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Malignant transformation is the process by which cells acquire the properties of
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
. This may occur as a primary process in normal tissue, or secondarily as ''malignant degeneration'' of a previously existing
benign tumor A benign tumor is a mass of cells (tumor) that does not invade neighboring tissue or metastasize (spread throughout the body). Compared to malignant (cancerous) tumors, benign tumors generally have a slower growth rate. Benign tumors have re ...
.


Causes

There are many causes of primary malignant transformation, or
tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
. Most human cancers in the United States are caused by external factors, and these factors are largely avoidable. These factors were summarized by Doll and Peto in 1981, and were still considered to be valid in 2015. These factors are listed in the table. a Reproductive and sexual behaviors include: number of partners; age at first menstruation; zero versus one or more live births


Examples of diet-related malignant transformation


Diet and colon cancer

Colon cancer provides one example of the mechanisms by which diet, the top factor listed in the table, is an external factor in cancer. The Western diet of African Americans in the United States is associated with a yearly colon cancer rate of 65 per 100,000 individuals, while the high fiber/low fat diet of rural Native Africans in South Africa is associated with a yearly colon cancer rate of <5 per 100,000. Feeding the Western diet for two weeks to Native Africans increased their secondary bile acids, including carcinogenic
deoxycholic acid Deoxycholic acid is a bile acid. Deoxycholic acid is one of the secondary bile acids, which are metabolic byproducts of intestinal bacteria. The two primary bile acids secreted by the liver are cholic acid and chenodeoxycholic acid. Bacteria met ...
, by 400%, and also changed the colonic microbiota. Evidence reviewed by Sun and Kato indicates that differences in human colonic microbiota play an important role in the progression of colon cancer.


Diet and lung cancer

A second example, relating a dietary component to a cancer, is illustrated by lung cancer. Two large population-based studies were performed, one in Italy and one in the United States. In Italy, the study population consisted of two cohorts: the first, 1721 individuals diagnosed with lung cancer and no severe disease, and the second, 1918 control individuals with absence of lung cancer history or any advanced diseases. All individuals filled out a food frequency questionnaire including consumption of walnuts, hazelnuts, almonds, and peanuts, and indicating smoking status. In the United States, 495,785 members of
AARP AARP (formerly called the American Association of Retired Persons) is an interest group in the United States focusing on issues affecting those over the age of fifty. The organization said it had more than 38 million members in 2018. The magazin ...
were questioned on consumption of peanuts, walnuts, seeds, or other nuts in addition to other foods and smoking status. In this U.S. study 18,533 incident lung cancer cases were identified during up to 16 years of follow-up. Overall, individuals in the highest quintile of frequency of nut consumption had a 26% lower risk of lung cancer in the Italian study and a 14% lower risk of lung cancer in the U.S. study. Similar results were obtained among individuals who were smokers.


Due to tobacco

The most important chemical compounds in smoked tobacco that are
carcinogenic A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substan ...
are those that produce DNA damage since such damage appears to be the primary underlying cause of cancer. Cunningham et al. combined the microgram weight of the compound in the smoke of one cigarette with the known
genotoxic Genotoxicity is the property of chemical agents that damage the genetic information within a cell causing mutations, which may lead to cancer. While genotoxicity is often confused with Mutagen, mutagenicity, all mutagens are genotoxic, but some geno ...
effect per microgram to identify the most
carcinogenic A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substan ...
compounds in cigarette smoke. These compounds and their genotoxic effects are listed in the article
Cigarette A cigarette is a narrow cylinder containing a combustible material, typically tobacco, that is rolled into thin paper for smoking. The cigarette is ignited at one end, causing it to smolder; the resulting smoke is orally inhaled via the opp ...
. The top three compounds are
acrolein Acrolein (systematic name: propenal) is the simplest unsaturated aldehyde. It is a colorless liquid with a piercing, acrid smell. The smell of burnt fat (as when cooking oil is heated to its smoke point) is caused by glycerol in the burning fa ...
,
formaldehyde Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section F ...
and
acrylonitrile Acrylonitrile is an organic compound with the formula and the structure . It is a colorless, volatile liquid although commercial samples can be yellow due to impurities. It has a pungent odor of garlic or onions. In terms of its molecular ...
, all known
carcinogen A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substan ...
s.


Due to infection


Viruses

In 2002 the
World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
s
International Agency for Research on Cancer The International Agency for Research on Cancer (IARC; french: Centre International de Recherche sur le Cancer, CIRC) is an intergovernmental agency forming part of the World Health Organization of the United Nations. Its role is to conduct and ...
estimated that 11.9% of human cancers are caused by one of seven viruses (see Oncovirus overview table). These are Epstein-Barr virus (EBV or HHV4);
Kaposi's sarcoma-associated herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) is the ninth known human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses (ICTV) is ''Human gammaherpesvirus 8'', or HHV-8 in short. Like other herpesvirus ...
(KSHV or HHV8);
Hepatitis B Hepatitis B is an infectious disease caused by the ''Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during an initial infection. Fo ...
and
Hepatitis C Hepatitis C is an infectious disease caused by the hepatitis C virus (HCV) that primarily affects the liver; it is a type of viral hepatitis. During the initial infection people often have mild or no symptoms. Occasionally a fever, dark urine, a ...
viruses (HBV and HCV);
Human T-lymphotrophic virus The human T-lymphotropic virus, human T-cell lymphotropic virus, or human T-cell leukemia-lymphoma virus (HTLV) family of viruses are a group of human retroviruses that are known to cause a type of cancer called adult T-cell leukemia/lymphoma an ...
1 (HTLV-1);
Merkel cell polyomavirus Merkel cell polyomavirus (MCV or MCPyV) was first described in January 2008 in Pittsburgh, Pennsylvania. It was the first example of a human viral pathogen discovered using unbiased metagenomic next-generation sequencing with a technique called d ...
(MCPyV); and a group of alpha
Human papillomaviruses Human papillomavirus infection (HPV infection) is caused by a DNA virus from the '' Papillomaviridae'' family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and re ...
(HPVs).


Bacteria


''Helicobacter pylori'' and gastric cancer

In 1995 epidemiologic evidence indicated that ''Helicobacter pylori'' infection increases the risk for gastric carcinoma. More recently, experimental evidence showed that infection with ''
Helicobacter pylori ''Helicobacter pylori'', previously known as ''Campylobacter pylori'', is a gram-negative, microaerophilic, spiral (helical) bacterium usually found in the stomach. Its helical shape (from which the genus name, helicobacter, derives) is though ...
'' cagA-positive bacterial strains results in severe degrees of inflammation and oxidative DNA damage, leading to progression to gastric cancer.


Other bacterial roles in carcinogenesis

Perera et al. referred to a number of articles pointing to roles of bacteria in other cancers. They pointed to single studies on the role of ''Chlamydia trachomatis'' in cervical cancer, ''Salmonella typhi'' in gallbladder cancer, and both ''Bacteroides fragilis'' and ''Fusobacterium nucleatum'' in colon cancer. Meurman has recently summarized evidence connecting oral microbiota with carcinogenesis. Although suggestive, these studies need further confirmation.


Common underlying factors in cancer


Mutations

One underlying commonality in cancers is genetic mutation, acquired either by inheritance, or, more commonly, by mutations in one's
somatic Somatic may refer to: * Somatic (biology), referring to the cells of the body in contrast to the germ line cells ** Somatic cell, a non-gametic cell in a multicellular organism * Somatic nervous system, the portion of the vertebrate nervous sys ...
DNA over time. The mutations considered important in cancers are those that alter protein coding genes (the
exome The exome is composed of all of the exons within the genome, the sequences which, when transcribed, remain within the mature RNA after introns are removed by RNA splicing. This includes untranslated regions of messenger RNA (mRNA), and coding r ...
). As Vogelstein et al. point out, a typical tumor contains two to eight exome "driver gene" mutations, and a larger number of exome mutations that are "passengers" that confer no selective growth advantage. Cancers also generally have
genome instability Genome instability (also genetic instability or genomic instability) refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneu ...
, that includes a high frequency of mutations in the
noncoding DNA Non-coding DNA (ncDNA) sequences are components of an organism's DNA that do not encode protein sequences. Some non-coding DNA is transcribed into functional non-coding RNA molecules (e.g. transfer RNA, microRNA, piRNA, ribosomal RNA, and regul ...
that makes up about 98% of the human genome. The average number of DNA sequence mutations in the entire genome of breast cancer tissue is about 20,000. In an average melanoma (where melanomas have a higher
exome The exome is composed of all of the exons within the genome, the sequences which, when transcribed, remain within the mature RNA after introns are removed by RNA splicing. This includes untranslated regions of messenger RNA (mRNA), and coding r ...
mutation frequency) the total number of DNA sequence mutations is about 80,000.


Epigenetic alterations


Transcription silencing

A second underlying commonality in cancers is altered
epigenetic In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
regulation of transcription. In cancers, loss of
gene expression Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce end products, protein or non-coding RNA, and ultimately affect a phenotype, as the final effect. The ...
occurs about 10 times more frequently by epigenetic transcription silencing (caused, for example, by promoter hypermethylation of CpG islands) than by mutations. As Vogelstein et al. point out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66
hitchhiker Hitchhiking (also known as thumbing, autostop or hitching) is a means of transportation that is gained by asking individuals, usually strangers, for a ride in their car or other vehicle. The ride is usually, but not always, free. Nomads hav ...
, or passenger, mutations. In contrast, the frequency of
epigenetic In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
alterations is much higher. In colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated
CpG islands The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG isl ...
in promoters of genes in the tumors while the corresponding CpG islands are not methylated in the adjacent mucosa. Such methylation turns off expression of a gene as completely as a mutation would. Around 60–70% of human genes have a CpG island in their promoter region. In colon cancers, in addition to hypermethylated genes, several hundred other genes have hypomethylated (under-methylated) promoters, thereby causing these genes to be turned on when they ordinarily would be turned off.


Post-transcriptional silencing

Epigenetic alterations are also carried out by another major regulatory element, that of
microRNA MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRN ...
s (miRNAs). In mammals, these small
non-coding RNA A non-coding RNA (ncRNA) is a functional RNA molecule that is not Translation (genetics), translated into a protein. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene. Abundant and functionally im ...
molecules regulate about 60% of the transcriptional activity of protein-encoding genes. Epigenetic silencing or epigenetic over-expression of miRNA genes, caused by aberrant DNA methylation of the promoter regions controlling their expression, is a frequent event in cancer cells. Almost one third of miRNA promoters active in normal mammary cells were found to be hypermethylated in breast cancer cells, and that is a several fold greater proportion of promoters with altered methylation than is usually observed for protein coding genes. Other microRNA promoters are hypomethylated in breast cancers, and, as a result, these microRNAs are over-expressed. Several of these over-expressed microRNAs have a major influence in progression to breast cancer.
BRCA1 Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a h ...
is normally expressed in the cells of
breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and secret ...
and other tissue, where it helps repair damaged DNA, or destroy cells if DNA cannot be repaired. BRCA1 is involved in the repair of
chromosomal A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...
damage with an important role in the error-free repair of DNA double-strand breaks.
BRCA1 Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a h ...
expression is reduced or undetectable in the majority of high grade, ductal breast cancers. Only about 3–8% of all women with breast cancer carry a mutation in BRCA1 or BRCA2. ''BRCA1''
promoter hypermethylation Promoter or Promotor may refer to: Art, entertainment, and media * ''The Promoter'' (1952), also known as ''The Card'' * ''The Promoter'' (2012 film) Professions * Promoter (entertainment), one who makes arrangements for events or markets them ...
was present in only 13% of unselected primary breast carcinomas. However, breast cancers were found to have an average of about 100-fold increase in miR-182, compared to normal breast tissue. In breast cancer cell lines, there is an inverse correlation of
BRCA1 Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the ''BRCA1'' () gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. ''BRCA1'' is a h ...
protein levels with miR-182 expression. Thus it appears that much of the reduction or absence of BRCA1 in high grade ductal breast cancers may be due to over-expressed miR-182. In addition to miR-182, a pair of almost identical microRNAs, miR-146a and miR-146b-5p, also repress BRCA1 expression. These two microRNAs are over-expressed in triple-negative tumors and their over-expression results in BRCA1 inactivation. Thus, miR-146a and/or miR-146b-5p may also contribute to reduced expression of BRCA1 in these triple-negative breast cancers.
Post-transcriptional regulation Post-transcriptional regulation is the control of gene expression at the RNA level. It occurs once the RNA polymerase has been attached to the gene's promoter and is synthesizing the nucleotide sequence. Therefore, as the name indicates, it occ ...
by microRNA occurs either through translational silencing of the target mRNA or through degradation of the target mRNA, via complementary binding, mostly to specific sequences in the
three prime untranslated region In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally ...
of the target gene's mRNA. The mechanism of translational silencing or degradation of target mRNA is implemented through the
RNA-induced silencing complex The RNA-induced silencing complex, or RISC, is a multiprotein complex, specifically a ribonucleoprotein, which functions in gene silencing via a variety of pathways at the transcriptional and translational levels. Using single-stranded RNA (ssRNA) ...
(RISC).


DNA repair gene silencing

Silencing of a DNA repair gene by
hypermethylation In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These t ...
or other
epigenetic In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
alteration appears to be a frequent step in progression to cancer. As summarized in a review, promoter hypermethylation of DNA repair gene ''
MGMT MGMT () is an American indie rock band formed in 2002 in Middletown, Connecticut. It was founded by multi-instrumentalists Andrew VanWyngarden and Ben Goldwasser. Alongside VanWyngarden and Goldwasser, MGMT's live lineup currently consists of ...
'' occurs in 93% of bladder cancers, 88% of stomach cancers, 74% of thyroid cancers, 40%-90% of colorectal cancers and 50% of brain cancers. In addition, promoter hypermethylation of DNA repair genes ''
LIG4 DNA ligase 4 is an enzyme that in humans is encoded by the LIG4 gene. Function The protein encoded by this gene is an ATP-dependent DNA ligase that joins double-strand breaks during the non-homologous end joining pathway of double-strand break ...
'', '' NEIL1'', '' ATM'', ''
MLH1 DNA mismatch repair protein Mlh1 or MutL protein homolog 1 is a protein that in humans is encoded by the MLH1 gene located on chromosome 3. It is a gene commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH1 h ...
'' or ''
FANCB Fanconi anemia group B protein is a protein that in humans is encoded by the ''FANCB'' gene. Function The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF ...
'' occurs at frequencies between 33% to 82% in one or more of
head and neck cancer Head and neck cancer develops from tissues in the lip and oral cavity (mouth), larynx (throat), salivary glands, nose, sinuses or the skin of the face. The most common types of head and neck cancers occur in the lip, mouth, and larynx. Symptoms ...
s,
non-small-cell lung cancer Non-small-cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to sm ...
s or
non-small-cell lung cancer Non-small-cell lung cancer (NSCLC) is any type of epithelial lung cancer other than small-cell lung carcinoma (SCLC). NSCLC accounts for about 85% of all lung cancers. As a class, NSCLCs are relatively insensitive to chemotherapy, compared to sm ...
squamous cell carcinomas. Further, the article
Werner syndrome ATP-dependent helicase Werner may refer to: People * Werner (name), origin of the name and people with this name as surname and given name Fictional characters * Werner (comics), a German comic book character * Werner Von Croy, a fictional character in the ''Tomb Rai ...
indicates the DNA repair gene '' WRN'' has a promoter that is often hypermethylated in a variety of cancers, with ''WRN'' hypermethylation occurring in 11% to 38% of
colorectal The large intestine, also known as the large bowel, is the last part of the gastrointestinal tract and of the digestive system in tetrapods. Water is absorbed here and the remaining waste material is stored in the rectum as feces before being ...
,
head and neck This article describes the anatomy of the head and neck of the human body, including the brain, bones, muscles, blood vessels, nerves, glands, nose, mouth, teeth, tongue, and throat. Structure Bones The head rests on the top part of the vertebra ...
,
stomach The stomach is a muscular, hollow organ in the gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...
,
prostate The prostate is both an Male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, ...
,
breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and secret ...
,
thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...
,
non-Hodgkin lymphoma Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredness. ...
,
chondrosarcoma Chondrosarcoma is a bone sarcoma, a primary cancer composed of cells derived from transformed cells that produce cartilage. A chondrosarcoma is a member of a category of tumors of bone and soft tissue known as sarcomas. About 30% of bone sarcomas ...
and
osteosarcoma An osteosarcoma (OS) or osteogenic sarcoma (OGS) (or simply bone cancer) is a cancerous tumor in a bone. Specifically, it is an aggressive malignant neoplasm that arises from primitive transformed cells of mesenchymal origin (and thus a sarcoma) a ...
cancers. Such silencing likely acts similarly to a germ-line mutation in a DNA repair gene, and predisposes the cell and its descendants to progression to cancer. Another review points out that when a gene necessary for DNA repair is epigenetically silenced, DNA repair would tend to be deficient and DNA damages can accumulate. Increased DNA damage can cause increased errors during DNA synthesis, leading to mutations that give rise to cancer.


Induced by heavy metals

The heavy metals
cadmium Cadmium is a chemical element with the symbol Cd and atomic number 48. This soft, silvery-white metal is chemically similar to the two other stable metals in group 12, zinc and mercury. Like zinc, it demonstrates oxidation state +2 in most of ...
,
arsenic Arsenic is a chemical element with the symbol As and atomic number 33. Arsenic occurs in many minerals, usually in combination with sulfur and metals, but also as a pure elemental crystal. Arsenic is a metalloid. It has various allotropes, but ...
and
nickel Nickel is a chemical element with symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel is a hard and ductile transition metal. Pure nickel is chemically reactive but large pieces are slow to ...
are all carcinogenic when present above certain levels. Cadmium is known to be carcinogenic, possibly due to reduction of DNA repair. Lei et al. evaluated five DNA repair genes in rats after exposure of the rats to low levels of cadmium. They found that cadmium caused repression of three of the DNA repair genes:
XRCC1 DNA repair protein XRCC1, also known as X-ray repair cross-complementing protein 1, is a protein that in humans is encoded by the ''XRCC1'' gene. XRCC1 is involved in DNA repair, where it complexes with DNA ligase III. Function XRCC1 is invol ...
needed for
base excision repair Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from t ...
, OGG1 needed for base excision repair, and
ERCC1 DNA excision repair protein ERCC-1 is a protein that in humans is encoded by the ''ERCC1'' gene. Together with ERCC4, ERCC1 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination. Many aspects of these two gene ...
needed for
nucleotide excision repair Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly because of chemicals (e.g. intercalating agents), radiation and other mutagens. Three excision repair pathways exist to repair single stranded DNA damage: Nucle ...
. Repression of these genes was not due to methylation of their promoters. Arsenic carcinogenicity was reviewed by Bhattacharjee et al. They summarized the role of arsenic and its metabolites in generating oxidative stress, resulting in DNA damage. In addition to causing DNA damage, arsenic also causes repression of several DNA repair enzymes in both the base excision repair pathway and the
nucleotide excision repair Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly because of chemicals (e.g. intercalating agents), radiation and other mutagens. Three excision repair pathways exist to repair single stranded DNA damage: Nucle ...
pathway. Bhattacharjee et al. further reviewed the role of arsenic in causing telomere dysfunction, mitotic arrest, defective apoptosis, as well as altered promoter methylation and miRNA expression. Each of these alterations could contribute to arsenic-induced carcinogenesis. Nickel compounds are carcinogenic and occupational exposure to nickel is associated with an increased risk of lung and nasal cancers. Nickel compounds exhibit weak mutagenic activity, but they considerably alter the transcriptional landscape of the DNA of exposed individuals. Arita et al. examined the
peripheral blood mononuclear cell A peripheral blood mononuclear cell (PBMC) is any peripheral blood cell having a round nucleus. These cells consist of lymphocytes (T cells, B cells, NK cells) and monocytes, whereas erythrocytes and platelets have no nuclei, and granulocytes ( ...
s of eight nickel-refinery workers and ten non-exposed workers. They found 2756 differentially expressed genes with 770 up-regulated genes and 1986 down-regulated genes. DNA repair genes were significantly over-represented among the differentially expressed genes, with 29 DNA repair genes repressed in the nickel-refinery workers and two over-expressed. The alterations in gene expression appear to be due to epigenetic alterations of histones, methylations of gene promoters, and hypermethylation of at least microRNA miR-152.


Clinical signs

Malignant transformation of cells in a benign tumor may be detected by
pathologic ''Pathologic'' ( rus, Мор. Утопия, Mor. Utopiya, ˈmor ʊˈtopʲɪjə, , More. Utopia – a pun on Thomas More's ''Utopia'' and the Russian word for "plague") is a 2005 role-playing and survival game developed by Russian studio Ice-Pic ...
examination of tissues. Often the clinical signs and symptoms are suggestive of a malignant tumor. The physician, during the
medical history The medical history, case history, or anamnesis (from Greek: ἀνά, ''aná'', "open", and μνήσις, ''mnesis'', "memory") of a patient is information gained by a physician by asking specific questions, either to the patient or to other peo ...
examination, can find that there have been changes in size or patient sensation and, upon direct examination, that there has been a change in the
lesion A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or trauma. ''Lesion'' is derived from the Latin "injury". Lesions may occur in plants as well as animals. Types There is no designated classifi ...
itself.
Risk assessment Broadly speaking, a risk assessment is the combined effort of: # identifying and analyzing potential (future) events that may negatively impact individuals, assets, and/or the environment (i.e. hazard analysis); and # making judgments "on the to ...
s can be done and are known for certain types of benign tumor which are known to undergo malignant transformation. One of the better-known examples of this phenomenon is the progression of a
nevus Nevus (plural nevi) is a nonspecific medical term for a visible, circumscribed, chronic lesion of the skin or mucosa. The term originates from ''nævus'', which is Latin for "birthmark"; however, a nevus can be either congenital (present at bir ...
to
melanoma Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
.


See also

* Abortive transformation


References

* * * {{DEFAULTSORT:Malignant Transformation Carcinogenesis Cellular processes