Cancer

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Cancer is a group of diseases in which cells are aggressive (grow and divide without respect to normal limits), invasive (invade and destroy adjacent tissues), and sometimes metastatic (spread to other locations in the body). These three malignant properties of cancers differentiate them from benign tumors, which are self-limited in their growth and don’t invade or metastasize (although some benign tumor types are capable of becoming malignant). Cancer may affect people at all ages, even fetuses, but risk for the more common varieties tends to increase with age.^[1] Cancer causes about 13% of all deaths.^[2] According to the American Cancer Society, 7.6 million people died from cancer in the world during 2007.^[3] Apart from humans, forms of cancer may affect other animals and plants.

Nearly all cancers are caused by abnormalities in the genetic material of the transformed cells. These abnormalities may be due to the effects of carcinogens, such as tobacco smoke, radiation, chemicals, or infectious agents. Other cancer-promoting genetic abnormalities may be randomly acquired through errors in DNA replication, or are inherited, and thus present in all cells from birth. Complex interactions between carcinogens and the host genome may explain why only some develop cancer after exposure to a known carcinogen. New aspects of the genetics of cancer pathogenesis, such as DNA methylation, and microRNAs are increasingly being recognized as important.

Genetic abnormalities found in cancer typically affect two general classes of genes. Cancer-promoting oncogenes are often activated in cancer cells, giving those cells new properties, such as hyperactive growth and division, protection against programmed cell death, loss of respect for normal tissue boundaries, and the ability to become established in diverse tissue environments. Tumor suppressor genes are often inactivated in cancer cells, resulting in the loss of normal functions in those cells, such as accurate DNA replication, control over the cell cycle, orientation and adhesion within tissues, and interaction with protective cells of the immune system.

Cancer is usually classified according to the tissue from which the cancerous cells originate, as well as the normal cell type they most resemble. These are location and histology, respectively. A definitive diagnosis usually requires the histologic examination of a tissue biopsy specimen by a pathologist, although the initial indication of malignancy can be symptoms or radiographic imaging abnormalities. Most cancers can be treated and some cured, depending on the specific type, location, and stage. Once diagnosed, cancer is usually treated with a combination of surgery, chemotherapy and radiotherapy. As research develops, treatments are becoming more specific for different varieties of cancer. There has been significant progress in the development of targeted therapy drugs that act specifically on detectable molecular abnormalities in certain tumors, and which minimize damage to normal cells. The prognosis of cancer patients is most influenced by the type of cancer, as well as the stage, or extent of the disease. In addition, histologic grading and the presence of specific molecular markers can also be useful in establishing prognosis, as well as in determining individual treatments.

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Today, the Greek term carcinoma is the medical term for a malignant tumor derived from epithelial cells. It is Celsus who translated carcinos into the Latin cancer, also meaning crab. Galen used “oncos” to describe all tumours, the root for the modern word oncology.^[1]

Hippocrates described several kinds of cancers. He called benign tumours oncos, Greek for swelling, and malignant tumours carcinos, Greek for crab or crayfish. This name probably comes from the appearance of the cut surface of a solid malignant tumour, with a roundish hard center surrounded by pointy projections, vaguely resembling the shape of a crab (see picture). He later added the suffix -oma, Greek for swelling, giving the name carcinoma. Since it was against Greek tradition to open the body, Hippocrates only described and made drawings of outwardly visible tumors on the skin, nose, and breasts. Treatment was based on the humor theory of four bodily fluids (black and yellow bile, blood, and phlegm). According to the patient’s humor, treatment consisted of diet, blood-letting, and/or laxatives. Through the centuries it was discovered that cancer could occur anywhere in the body, but humor-theory based treatment remained popular until the 19th century with the discovery of cells.

The first known surgical treatment for cancer was described in the 1020s by Avicenna (Ibn Sina) in The Canon of Medicine. He stated that the excision should be radical and that all diseased tissue should be removed, which included the use of amputation or the removal of veins running in the direction of the tumor. He also recommended the use of cauterization for the area being treated if necessary.^[2]

In the 16th and 17th centuries, it became more acceptable for doctors to dissect bodies to discover the cause of death. The German professor Wilhelm Fabry believed that breast cancer was caused by a milk clot in a mammary duct. The Dutch professor Francois de la Boe Sylvius, a follower of Descartes, believed that all disease was the outcome of chemical processes, and that acidic lymph fluid was the cause of cancer. His contemporary Nicolaes Tulp believed that cancer was a poison that slowly spreads, and concluded that it was contagious.^[3]

With the widespread use of the microscope in the 18th century, it was discovered that the ‘cancer poison’ spread from the primary tumor through the lymph nodes to other sites (“metastasis“). This view of the disease was first formulated by the English surgeon Campbell De Morgan between 1871 and 1874.^[4] The use of surgery to treat cancer had poor results due to problems with hygiene. The renowned Scottish surgeon Alexander Monro saw only 2 breast tumor patients out of 60 surviving surgery for two years. In the 19th century, asepsis improved surgical hygiene and as the survival statistics went up, surgical removal of the tumor became the primary treatment for cancer. With the exception of William Coley who in the late 1800s felt that the rate of cure after surgery had been higher before asepsis (and who injected bacteria into tumors with mixed results), cancer treatment became dependent on the individual art of the surgeon at removing a tumor. During the same period, the idea that the body was made up of various tissues, that in turn were made up of millions of cells, laid rest the humor-theories about chemical imbalances in the body. The age of cellular pathology was born.

When Marie Curie and Pierre Curie discovered radiation at the end of the 19th century, they stumbled upon the first effective non-surgical cancer treatment. With radiation came also the first signs of multi-disciplinary approaches to cancer treatment. The surgeon was no longer operating in isolation, but worked together with hospital radiologists to help patients. The complications in communication this brought, along with the necessity of the patient’s treatment in a hospital facility rather than at home, also created a parallel process of compiling patient data into hospital files, which in turn led to the first statistical patient studies.

Cancer patient treatment and studies were restricted to individual physicians’ practices until World War II, when medical research centers discovered that there were large international differences in disease incidence. This insight drove national public health bodies to make it possible to compile health data across practises and hospitals, a process that many countries do today. The Japanese medical community observed that the bone marrow of bomb victims in Hiroshima and Nagasaki was completely destroyed. They concluded that diseased bone marrow could also be destroyed with radiation, and this led to the discovery of bone marrow transplants for leukemia. Since WWII, trends in cancer treatment are to improve on a micro-level the existing treatment methods, standardize them, and globalize them as a way to find cures through epidemiology and international partnerships.

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The following closely related terms may be used to designate abnormal growths:

• Tumor: originally, it meant any abnormal swelling, lump or mass. In current English, however, the word Tumor has become synonymous with Neoplasm, specifically solid neoplasm. Note that some neoplasms, such as Leukemia, do not form tumors.
• Neoplasm: the scientific term to describe an abnormal proliferation of genetically altered cells. Neoplasms can be benign or malignant:
  • Malignant neoplasm or malignant tumor: synonymous with cancer.
  • Benign neoplasm or benign tumor: a tumor (solid neoplasm) that stops growing by itself, does not invade other tissues and does not form metastases.
• Invasive tumor is another synonym of cancer. The name refers to invasion of surrounding tissues.
• Pre-malignancy, pre-cancer or non-invasive tumor: A neoplasm that is not invasive but has the potential to progress to cancer (become invasive) if left untreated. These lesions are, in order of increasing potential for cancer, atypia, dysplasia and carcinoma in situ.

The following terms can be used to describe a cancer:

• Screening: a test done on healthy people to detect tumors before they become apparent. A mammogram is a screening test.
• Diagnosis: the confirmation of the cancerous nature of a lump. This usually requires a biopsy or removal of the tumor by surgery, followed by examination by a pathologist.
• Surgical excision: the removal of a tumor by a surgeon.
  • Surgical margins: the evaluation by a pathologist of the edges of the tissue removed by the surgeon to determine if the tumor was removed completely (“negative margins”) or if tumor was left behind (“positive margins”).
• Grade]: a number (usually on a scale of 3) established by a pathologist to describe the degree of resemblance of the tumor to the surrounding benign tissue.
• Stage: a number (usually on a scale of 4) established by the oncologist to describe the degree of invasion of the body by the tumor.
• Recurrence: new tumors that appear a the site of the original tumor after surgery.
• Metastasis: new tumors that appear far from the original tumor.
• Transformation: the concept that a low-grade tumor transforms to a high-grade tumor over time. Example: Richter’s transformation.
• Chemotherapy: treatment with drugs.
• Radiation therapy: treatment with radiations.
• Adjuvant therapy: treatment, either chemotherapy or radiation therapy, given after surgery to kill the remaining cancer cells.
• Prognosis: the probability of cure after the therapy. It is usually expressed as a probability of survival five years after diagnosis. Alternatively, it can be expressed as the number of years when 50% of the patients are still alive. Both numbers are derived from statistics accumulated with hundreds of similar patients to give a Kaplan-Meier curve.

Cancers are classified by the type of cell that resembles the tumor and, therefore, the tissue presumed to be the origin of the tumor. Examples of general categories include:

• Carcinoma: Malignant tumors derived from epithelial cells. This group represents the most common cancers, including the common forms of breast, prostate, lung and colon cancer.
• Sarcoma: Malignant tumors derived from connective tissue, or mesenchymal cells.
• Lymphoma and leukemia: Malignancies derived from hematopoietic (blood-forming) cells
• Germ cell tumor: Tumors derived from totipotent cells. In adults most often found in the testicle and ovary; in fetuses, babies, and young children most often found on the body midline, particularly at the tip of the tailbone; in horses most often found at the poll (base of the skull).
• Blastic tumor: A tumor (usually malignant) which resembles an immature or embryonic tissue. Many of these tumors are most common in children.

Malignant tumors (cancers) are usually named using -carcinoma, -sarcoma or -blastoma as a suffix, with the Latin or Greek word for the organ of origin as the root. For instance, a cancer of the liver is called hepatocarcinoma; a cancer of the fat cells is called liposarcoma. For common cancers, the English organ name is used. For instance, the most common type of breast cancer is called ductal carcinoma of the breast or mammary ductal carcinoma. Here, the adjective ductal refers to the appearance of the cancer under the microscope, resembling normal breast ducts.

Benign tumors are named using -oma as a suffix with the organ name as the root. For instance, a benign tumor of the smooth muscle of the uterus is called leiomyoma (the common name of this frequent tumor is fibroid). Unfortunately, some cancers also use the -oma suffix, examples being melanoma and seminoma.

In the U.S. and other developed countries, cancer is presently responsible for about 25% of all deaths.^[1] On a yearly basis, 0.5% of the population is diagnosed with cancer. The statistics below are for adults in the United States, and may vary substantially in other countries:

Male			Female
most common (by occurrence)	most common (by mortality) [1]		most common (by occurrence)	most common (by mortality) [1]
prostate cancer (33%)	lung cancer (31%)		breast cancer (32%)	lung cancer (27%)
lung cancer (13%)	prostate cancer (10%)		lung cancer (12%)	breast cancer (15%)
colorectal cancer (10%)	colorectal cancer (10%)		colorectal cancer (11%)	colorectal cancer (10%)
bladder cancer (7%)	pancreatic cancer (5%)		endometrial cancer (6%)	ovarian cancer (6%)
cutaneous melanoma (5%)	leukemia (4%)		non-Hodgkin lymphoma (4%)	pancreatic cancer (6%)

Cancer can also occur in young children and adolescents, but it is rare (about 150 cases per million yearly in the US). Statistics from the SEER program of the US NCI demonstrate that childhood cancers increased 19% between 1975 and 1990, mainly due to an increased incidence in acute leukemia. Since 1990, incidence rates have decreased ^[2]

The age of peak incidence of cancer in children occurs during the first year of life. Leukemia (usually ALL) is the most common infant malignancy (30%), followed by the central nervous system cancers and neuroblastoma. The remainder consists of Wilms’ tumor, lymphomas, rhabdomyosarcoma (arising from muscle), retinoblastoma, osteosarcoma and Ewing’s sarcoma.^[1] Teratoma is the most common tumor in this age group, but most teratomas are surgically removed while still benign, hence not necessarily cancer.

Female and male infants have essentially the same overall cancer incidence rates, but white infants have substantially higher cancer rates than black infants for most cancer types. Relative survival for infants is very good for neuroblastoma, Wilms’ tumor and retinoblastoma, and fairly good (80%) for leukemia, but not for most other types of cancer.

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Cancer is fundamentally a disease of regulation of tissue growth. In order for a normal cell to transform into a cancer cell, genes which regulate cell growth and differentiation must be altered. Genetic changes can occur at many levels, from gain or loss of entire chromosomes to a mutation affecting a single DNA nucleotide. There are two broad categories of genes which are affected by these changes. Oncogenes may be normal genes which are expressed at inappropriately high levels, or altered genes which have novel properties. In either case, expression of these genes promotes the malignant phenotype of cancer cells. Tumor suppressor genes are genes which inhibit cell division, survival, or other properties of cancer cells. Tumor suppressor genes are often disabled by cancer-promoting genetic changes. Typically, changes in many genes are required to transform a normal cell into a cancer cell.

There is a diverse classification scheme for the various genomic changes which may contribute to the generation of cancer cells. Most of these changes are mutations, or changes in the nucleotide sequence of genomic DNA. Aneuploidy, the presence of an abnormal number of chromosomes, is one genomic change which is not a mutation, and may involve either gain or loss of one or more chromosomes through errors in mitosis.

Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR–abl fusion protein, an oncogenic tyrosine kinase.

Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter of a gene and affect its expression, or may occur in the gene’s coding sequence and alter the function or stability of its protein product. Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, and such an event may also result in the expression of viral oncogenes in the affected cell and its descendants.

Epigenetics is the study of the regulation of gene expression through chemical, non-mutational changes in DNA structure. The theory of epigenetics in cancer pathogenesis is that non-mutational changes to DNA can lead to alterations in gene expression. Normally, oncogenes are silent, for example, because of DNA methylation. Loss of that methylation can induce the aberrant expression of oncogenes, leading to cancer pathogenesis. Known mechanisms of epigenetic change include DNA methylation, and methylation or acetylation of histone proteins bound to chromosomal DNA at specific locations. Classes of medications, known as HDAC inhibitors and DNA methyltransferase inhibitors, can re-regulate the epigenetic signaling in the cancer cell.

Oncogenes promote cell growth through a variety of ways. Many can produce hormones, a “chemical messenger” between cells which encourage mitosis, the effect of which depends on the signal transduction of the receiving tissue or cells. In other words, when a hormone receptor on a recipient cell is stimulated, the signal is conducted from the surface of the cell to the cell nucleus to effect some change in gene transcription regulation at the nuclear level. Some oncogenes are part of the signal transduction system itself, or the signal receptors in cells and tissues themselves, thus controlling the sensitivity to such hormones. Oncogenes often produce mitogens, or are involved in transcription of DNA in protein synthesis, which creates the proteins and enzymes responsible for producing the products and biochemicals cells use and interact with.

Mutations in proto-oncogenes, which are the normally quiescent counterparts of oncogenes, can modify their expression and function, increasing the amount or activity of the product protein. When this happens, the proto-oncogenes become oncogenes, and this transition upsets the normal balance of cell cycle regulation in the cell, making uncontrolled growth possible. The chance of cancer cannot be reduced by removing proto-oncogenes from the genome, even if this were possible, as they are critical for growth, repair and homeostasis of the organism. It is only when they become mutated that the signals for growth become excessive.

One of the first oncogenes to be defined in cancer research is the ras oncogene. Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumours.^[1] Ras was originally identified in the Harvey sarcoma virus genome, and researchers were surprised that not only was this gene present in the human genome but that, when ligated to a stimulating control element, could induce cancers in cell line cultures.^[2]

Tumor suppressor genes code for anti-proliferation signals and proteins that suppress mitosis and cell growth. Generally, tumor suppressors are transcription factors that are activated by cellular stress or DNA damage. Often DNA damage will cause the presence of free-floating genetic material as well as other signs, and will trigger enzymes and pathways which lead to the activation of tumor suppressor genes. The functions of such genes is to arrest the progression of the cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells. The p53 protein, one of the most important studied tumor suppressor genes, is a transcription factor activated by many cellular stressors including hypoxia and ultraviolet radiation damage.

Despite nearly half of all cancers possibly involving alterations in p53, its tumor suppressor function is poorly understood. p53 clearly has two functions: one a nuclear role as a transcription factor, and the other a cytoplasmic role in regulating the cell cycle, cell division, and apoptosis.

The Warburg hypothesis is the preferential use of glycolysis for energy to sustain cancer growth. p53 has been shown to regulate the shift from the respiratory to the glycolytic pathway.^[3]

However, a mutation can damage the tumor suppressor gene itself, or the signal pathway which activates it, “switching it off”. The invariable consequence of this is that DNA repair is hindered or inhibited: DNA damage accumulates without repair, inevitably leading to cancer.

Mutations of tumor suppressor genes that occur in germline cells are passed along to offspring, and increase the likelihood for cancer diagnoses in subsequent generations. Members of these families have increased incidence and decreased latency of multiple tumors. The tumor types are typical for each type of tumor suppressor gene mutation, with some mutations causing particular cancers, and other mutations causing others. The mode of inheritance of mutant tumor suppressors is that an affected member inherits a defective copy from one parent, and a normal copy from the other. For instance, individuals who inherit one mutant p53 allele (and are therefore heterozygous for mutated p53) can develop melanomas and pancreatic cancer, known as Li-Fraumeni syndrome. Other inherited tumor suppressor gene syndromes include Rb mutations, linked to retinoblastoma, and APC gene mutations, linked to adenopolyposis colon cancer. Adenopolyposis colon cancer is associated with thousands of polyps in colon while young, leading to colon cancer at a relatively early age. Finally, inherited mutations in BRCA1 and BRCA2 lead to early onset of breast cancer.

Development of cancer was proposed in 1971 to depend on at least two mutational events. In what became known as the Knudson two-hit hypothesis, an inherited, germ-line mutation in a tumor suppressor gene would only cause cancer if another mutation event occurred later in the organism’s life, inactivating the other allele of that tumor suppressor gene.^[4]

Usually, oncogenes are dominant, as they contain gain-of-function mutations, while mutated tumor suppressors are recessive, as they contain loss-of-function mutations. Each cell has two copies of the same gene, one from each parent, and under most cases gain of function mutations in just one copy of a particular proto-oncogene is enough to make that gene a true oncogene. On the other hand, loss of function mutations need to happen in both copies of a tumor suppressor gene to render that gene completely non-functional. However, cases exist in which one mutated copy of a tumor suppressor gene can render the other, wild-type copy non-functional. This phenomenon is called the dominant negative effect and is observed in many p53 mutations.

Knudson’s two hit model has recently been challenged by several investigators. Inactivation of one allele of some tumor suppressor genes is sufficient to cause tumors. This phenomenon is called haploinsufficiency and has been demonstrated by a number of experimental approaches. Tumors caused by haploinsufficiency usually have a later age of onset when compared with those by a two hit process.^[5]

Often, the multiple genetic changes which result in cancer may take many years to accumulate. During this time, the biological behavior of the pre-malignant cells slowly change from the properties of normal cells to cancer-like properties. Pre-malignant tissue can have a distinctive appearance under the microscope. Among the distinguishing traits are an increased number of dividing cells, variation in nuclear size and shape, variation in cell size and shape, loss of specialized cell features, and loss of normal tissue organization. Dysplasia is an abnormal type of excessive cell proliferation characterized by loss of normal tissue arrangement and cell structure in pre-malignant cells. These early neoplastic changes must be distinguished from hyperplasia, a reversible increase in cell division caused by an external stimulus, such as a hormonal imbalance or chronic irritation.

The most severe cases of dysplasia are referred to as “carcinoma in situ.” In Latin, the term “in situ” means “in place”, so carcinoma in situ refers to an uncontrolled growth of cells that remains in the original location and has not shown invasion into other tissues. Nevertheless, carcinoma in situ may develop into an invasive malignancy and is usually removed surgically, if possible.

The process of malignancy can be explained from an evolutionary perspective. Millions of years of biological evolution insure that the cellular metabolic changes that enable cancer to grow occur only very rarely. Most changes in cellular metabolism that allow cells to grow in a disorderly fashion lead to cell death. Cancer cells undergo a process analogous to natural selection, in that the few cells with new genetic changes that enhance their survival continue to multiply, and soon come to dominate the growing tumor, as cells with less favorable genetic change are outcompeted. This process is called clonal evolution. Tumors often continue to evolve in response to chemotherapy treatments, and on occasion aberrant cells may acquire resistance to particular anti-cancer pharmaceuticals.

In a 2000 article by Hanahan and Weinberg, the biological properties of malignant tumor cells were summarized as follows:^[6]

• Acquisition of self-sufficiency in growth signals, leading to unchecked growth.
• Loss of sensitivity to anti-growth signals, also leading to unchecked growth.
• Loss of capacity for apoptosis, in order to allow growth despite genetic errors and external anti-growth signals.
• Loss of capacity for senescence, leading to limitless replicative potential (immortality)
• Acquisition of sustained angiogenesis, allowing the tumor to grow beyond the limitations of passive nutrient diffusion.
• Acquisition of ability to invade neighbouring tissues, the defining property of invasive carcinoma.
• Acquisition of ability to build metastases at distant sites, the classical property of malignant tumors (carcinomas or others).

The completion of these multiple steps would be a very rare event without :

• Loss of capacity to repair genetic errors, leading to an increased mutation rate (genomic instability), thus accelerating all the other changes.

These biological changes are classical in carcinomas; other malignant tumor may not need all to achieve them all. For example, tissue invasion and displacement to distant sites are normal properties of leukocytes; these steps are not needed in the development of Leukemia. The different steps do not necessarily represent individual mutations. For example, inactivation of a single gene, coding for the P53 protein, will cause genomic instability, evasion of apoptosis and increased angiogenesis.

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Cancer is a diverse class of diseases which differ widely in their causes and biology. The common thread in all known cancers is the acquisition of abnormalities in the genetic material of the cancer cell and its progeny. Research into the pathogenesis of cancer can be divided into three broad areas of focus. The first area of research focuses on the agents and events which cause or facilitate genetic changes in cells destined to become cancer. Second, it is important to uncover the precise nature of the genetic damage, and the genes which are affected by it. The third focus is on the consequences of those genetic changes on the biology of the cell, both in generating the defining properties of a cancer cell, and in facilitating additional genetic events, leading to further progression of the cancer.

Cancer pathogenesis is traceable back to DNA mutations that impact cell growth and metastasis. Substances that cause DNA mutations are known as mutagens, and mutagens that cause cancers are known as carcinogens. Particular substances have been linked to specific types of cancer. Tobacco smoking is associated with lung cancer and bladder cancer. Prolonged exposure to asbestos fibers is associated with mesothelioma.

Many mutagens are also carcinogens, but some carcinogens are not mutagens. Alcohol is an example of a chemical carcinogen that is not a mutagen. Such chemicals are thought to promote cancers through their stimulating effect on the rate of cell mitosis. Faster rates of mitosis leaves less time for repair enzymes to repair damaged DNA during DNA replication, increasing the likelihood of a genetic mistake. A mistake made during mitosis can lead to the daughter cells receiving the wrong number of chromosomes (see aneuploidy above).

Decades of research have demonstrated the strong association between tobacco use and cancers of many sites, making it perhaps the most important human carcinogen. Hundreds of epidemiological studies have confirmed this association. Further support comes from the fact that lung cancer death rates in the United States have mirrored smoking patterns, with increases in smoking followed by dramatic increases in lung cancer death rates and, more recently, decreases in smoking followed by decreases in lung cancer death rates in men.

Sources of ionizing radiation, such as radon gas, can cause cancer. Prolonged exposure to ultraviolet radiation from the sun can lead to melanoma and other skin malignancies.

Furthermore, many cancers originate from a viral infection; this is especially true in animals such as birds, but also in humans, as viruses are responsible for 15% of human cancers worldwide. The main viruses associated with human cancers are human papillomavirus, hepatitis B and hepatitis C virus, Epstein-Barr virus, and human T-lymphotropic virus. Experimental and epidemiological data imply a causative role for viruses and they appear to be the second most important risk factor for cancer development in humans, exceeded only by tobacco usage.^[1] The mode of virally-induced tumors can be divided into two, acutely-transforming or slowly-transforming. In acutely transforming viruses, the viral particles carry a gene that encodes for an overactive oncogene called viral-oncogene (v-onc), and the infected cell is transformed as soon as v-onc is expressed. In contrast, in slowly-transforming viruses, the virus genome is inserted, especially as viral genome insertion is an obligatory part of retroviruses, near a proto-oncogene in the host genome. The viral promoter or other transcription regulation elements in turn cause overexpression of that proto-oncogene, which in turn induces uncontrolled cellular proliferation. Because viral genome insertion is not specific to proto-oncogenes and the chance of insertion near that proto-oncogene is low, slowly-transforming viruses have very long tumor latency compared to acutely-transforming viruses, which already carry the viral oncogene.

Hepatitis viruses, including hepatitis B and hepatitis C, can induce a chronic viral infection that leads to liver cancer in 0.47% of hepatitis B patients per year (especially in Asia, less so in North America), and in 1.4% of hepatitis C carriers per year. Liver cirrhosis, whether from chronic viral hepatitis infection or alcoholism, is associated with the development of liver cancer, and the combination of cirrhosis and viral hepatitis presents the highest risk of liver cancer development. Worldwide, liver cancer is one of the most common, and most deadly, cancers due to a huge burden of viral hepatitis transmission and disease.

Advances in cancer research have made a vaccine designed to prevent cancer available. In 2006, the US FDA approved a human papilloma virus vaccine, called Gardasil®. The vaccine protects against four HPV types, which together cause 70% of cervical cancers and 90% of genital warts. In March 2007, the US CDC Advisory Committee on Immunization Practices (ACIP) officially recommended that females aged 11-12 receive the vaccine, and indicated that females as young as age 9 and as old as age 26 are also candidates for immunization.

In addition to viruses, researchers have noted a connection between bacteria and certain cancers. The most prominent example is the link between chronic infection of the wall of the stomach with Helicobacter pylori and gastric cancer.^[2]

Some hormones can act in a similar manner to non-mutagenic carcinogens in that they may stimulate excessive cell growth. A well-established example is the role of hyperestrogenic states in promoting endometrial cancer.

HIV is associated with a number of malignancies, including Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and HPV-associated malignancies such as anal cancer and cervical cancer. AIDS-defining illnesses have long included these diagnoses. The increased incidence of malignancies in HIV patients points to the breakdown of immune surveillance as a possible etiology of cancer.^[3] Certain other immune deficiency states (e.g. common variable immunodeficiency and IgA deficiency) are also associated with increased risk of malignancy.^[4]

Most forms of cancer are “sporadic”, and have no basis in heredity. There are, however, a number of recognised syndromes of cancer with a hereditary component, often a defective tumor suppressor allele. Famous examples are:

• Certain inherited mutations in the genes BRCA1 and BRCA2 are associated with an elevated risk of breast cancer and ovarian cancer
• Tumors of various endocrine organs in multiple endocrine neoplasia (MEN types 1, 2a, 2b)
• Li-Fraumeni syndrome (various tumors such as osteosarcoma, breast cancer, soft tissue sarcoma, brain tumors) due to mutations of p53
• Turcot syndrome (brain tumors and colonic polyposis)
• Familial adenomatous polyposis an inherited mutation of the APC gene that leads to early onset of colon carcinoma.
• Hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome) can include familial cases of colon cancer, uterine cancer, gastric cancer, and ovarian cancer, without a preponderance of colon polyps.
• Retinoblastoma, when occurring in young children, is due to a hereditary mutation in the retinoblastoma gene.
• Down syndrome patients, who have an extra chromosome 21, are known to develop malignancies such as leukemia and testicular cancer, though the reasons for this difference are not well understood.

• Becaplermin
• Belimumab
• Doxorubicin Hydrochloride
• Certolizumab

A few types of cancer in non-humans have been found to be caused by the tumor cells themselves. This phenomenon is seen in Sticker’s sarcoma, also known as canine transmissible venereal tumor (CTVT).^[5] The closest known analogue to this in humans is individuals who have developed cancer from tumors hiding inside organ transplants.

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Cancer epidemiology is the study of the incidence of cancer as a way to infer possible trends and causes. The first such cause of cancer was identified by British surgeon Percivall Pott, who discovered in 1775 that cancer of the scrotum was a common disease among chimney sweeps. The work of other individual physicians led to various insights, but when physicians started working together they could make firmer conclusions.

A founding paper of this discipline was the work of Janet Lane-Claypon, who published a comparative study in 1926 of 500 breast cancer cases and 500 control patients of the same background and lifestyle for the British Ministry of Health. Her ground-breaking work on cancer epidemiology was carried on by Richard Doll and Austin Bradford Hill, who published “Lung Cancer and Other Causes of Death In Relation to Smoking. A Second Report on the Mortality of British Doctors” followed in 1956 (otherwise known as the British doctors study). Richard Doll left the London Medical Research Center (MRC), to start the Oxford unit for Cancer epidemiology in 1968. With the use of computers, the unit was the first to compile large amounts of cancer data. Modern epidemiological methods are closely linked to current concepts of disease and public health policy. Over the past 50 years, great efforts have been spent on gathering data across medical practise, hospital, provincial, state, and even country boundaries, as a way to study the interdependence of environmental and cultural factors on cancer incidence.

Cancer epidemiology must contend with problems of lead time bias and length time bias. Lead time bias is the concept that early diagnosis may artificially inflate the survival statistics of a cancer, without really improving the natural history of the disease. Length bias is the concept that slower growing, more indolent tumors are more likely to be diagnosed by screening tests, but improvements in diagnosing more cases of indolent cancer may not translate into better patient outcomes after the implementation of screening programs. A similar epidemiological concern is overdiagnosis, the tendency of screening tests to diagnose diseases that may not actually impact the patient’s longevity. This problem especially applies to prostate cancer and PSA screening.^[1]

Some cancer researchers have argued that negative cancer clinical trials lack sufficient statistical power to discover a benefit to treatment. This may be due to fewer patients enrolled in the study than originally planned.^[2]

State and regional cancer registries are organizations that abstract clinical data about cancer from patient medical records. These institutions provide information to state and national public health groups to help track trends in cancer diagnosis and treatment. One of the largest and most important cancer registries is SEER, administered by the US Federal government.^[3] Health information privacy concerns have led to the restricted use of cancer registry data in the United States Department of Veterans Affairs ^[4][5][6] and other institutions.^[7]

In some Western countries, such as the USA, and the UK^[8] cancer is overtaking cardiovascular disease as the leading cause of death. In many Third World countries cancer incidence (insofar as this can be measured) appears much lower, most likely because of the higher death rates due to infectious disease or injury. With the increased control over malaria and tuberculosis in some Third World countries, incidence of cancer is expected to rise; this is termed the epidemiologic transition in epidemiological terminology.

Cancer epidemiology closely mirrors risk factor spread in various countries. Hepatocellular carcinoma (liver cancer) is rare in the West but is the main cancer in China and neighbouring countries, most likely due to the endemic presence of hepatitis B and aflatoxin in that population. Similarly, with tobacco smoking becoming more common in various Third World countries, lung cancer incidence has increased in a parallel fashion.

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Factors that increase the chance of developing cancer are called risk factors. There are 2 types of risk factors: Modifiable and Non-modifiable. Modifiable risk factors are attitudes or circumstances that people can avoid, for example smoking. Non-modifiable risk factors are conditions that can’t be changed, for example genetic predisposition to certain diseases. Factors that decrease the chance of developing cancer are called protective factors.

Information below is based on the National Cancer Institute Cancer Prevention Overview: Risk Factors page.^[1]

• Tobacco use is strongly linked to an increased risk for many kinds of cancer. Cigarette smoking is the leading cause of the following types of cancer:

• Acute myelogenous leukemia (AML)
• Bladder cancer
• Esophageal cancer
• Kidney cancer
• Lung cancer
• Oral cancer
• Pancreatic cancer
• Stomach cancer

• Not smoking or quitting smoking lowers the risk of getting cancer and dying from cancer.
• Cigarette smoking causes about 30% of all cancer deaths in the United States.
• Cigarette smoking causes an estimated 443,000 deaths each year, including approximately 49,000 deaths due to exposure to secondhand smoke.
• Lung cancer is the leading cause of cancer death among both men and women in the United States, and 90% of lung cancer deaths among men and approximately 80% of lung cancer deaths among women are due to smoking.

Information below is based on the National Cancer Institute causes and risk factors page.^[2][3][4]

Certain viral and bacterial infections are able to cause cancer. Infection as a cancer cause is more common in developing countries (about 1 in 4 cases of cancer) than in developed countries (less than 1 in 10 cases of cancer). Examples of infection caused cancers:

• Human immunodeficiency virus (HIV): People infected with HIV have a substantially higher risk of some types of cancer compared with uninfected people of the same age.

• Several thousand times more risk of Kaposi sarcoma
• 70 times more risk of Non-Hodgkin lymphoma
• 5 times more risk of Cervical cancer
• Other cancers associated with HIV: Anal cancer, liver cancer, lung cancer and Hodgkin lymphoma.

• Human papillomavirus (HPV): HPV infections are the most common sexually transmitted infections in the United States. High-risk or oncogenic HPVs, which can cause cancer. At least 13 high-risk HPV types have been identified: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. wo of these, HPV types 16 and 18, are responsible for the majority of HPV-caused cancers.

• Cervical cancer
• Penis cancer
• Vaginal cancer
• Anal cancer
• Oropharyngeal cancer

• Helicobacter pylori:

• Major cause of gastric cancer, specifically non-cardia gastric cancer. Epidemiologic studies have shown that individuals infected with H. pylori have an increased risk of gastric adenocarcinoma
• H. pylori infection also causes gastric mucosa-associated lymphoid tissue lymphoma (MALT lymphoma).
• Several studies have detected an inverse relationship between H. pylori infection and gastric cardia cancer and esophageal adenocarcinoma.
• Studies investigating the possibility that H. pylori is a risk factor for colorectal adenocarcinoma or lung cancer have found no evidence that it is associated with the risk of either type of cancer.
• Long-term follow-up of data from a randomized clinical trial carried out in Shandong, China (an area where rates of gastric cancer are very high) demonstrated that short-term treatment with antibiotics to eradicate H. pylori reduced the incidence of gastric cancer.

• During a nearly 15-year period after treatment, gastric cancer incidence was reduced by almost 40%

• Hepatitis B and hepatitis C viruses increase the risk for liver cancer
• Epstein-Barr virus increases the risk for Burkitt lymphoma

Two vaccines to prevent infection by cancer-causing agents have already been developed and approved by the U.S. Food and Drug Administration (FDA):

• Hepatitis B vaccine
• Human papillomavirus vaccine

There are two main types of radiation linked with an increased risk for cancer:^[1]

• Ultraviolet radiation from sunlight: This is the main cause of nonmelanoma skin cancers.
• Ionizing radiation including:

• Medical radiation from tests such as x-rays, CT scans, fluoroscopy, and nuclear medicine scans.
• Radon gas found in homes.

• Radiation exposure from diagnostic X-rays increases the risk of cancer in patients and X-ray technicians.
• The growing use of CT scans over the last 20 years has increased exposure to ionizing radiation. The risk of cancer also increases with the number of CT scans a patient has and the radiation dose used each time.

Ionizing radiation has been associated with:

• Leukemia
• Thyroid cancer
• Breast cancer
• Myeloma
• Lung cancer
• Gastric cancer
• Colon cancer
• Esophageal cancer
• Bladder cancer
• Ovarian cancer

Non-ionizing radiation:^[5]

• The most common exposures to radiofrequency energy are from telecommunications devices and equipment (cell phones, chordless phones). Other radiofrequency energy sources are: AM/FM radios and VHF/UHF televisions, radar, satellite stations, magnetic resonance imaging (MRI) devices, industrial equipment, and microwave ovens.
• It is generally accepted that damage to DNA is necessary for cancer to develop. However, radiofrequency energy, unlike ionizing radiation, does not cause DNA damage in cells, and it has not been found to cause cancer in animals or to enhance the cancer-causing effects of known chemical carcinogens in animals.
• The American Cancer Society, the National Institute of Environmental Health Sciences, the FDA and the CDC have concluded that there is not enough evidence to consider non-ionizing radiofrequency energy as a cause for cancer.
• The International Agency for Research in Cancer classified radiofrequency fields as “possibly carcinogenicto humans”.

Immunosuppressive medicines are linked to an increased risk of cancer because these medications lower the immune system’s ability to stop cancer from forming.^[1]

Information below is based on the National Cancer Institute Asbestos Exposure and Cancer Risk page.^[6]

• Asbestos has been classified as a known human carcinogen by the U.S. Department of Health and Human Services, the EPA, and the International Agency for Research on Cancer.
• Studies have shown that exposure to asbestos may increase the risk of lung cancer and mesothelioma.
• Mesothelioma is the most common form of cancer associated with asbestos exposure.
• Though inconclusive, studies have shown an association between asbestos and other cancers:

• Gastric cancer
• Colorectal cancer
• Throat cancer
• Kidney cancer
• Esophageal cancer
• Gallbladder cancer

• Smokers who are also exposed to asbestos have a risk of developing lung cancer that is greater than the individual risks from asbestos and smoking added together.

Information below is based on the National Cancer Institute Formaldehyde and Cancer Risk page.^[7]

• The International Agency for Research on Cancer (IARC) and the National Toxicology Program classify formaldehyde as a human carcinogen.
• Several National Cancer Institute (NCI) surveys suggested that professionals who are potentially exposed to formaldehyde in their work, such as anatomists and embalmers, have an increased risk of leukemia (particularly myeloid leukemia) and brain cancer compared with the general population.
• Several epidemiologic studies have shown the risk of formaldehyde exposure and cancer. This risk was associated with increasing peak, average levels and duration of exposure, but it was not associated with cumulative exposure.
• A 10-year follow-up study showed the risk of leukemia was highest earlier in the follow-up period. Risks declined steadily over time, such that the cumulative excess risk of myeloid leukemia was no longer statistically significant at the end of the follow-up period.
• Several case-control studies, as well as analysis of the large NCI industrial cohort, found an association between formaldehyde exposure and nasopharyngeal cancer.
• Data from extended follow-up of the NCI cohort found that the excess of nasopharyngeal cancer observed in the earlier report persisted.

Information below is based on the National Cancer Institute Hair Dyes and Cancer Risk page.^[8]

• Studies have shown that professional hairdressers have an increased risk of bladder cancer that may be due to occupational exposure to hair dye. However, the information is inconclusive.
• A review of 14 studies of female breast cancer and hair dye published between 1977 and 2002 found that dye users had no increase in the risk of breast cancer compared with nonusers.
• Studies of the association between personal hair dye use and the risk of leukemia have had conflicting results.

Information below is based on the National Cancer Institute Acrylamide in Food and Cancer Risk page.^[9]

• The National Toxicology Program and the International Agency for Research on Cancer consider acrylamide to be a “probable human carcinogen,” based on studies in laboratory animals.
• One study showed that women with higher levels of acrylamide bound to the hemoglobin in their blood, had a statistically significant increase in risk of estrogen receptor-positive breast cancer.
• A questionnaire-based cohort study performed the Netherlands found an excess of endometrial and ovarian cancer associated with higher levels of acrylamide exposure

Information below is based on the National Cancer Institute Artificial Sweeteners and Cancer Risk page.^[10]

• Saccharin:

• Studies in rats showed an increased incidence of bladder cancer at high doses of saccharin, especially in male rats. However, mechanistic studies have shown that these results apply only to rats.
• Human epidemiology studies have shown no consistent evidence that saccharin is associated with bladder cancer incidence.

• Aspartame: NCI examined human data from the NIH-AARP Diet and Health Study of over half a million retirees. Increasing consumption of aspartame-containing beverages was not associated with the development of lymphoma, leukemia, or brain cancer.
• Acesulfame potassium, Sucralose and Neotame: These three artificial sweeteners are currently permitted for use in food in the United States. Before approving these sweeteners, the FDA reviewed more than 100 safety studies that were conducted on each sweetener, including studies to assess cancer risk. The results of these studies showed no evidence that these sweeteners cause cancer or pose any other threat to human health.
• Cyclamate: Early studies showed that cyclamate in combination with saccharin caused bladder cancer in laboratory animals.

• Results from subsequent studies of cyclamate’s carcinogenicity and the evaluation of additional data, it was concluded that cyclamate was not a carcinogen or a co-carcinogen.
• A food additive petition was filed with the FDA for the reapproval of cyclamate, but this petition is currently being held in abeyance. The FDA’s concerns about cyclamate are not cancer related.

Information below is based on the National Cancer Institute Genetic Testing for Hereditary Cancer Syndromes page.^[11]

Genetic mutations play a role in the development of all cancers. Most of these mutations occur during a person’s lifetime, but some mutations, including those that are associated with hereditary cancer syndromes, can be inherited from a person’s parents. Inherited mutations play a major role in the development of about 5% to 10% of all cancers. Inherited genetic mutations can increase a person’s risk of developing cancer; however, a cancer-predisposing mutation does not necessarily mean that everyone who inherits the mutation will develop cancer. Several factors influence the outcome in a given person with the mutation. The list below includes some of the more common inherited cancer syndromes:

• Hereditary breast cancer and ovarian cancer syndrome

• Genes: BRCA1, BRCA2
• Related cancer types: Female breast cancer, ovarian cancer, prostate cancer, pancreatic cancer and male breast cancer

• Li-Fraumeni syndrome

• Gene: TP53
• Related cancer types: Breast cancer, soft tissue sarcoma, osteosarcoma, leukemia, brain tumors, adrenocortical carcinoma

• Cowden syndrome (PTEN hamartoma tumor syndrome)

• Gene: PTEN
• Related cancer types: Breast cancer, thyroid cancer, endometrial cancer.

• Hereditary nonpolyposis colorectal cancer (Lynch syndrome)

• Genes: MSH2, MLH1, MSH6, PMS2, EPCAM
• Related cancer types: Colorectal cancer, endometrial cancer, ovarian cancer, renal pelvis cancer, pancreatic cancer, small intestine cancer, liver and biliary tract cancer, stomach cancer, brain cancer, and breast cancer

• Familial adenomatous polyposis

• Gene: APC
• Related cancer types: Colorectal cancer, multiple non-malignant colon polyps, and both benign and cancerous tumors in the small intestine, brain, stomach, bone, skin.

• Retinoblastoma

• Gene: RB1
• Related cancer types: Retinoblastoma, pinealoma, osteosarcoma, melanoma and soft tissue sarcoma

• Multiple endocrine neoplasia type 1 (Wermer syndrome)

• Gene: MEN1
• Related cancer types: Pancreatic endocrine tumors and (usually benign) parathyroid and pituitary gland tumors

• Multiple endocrine neoplasia type 2

• Gene: RET
• Related cancer types: Medullar thyroid carcinoma and pheochromocytoma

• Von Hippel-Lindau syndrome

• Gene: VHL
• Related cancer types: Kidney cancer and multiple noncancerous tumors, including pheochromocytoma

• The results of population studies to examine associations between oral contraceptive use and cancer risk have not always been consistent.

• The risks of endometrial cancer and ovarian cancer appear to be reduced with the use of oral contraceptives.
• The risks of breast cancer, cervical cancer and liver cancer appear to be increased.

• Studies showed that women who stopped taking oral contraceptives, the risk tended to decline over time for breast cancer and cervical cancer.
• Some studies have found that women who take oral contraceptives for more than 5 years have an increased risk of hepatocellular carcinoma, but others have not found that relationship.

The most comprehensive evidence about risks and benefits of MHT comes from two randomized clinical trials that were sponsored by the National Institutes of Health as part of the Women’s Health Initiative (WHI): The WHI Estrogen-plus-Progestin Study, in which women with a uterus were randomly assigned to receive either a hormone medication containing both estrogen and progestin or a placebo and The WHI Estrogen-Alone Study, in which women without a uterus were randomly assigned to receive either a hormone medication containing estrogen alone or a placebo.

• Women who took estrogen plus progestin were more likely to be diagnosed with breast cancer.

• The breast cancers in these women were larger and more likely to have spread to the lymph nodes by the time they were diagnosed.
• The number of breast cancers in this group of women increased with the length of time that they took the hormones and decreased after they stopped taking the hormones.

• Women who took estrogen plus progestin had the same risk of lung cancer as women who took the placebo.

• Among women who were diagnosed with lung cancer, women who took estrogen plus progestin were more likely to die of the disease than those who took the placebo.

• Women who have had a hysterectomy and who use estrogen-alone MHT have a reduced risk of breast cancer that continues for at least 5 years after they stop taking MHT.
• Women who take estrogen plus progestin have an increased risk of breast cancer that continues after they stop taking the medication.
• Studies have documented a decline in breast cancer diagnoses in the United States after the sharp reduction in the use of MHT that followed publication of the initial results of the Estrogen-plus-Progestin Study in July 2002

^[1]

• Diet is being studied as a risk factor for cancer.
• Some studies show that fruits and non-starchy vegetables may protect against oral cancer, esophageal cancer, gastric cancer and lung cancer
• Results from studies on the effect of a diet high in fat, proteins, calories, and red meat as a risk factor for colorectal cancer are controversial. There are studies that have showed a clear relationship and studies that haven’t.

• It is not known if a diet low in fat and high in fiber, fruits, and vegetables lowers the risk of colorectal cancer.

• Epidemiological studies have shown that high consumption of well-done, fried, or barbecued meats was associated with increased risks of colorectal cancer, pancreatic cancer and prostate cancer.

Information below is based on the National Cancer Institute Alcohol and Cancer Risk page.^[14]

• Based on extensive reviews of research studies, there is a strong consensus about the association between alcohol drinking and several types of cancer.
• The National Toxicology Program of the US Department of Health and Human Services lists consumption of alcoholic beverages as a known human carcinogen.
• Evidence indicates that the more alcohol a person drinks -particularly the more alcohol a person drinks regularly over time- the higher his or her risk of developing an alcohol-associated cancer.
• Drinking alcohol is related with an increased risk of the following types of cancers:

• Head and neck cancer: Alcohol consumption is a major risk factor for certain head and neck cancers, particularly cancers of the oral cavity, pharynx, and larynx.

• People who consume 50 or more grams of alcohol per day (approximately 3.5 or more drinks per day) have at least a two to three times greater risk of developing these cancers than nondrinkers.
• The risks of these cancers are substantially higher among persons who consume this amount of alcohol and also use tobacco.

• Esophageal cancer: Alcohol consumption is a major risk factor for esophageal squamous cell carcinoma. People who inherit a deficiency or polymorphisms in ALDH2 (an enzyme that metabolizes alcohol) have been found to have substantially increased risks of alcohol-related esophageal squamous cell carcinoma.^[15][16]
• Breast cancer: More than 100 epidemiologic studies have looked at the association between alcohol consumption and the risk of breast cancer in women. ::* These studies have consistently found an increased risk of breast cancer associated with increasing alcohol intake. A meta-analysis of 53 of these studies (which included a total of 58,000 women with breast cancer) showed that women who drank more than 45 grams of alcohol per day (approximately three drinks) had 1.5 times more risk of developing breast cancer as nondrinkers.

• The risk of breast cancer was higher across all levels of alcohol intake: The Million Women Study in the United Kingdom showed an estimate of breast cancer risk at low to moderate levels of alcohol consumption: every 10 grams of alcohol consumed per day was associated with a 12 percent increase in the risk of breast cancer.

• Colorectal cancer: Alcohol consumption is associated with a modestly increased risk of cancers of the colon and rectum.

• A meta-analysis of 57 cohort and case-control studies that examined the association between alcohol consumption and colorectal cancer risk showed that people who regularly drank 50 grams or more of alcohol per day (approximately 3.5 drinks) had 1.5 times the risk of developing colorectal cancer as nondrinkers or occasional drinkers.
• For every 10 grams of alcohol consumed per day, there was a small 7% increase in the risk of colorectal cancer.

• Liver cancer: Alcohol consumption is an independent risk factor for and a primary cause of liver cancer.

• Multiple studies have shown that increased alcohol consumption is associated with a decreased risk renal cell carcinoma and Non-Hodgkin’s Lymphoma (NHL). A meta-analysis of the NHL studies found a 15% lower risk of NHL among alcohol drinkers compared with nondrinkers. The mechanisms by which alcohol consumption would decrease the risks of either renal cell carcinoma or NHL are not understood.

Information below is based on the National Cancer Institute Reproductive History and Breast Cancer Risk page.^[17]

Studies have shown that a woman’s risk of developing breast cancer is related to her exposure to hormones that are produced by her ovaries (estrogen and progesterone). Reproductive factors that increase the duration and/or levels of exposure to ovarian hormones, which stimulate cell growth, have been associated with an increase in breast cancer risk. Pregnancy and breastfeeding both reduce a woman’s lifetime number of menstrual cycles, and thus her cumulative exposure to endogenous hormones. In addition, pregnancy and breastfeeding have direct effects on breast cells, causing them to differentiate, or mature, so they can produce milk. Some factors related to pregnancy may increase the risk of breast cancer. These factors include the following:

• Older age at birth of first child: Women who are older than 30 years-old when they give birth to their first child have a higher risk of breast cancer than women who have never given birth.
• Recent childbirth: Women who have recently given birth have a short-term increase in risk that declines after about 10 years. The reason for this temporary increase is not known, but it is believed that it may be due to the effect of high levels of hormones on microscopic cancers or to the rapid growth of breast cells during pregnancy.
• Taking diethylstilbestrol (DES) during pregnancy: Women who took DES during pregnancy have a slightly higher risk of developing breast cancer than women who did not take DES during pregnancy. Daughters of women who took DES during pregnancy may also have a slightly higher risk of developing breast cancer after age 40 than women who were not exposed to DES while in the womb.
• Abortion and miscarriage: The evidence does not support early termination of pregnancy as a cause of breast cancer.^[18]
• Women who have had a full-term pregnancy have reduced risks of ovarian cancer and endometrial cancer. The risks of these cancers decline with each additional full-term pregnancy.

Information below is based on the National Cancer Institute Cancer Prevention Overview: Risk Factors page.^[1]

Studies have shown that physically active people have a lower risk of certain cancers than those who are not. It is not known if physical activity itself is the reason for this. Physical activity has been associated with a lower risk of the following cancers:

• Colorectal cancer
• Postmenopausal breast cancer
• Endometrial cancer

Information below is based on the National Cancer Institute Cancer Prevention Overview: Risk Factors page.^[1]

• Studies show that obesity is linked to a higher risk of the following types of cancer:

• Postmenopausal breast cancer
• Colorectal cancer
• Endometrial cancer
• Esophageal cancer
• Kidney cancer
• Pancreatic cancer
• Some studies have shown obesity a risk factor for gallbladder cancer

• It is not known if losing weight lowers the risk of cancer

Information below is based on the National Cancer Institute Cancer Prevention Overview: Risk Factors page.^[1]

Being exposed to chemicals and other substances in the environment has been linked to some cancers:

• Air pollution as a cancer risk factor has been demonstrated. These includes:

• Association between lung cancer and secondhand smoke, outdoor air pollution, and asbestos
• Association between drinking water that contains a large amount of arsenic and skin cancer, bladder cancer, and lung cancer
• There are inconclusive results from studies performed to see if pesticides and other pollutants increase the risk of cancer. The results of those studies have been unclear because other factors can change the results of the studies.

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Cancer screening is an attempt to detect unsuspected cancers in an asymptomatic population. Screening tests suitable for large numbers of healthy people must be relatively affordable, safe, noninvasive procedures with acceptably low rates of false positive results. If signs of cancer are detected, more definitive and invasive follow up tests are performed to confirm the diagnosis.

Screening for cancer can lead to earlier diagnosis in specific cases. Early diagnosis may lead to extended life, but may also falsely prolong the lead time to death through lead time bias or length time bias.

A number of different screening tests have been developed for different malignancies. Breast cancer screening can be done by breast self-examination, though this approach was discredited by a 2005 study in over 300,000 Chinese women. Screening for breast cancer with mammograms has been shown to reduce the average stage of diagnosis of breast cancer in a population. Stage of diagnosis in a country has been shown to decrease within ten years of introduction of mammographic screening programs. Colorectal cancer can be detected through fecal occult blood testing and colonoscopy, which reduces both colon cancer incidence and mortality, presumably through the detection and removal of pre-malignant polyps. Similarly, cervical cytology testing (using the Pap smear) leads to the identification and excision of precancerous lesions. Over time, such testing has been followed by a dramatic reduction of cervical cancer incidence and mortality. Testicular self-examination is recommended for men beginning at the age of 15 years to detect testicular cancer. Prostate cancer can be screened using a digital rectal exam along with prostate specific antigen (PSA) blood testing, though some authorities (such as the US Preventive Services Task Force) recommend against routinely screening all men.

Screening for cancer is controversial in cases when it is not yet known if the test actually saves lives. The controversy arises when it is not clear if the benefits of screening outweigh the risks of follow-up diagnostic tests and cancer treatments. For example: when screening for prostate cancer, the PSA test may detect small cancers that would never become life threatening, but once detected will lead to treatment. This situation, called overdiagnosis, puts men at risk for complications from unnecessary treatment such as surgery or radiation. Follow up procedures used to diagnose prostate cancer (prostate biopsy) may cause side effects, including bleeding and infection. Prostate cancer treatment may cause incontinence (inability to control urine flow) and erectile dysfunction (erections inadequate for intercourse). Similarly, for breast cancer, there have recently been criticisms that breast screening programs in some countries cause more problems than they solve. This is because screening of women in the general population will result in a large number of women with false positive results which require extensive follow-up investigations to exclude cancer, leading to having a high number-to-treat (or number-to-screen) to prevent or catch a single case of breast cancer early.

Cervical cancer screening via the Pap smear has the best cost-benefit profile of all the forms of cancer screening from a public health perspective as, being largely caused by a virus, it has clear risk factors (sexual contact), and the natural progression of cervical cancer is that it normally spreads slowly over a number of years therefore giving more time for the screening program to catch it early. Moreover, the test itself is easy to perform and relatively cheap.

For these reasons, it is important that the benefits and risks of diagnostic procedures and treatment be taken into account when considering whether to undertake cancer screening.

Use of medical imaging to search for cancer in people without clear symptoms is similarly marred with problems. There is a significant risk of detection of what has been recently called an incidentaloma – a benign lesion that may be interpreted as a malignancy and be subjected to potentially dangerous investigations. Recent studies of CT scan-based screening for lung cancer in smokers have had equivocal results, and systematic screening is not recommended as of July 2007. Randomized clinical trials of plain-film chest X-rays to screen for lung cancer in smokers have shown no benefit for this approach.

Canine cancer detection has shown promise, but is still in the early stages of research.

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Cancer has a reputation for being a deadly disease. While this certainly applies to certain particular types, the truths behind the historical connotations of cancer are increasingly being overturned by advances in medical care. Some types of cancer have a prognosis that is substantially better than nonmalignant diseases such as heart failure and stroke.

Progressive and disseminated malignant disease has a substantial impact on a cancer patient’s quality of life, and many cancer treatments (such as chemotherapy) may have severe side-effects. In the advanced stages of cancer, many patients need extensive care, affecting family members and friends. Palliative care solutions may include permanent or “respite” hospice nursing.

Cancer patients, for the first time in the history of oncology, are visibly returning to the athletic arena and workplace. Patients are living longer with either quiescent persistent disease or even complete, durable remissions. The stories of Lance Armstrong, who won the Tour de France after treatment for metastatic testicular cancer, or Tony Snow, who was working as the White House Press Secretary as of June, 2007 despite relapsed colon cancer, continue to be an inspiration to cancer patients everywhere.

Randomized controlled trials have examined the role of anticoagulation for the primary prevention of thrombosis among patients with cancer^[1][2].

The prediction of patients at high-risk of thrombosis in cancer has been reviewed^[3].

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