Causes of Cancer

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Why Research on Causes of Cancer Is Critical to Progress against the Disease

Studying the causes of cancer helps researchers understand the process of carcinogenesis and can lead to new ways of preventing the disease.

Research on the causes of cancer also creates opportunities to improve public health, not only by identifying genetic, environmental, and behavioral risk factors in populations, but also by providing data that regulatory agencies can use to set safety standards or to reduce exposure to toxins that are found to be associated with cancer. Findings from this area of research can also inform the development of clinical practice guidelines for physicians and advances such as safer computed tomography (CT) scans and risk-reducing surgeries.

Studying the interactions between genetic factors, lifestyle factors, and environmental exposures could reveal previously unknown biological processes involved in cancer. Knowledge of cancer risk factors creates opportunities to develop risk prediction models for identifying individuals who may be at increased risk of certain cancers. And, for some cancers, individuals at increased risk may be able to take steps to reduce their risk.

Many different approaches are used to identify potential causes of cancer. Genome analyses such as genome-wide association studies, exome sequencing, and whole-genome sequencing allow researchers to identify genetic changes that may be associated with cancer risk. Family studies can provide information by identifying genes that are responsible for familial cancers and that may yield insights into nonfamilial (sporadic) forms of the disease.

Researchers also use a variety of epidemiological approaches—including cohort studies, case-control studies, exposure-assessment studies, family studies, and genomic studies—to identify possible causes of cancer and study the patterns of risk in large populations.

Another approach, known as descriptive epidemiology, characterizes trends in cancer incidence and mortality within a given population, between populations over time, and in relation to overall patterns of exposure in populations to yield clues that may point researchers to cancer causes and risk factors.

Opportunities in Research on Causes of Cancer

Advances in technology are enabling researchers to store and access findings in online databases and allowing teams of investigators worldwide to pool data on an unprecedented scale. Multidisciplinary research teams are increasingly common and often include a range of experts, from epidemiologists, physicians, and oncologists to toxicologists, geneticists, and health physicists.

Technological advances could also lead to more accurate studies of substances in the environment suspected of causing cancer. The development of devices that can accurately measure environmental exposures and biochemical assays in biologic specimens that might be associated with cancer could improve researchers’ ability to identify cancer-causing agents.

Challenges in Research on Causes of Cancer

Demonstrating cause and effect relationships in population studies of potential cancer risk factors is a challenge because there are often many possible explanations for observed associations between a risk factor and cancer. For researchers, the development of statistical methods can improve the analysis of data from these studies and aid in identifying the causes.

Identifying which particular component of an exposure is associated with an increased or decreased risk of cancer can also be a challenge in studying certain exposures, such as dietary components. Retrospective studies have additional limitations, such as the reliability of participants to accurately remember and report past exposures or exposure levels.

There is a continual need for new and improved techniques for measuring risk factors and exposures to potential causes of cancer. For example, studies that estimate radiation exposures among an exposed population must also quantify the uncertainties inherent to those estimates.

To identify cancer causes and risk factors that may be experienced by only a portion of the population, very large studies may be needed to have the statistical power required to establish an association.

Investigating interactions between genes and environmental exposures that have been associated with cancer can be a challenge, as well, in part because some of these studies involve very large data sets and require sophisticated computational analysis. Once a causative agent has been identified, another challenge is figuring out how to reduce a person’s exposure or ameliorate its harmful effects.

Although genome-wide association studies can point to chromosomal regions associated with cancer risk in certain individuals, additional studies and analyses are usually needed to identify the specific genetic changes involved and to understand how they play a role in the development of cancer.

NCI’s Role in Research on Causes of Cancer

In addition to funding extramural research on the causes of cancer, NCI conducts intramural research on this topic. The intramural research program allows NCI to conduct studies that require the type of long-term, sustained support that may not be possible elsewhere. Moreover, the intramural research program provides NCI the flexibility to redirect resources to respond quickly to emerging public health concerns.

NCI and NCI-funded researchers aim to understand the exposures and risk factors that cause cancer, as well as the genetic basis for the development of cancer. They also seek to identify ways to translate this information into tangible benefits in the areas of cancer prevention and the identification and monitoring of those at risk.

Environmental and Behavioral Risk Factors

NCI’s Division of Cancer Epidemiology and Genetics (DCEG) and the Epidemiology and Genomics Research Program in NCI’s Division of Cancer Control and Populations Sciences(DCCPS) conduct and fund research to identify and evaluate a range of exposures and risk factors that may be associated with cancer, including:

• substances in the environment and workplace, such as air pollutants, water pollutants, and chemicals. (For example, the Diesel Exhaust in Miners Study found that heavy exposure to diesel exhaust is associated with an increased risk of lung cancer.)
• infectious agents, such as viruses and bacteria. (The Study to Understand Cervical Cancer Early Endpoints and Determinants, for example, aims to distinguish which women with human papillomavirus infections are at highest risk of cervical cancer.)
• radiation, including ionizing radiation and non-ionizing radiation. (DCEG investigators are involved in several studies of cancer incidence among children undergoing CT scans.)
• pharmaceutical agents and exogenous and endogenous hormones. (Researchers involved in the DES Follow-Up Study, for example, are following diethylstilbestrol-exposed and unexposed mothers and their daughters, sons, and granddaughters for adverse health effects, including cancer.)
• behavioral and lifestyle factors, such as diet and nutrition, tobacco use, alcohol use, energy balance, physical activity, and obesity. (DCCPS’ Transdisciplinary Research on Energetics and CancerExit Disclaimer initiative funds research in this area.)
• immune system status and inflammation. (DCEG researchers are studying how chronic inflammation from Helicobacter pylori infection is related to gastric cancer risk.)

DCEG researchers and those funded by DCCPS are also engaged in research to address risks of second primary cancers. Nearly one in five cancers occurs in an individual with a previous diagnosis of cancer, and these second cancers are a leading cause of morbidity and mortality among cancer survivors. Active research on treatment, lifestyle, environmental, and medical history factors associated with second cancers is ongoing, as is research on genetic susceptibility to second cancers.

Genetic Factors

NCI and NCI-funded investigators are also studying genetic factors that may predispose individuals to cancer. A number of efforts in this area use genome-wide association studies, whole genome scans, and other approaches to investigate the role of gene variants and gene-environment interactions in cancer risk.

Changes in an individual’s genes, including gene mutations, genetic modifiers, and polymorphisms, can alter his or her lifetime risk of cancer. To explain the genetic factors that influence a person’s risk for cancer, investigators from DCEG and NCI's Center for Cancer Research (CCR) are:

• conducting human genetic studies to identify and validate key susceptibility genes and their modifiers using knowledge gained from gene expression profiles and protein “fingerprints”
• identifying genetic and environmental factors that influence the cancer epigenome, i.e., chemical modifications to DNA that do not involve DNA sequence changes
• defining the role of inherited or acquired genetic alterations, in combination with lifestyle factors and environmental exposures (such as radiation and chemicals), as important determinants of an individual’s cancer susceptibility
• identifying new tumor suppressor genes and oncogenes and elucidating their mechanisms of action

For example, investigators in DCEG’s Radiation Epidemiology Branch are partnering with investigators from the Childhood Cancer Survivor StudyExit Disclaimer to conduct a genome-wide association study of second cancers in childhood cancer survivors.

NCI researchers are also studying a range of hereditary cancer syndromes that may predispose affected individuals and their family members to cancer. These include inherited bone marrow failure syndromes, Li-Fraumeni syndrome, and others.

Studies of family cancer syndromes may help not only people with these syndromes, but these studies may also provide insights into the genetic basis for noninherited, or sporadic, forms of cancers. That was true of research by CCR's W. Marston Linehan, M.D. on familial kidney cancer.

How Exposures and Risk Factors Act

NCI supports research to understand the mechanisms by which external exposures and risk factors induce and promote cancer.

The Cancer Immunology, Hematology and Etiology Branch (CIHEB), part of NCI’s Division of Cancer Biology, supports research on the structure, infectious process, and oncogenic mechanisms of cancer-associated viruses, as well as on the host immune and inflammatory response. CIHEB, for example, funds studies of the possible role of the microbiome in the development of cancer.

CIHEB also supports research to identify chemical carcinogens and other substances that initiate and promote tumor development, to understand how these are altered by and affect the body, and to identify markers of their activity.

CCR researchers are trying to elucidate mechanisms that influence tumor initiation, promotion, and progression, including those associated with lifestyle, the environment, inflammation, the immune system, viruses, and host-tumor interaction.

NCI’s Office of HIV and AIDS Malignancy (OHAM) coordinates and oversees NCI research programs that focus specifically on HIV/AIDS and AIDS-associated cancers. For example, OHAM’s AIDS Cancer Specimen Resource is a biorepository for HIV-infected human biospecimens that serves as a resource for investigators conducting basic research in the pathogenesis of AIDS-related malignancies