research efforts among the participating centers are core tasks of the consortium. Countries participating in the consortium include the United States, the United Kingdom, France, and Italy.

The Australian Breast Cancer Family Registry and the Australasian Colorectal Cancer Family Registry to identify genetic and environmental risk factors for breast and colorectal cancer
These large cancer family registries are resources for population-based, case-control family studies conducted by the Centre for Molecular, Environmental, Genetic and Analytic Epidemiology at the University of Melbourne's School of Population Health.

The Australian Breast Cancer Family Registry is also part of the Cooperative Family Registry for Breast Cancer Studies (CFRBCS), which is an international collaboration involving six registries that was initiated by NCI in 1995 to provide the scientific community with a resource for interdisciplinary and translational breast cancer research. CFRBCS resources include a repository of biological specimens from a racially and ethnically diverse set of families that have a history of breast cancer and a large, computerized database containing both genetic and environmental risk information.

Similarly, the Australasian Colorectal Cancer Family Registry is part of the Cooperative Family Registry for Colorectal Cancer Studies (CFRCCS), which is another international collaboration initiated by NCI in 1998. The six CFRCCS registries perform several tasks, including the assembly and maintenance of comprehensive lists of families with histories of colorectal cancer, the collection of detailed information about possible factors involved in the cancer process, and the storage of blood samples and tumor biopsy specimens from family members for research purposes. The data and samples collected by the participating registries are available to researchers worldwide.

The Ontario Familial Breast Cancer Registry and the Ontario Familial Colorectal Cancer Registry to identify genetic and environmental risk factors for breast and colorectal cancer
These registries collect and store personal and family health information from residents of Ontario, Canada, who have a family history of breast or colorectal cancer and who are willing to participate in research studies. The registries provide an infrastructure for current and future research on breast and colorectal cancer genetics and new preventive and therapeutic strategies to combat these diseases. The Ontario registries are partner registries in the Cooperative Family Registry for Breast Cancer Studies and the Cooperative Family Registry for Colorectal Cancer Studies (see The International Familial Chronic Lymphocytic Leukemia (CLL) Consortium to identify inherited susceptibility genes).

A collaboration of NCI scientists and research groups in Canada, the United Kingdom, and Ireland to understand the molecular etiology of kidney cancers
The study of kidney cancers associated with rare genetic disorders is limited by the infrequent occurrence of the individual diseases and the small numbers of patients available for study in any one nation. Therefore, international collaboration is essential.

One such collaboration between NCI scientists and investigators at the University of Manitoba in Winnipeg, Canada and the University of Birmingham in the United Kingdom led to the successful cloning of the Birt Hogg Dube (BHD) gene, which is associated with a rare hereditary syndrome characterized, in part, by a high predisposition to malignant kidney tumors that are often bilateral and multifocal.

Ongoing efforts include the identification of additional patients with familial kidney cancers of undetermined etiology worldwide to increase our ability to identify major genes that contribute to the development of kidney tumors.

A study at the Karolinska Institute in Stockholm, Sweden of the influence of human papilloma virus (HPV) viral load on the progression of localized cervical carcinoma to invasive cervical cancer
Although HPV infection is an established cause of cervical cancer, it is not known whether viral load influences the progression from localized cervical carcinoma in situ (CIS) to invasive cancer and/or interacts with host genetic factors. Since clinical intervention precludes direct observation of this progression, unconventional approaches are required. The investigators are attempting to: 1) quantify the absolute and relative risks for CIS and invasive cancer as a function of time since the detection of HPV and high viral load of HPV strain 16 (HPV-16); 2) assess whether a persistent HPV-16 high viral load is a determinant of CIS and invasive cancer development; 3) assess whether a specific histocompatibility antigen genotype is associated with risks for CIS and invasive cancer and if the association is mediated via a higher viral load and/or persistence of HPV infection; and 4) assess whether infection with the bacterium Chlamydia trachomatis is associated with risks for CIS and invasive cancer. The researchers will take advantage of Sweden's extensive documentation in computerized registries of its population-based Pap smear screening program, its ascertainment of all incident cases of cervical CIS and invasive cancer, and archived Pap smears and tissue specimens.

Molecular Diagnosis of Burkitt's Lymphoma	Epstein-Barr Virus (EBV)

A U.S.-Brazil binational study of Epstein-Barr virus (EBV)-associated lymphoma, particularly Burkitt lymphoma, in Brazil
EBV is ubiquitous worldwide, with more than 80 percent of people over the age of 30 having been infected. Once EBV infection has occurred, it persists for the lifetime of the individual. EBV infection is strongly associated with the development of several cancers, including Hodgkin disease and Burkitt lymphoma (BL). Three variants of BL have been identified: endemic, sporadic, and human immunodeficiency virus-1 (HIV-1)-associated. However, the molecular differences between these variants have not been well characterized. BL is also commonly identified in patients with acquired immunodeficiency syndrome (AIDS), with the EBV association being more common in developing countries.

In this study, scientists from the University of Miami; the University of North Carolina, Chapel Hill; the Federal University of Bahia in Salvador, Brazil; and the Brazilian Pediatric Non-Hodgkin Lymphoma Treatment Group are molecularly characterizing primary EBV-positive BLs using virus-specific microarrays. Other goals of the study are to identify the mechanism by which the common antiretroviral drug azidothymidine (AZT) induces apoptosis (cell suicide) in EBV-positive BL and to use the data to develop novel therapies.

The study is supported by independent grants and by supplemental funding from the NCI-sponsored AIDS-Associated Malignancies Clinical Trials Consortium.

International Agency for Research on Cancer Monographs on Carcinogens Since 1972, the International Agency for Research on Cancer (IARC), which is part of the World Health Organization, has published a series of monographs on the carcinogenic risks posed to humans by a variety of agents, mixtures, exposures, and other factors. Each volume in the series is an authoritative report on the degree of carcinogenic risk associated with a specific chemical, group of chemicals, industrial process, occupational exposure, lifestyle factor, or biologic agent. To date, assessments of approximately 900 agents and exposures have been published. Each assessment is carried out by a working group of international experts who review all published epidemiologic and experimental data related to the particular agent or exposure. The working group is also charged with indicating where additional research efforts are needed. Evaluated agents or exposures are assigned to one of five groups according to the strength of the published scientific evidence for carcinogenicity: Group 1, carcinogenic to humans; Group 2A, probably carcinogenic to humans; Group 2B, possibly carcinogenic to humans; Group 3, not classifiable as to carcinogenicity to humans; and Group 4, probably not carcinogenic to humans. IARC makes every effort to ensure that the factual material presented in the monographs is reported without bias and all information is checked meticulously for accuracy. The IARC monographs are recognized as authoritative sources of information by governments and regulatory bodies worldwide. NCI has supported the IARC monographs program from its beginning. In addition, NCI represents the United States on IARC's Governing Council. A portion of IARC's regular budget is provided by the U.S. Department of State. A complete list of the IARC monographs and up-to-date news about recent assessments and meetings can be found on the IARC Monographs Web site (http://monographs.iarc.fr).