Editing Cancer (section)

== Pathophysiology ==
{{Main|Carcinogenesis}}

=== Genetics ===
{{Main|Oncogenomics}}
[[File:Cancer requires multiple mutations from NIHen.png|thumb|upright|Cancers are caused by a series of mutations. Each mutation alters the behavior of the cell somewhat.]]
Cancer is fundamentally a disease of tissue growth regulation. For a normal cell to [[malignant transformation|transform]] into a cancer cell, the [[gene]]s that regulate cell growth and differentiation must be altered.<ref name="pmid18234754">{{cite journal |vauthors=Croce CM |s2cid=8813076 |title=Oncogenes and cancer |journal=The New England Journal of Medicine |volume=358 |issue=5 |pages=502–11 |date=January 2008 |pmid=18234754 |doi=10.1056/NEJMra072367}}</ref>

The affected genes are divided into two broad categories. [[Oncogene]]s are genes that promote cell growth and reproduction. [[Tumor suppressor gene]]s are genes that inhibit cell division and survival. Malignant transformation can occur through the formation of novel oncogenes, the inappropriate over-expression of normal oncogenes, or by the under-expression or disabling of tumor suppressor genes. Typically, changes in multiple genes are required to transform a normal cell into a cancer cell.<ref name="pmid11905807">{{cite journal |vauthors=Knudson AG |s2cid=20201610 |title=Two genetic hits (more or less) to cancer |journal=Nature Reviews. Cancer |volume=1 |issue=2 |pages=157–62 |date=November 2001 |pmid=11905807 |doi=10.1038/35101031}}</ref>

Genetic changes can occur at different levels and by different mechanisms. The gain or loss of an entire [[chromosome]] can occur through errors in [[mitosis]]. More common are [[mutation]]s, which are changes in the [[nucleotide]] sequence of genomic DNA.

Large-scale mutations involve the deletion or gain of a portion of a chromosome. [[Gene duplication|Genomic amplification]] occurs when a cell gains copies (often 20 or more) of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material. [[Chromosomal translocation|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 (gene)|BCR]]-[[aBL (gene)|abl]] [[fusion protein]], an oncogenic [[tyrosine kinase]].

Small-scale mutations include point mutations, deletions, and insertions, which may occur in the [[promoter (genetics)|promoter]] region of a gene and affect its [[gene expression|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 [[provirus|integration of genomic material]] from a [[DNA virus]] or [[retrovirus]], leading to the expression of ''viral'' oncogenes in the affected cell and its descendants.

Replication of the data contained within the DNA of living cells will [[probability|probabilistically]] result in some errors (mutations). Complex error correction and prevention are built into the process and safeguard the cell against cancer. If a significant error occurs, the damaged cell can self-destruct through programmed cell death, termed [[apoptosis]]. If the error control processes fail, then the mutations will survive and be passed along to [[cell division|daughter cells]].

Some environments make errors more likely to arise and propagate. Such environments can include the presence of disruptive substances called [[carcinogen]]s, repeated physical injury, heat, ionising radiation, or [[hypoxia (medical)|hypoxia]].<ref>{{cite journal |vauthors=Nelson DA, Tan TT, Rabson AB, Anderson D, Degenhardt K, White E |title=Hypoxia and defective apoptosis drive genomic instability and tumorigenesis |journal=Genes & Development |volume=18 |issue=17 |pages=2095–107 |date=September 2004 |pmid=15314031 |pmc=515288 |doi=10.1101/gad.1204904}}</ref>

The errors that cause cancer are self-amplifying and compounding, for example:
* A mutation in the error-correcting machinery of a cell might cause that cell and its children to accumulate errors more rapidly.
* A further mutation in an oncogene might cause the cell to reproduce more rapidly and more frequently than its normal counterparts.
* A further mutation may cause the loss of a tumor suppressor gene, disrupting the apoptosis signaling pathway and immortalizing the cell.
* A further mutation in the signaling machinery of the cell might send error-causing signals to nearby cells.

The transformation of a normal cell into cancer is akin to a [[chain reaction]] caused by initial errors, which compound into more severe errors, each progressively allowing the cell to escape more controls that limit normal tissue growth. This rebellion-like scenario is an undesirable [[survival of the fittest]], where the driving forces of [[evolution]] work against the body's design and enforcement of order. Once cancer has begun to develop, this ongoing process, termed ''[[Somatic evolution in cancer|clonal evolution]]'', drives progression towards more invasive [[cancer staging|stages]].<ref name="pmid17109012">{{cite journal |vauthors=Merlo LM, Pepper JW, Reid BJ, Maley CC |s2cid=8040576 |title=Cancer as an evolutionary and ecological process |journal=Nature Reviews. Cancer |volume=6 |issue=12 |pages=924–35 |date=December 2006 |pmid=17109012 |doi=10.1038/nrc2013}}</ref> Clonal evolution leads to intra-[[tumour heterogeneity]] (cancer cells with heterogeneous mutations) that complicates designing effective treatment strategies and requires an [[Evolutionary therapy|evolutionary approach to designing treatment]].

Characteristic abilities developed by cancers are divided into categories, specifically evasion of apoptosis, self-sufficiency in growth signals, insensitivity to anti-growth signals, sustained angiogenesis, limitless replicative potential, metastasis, reprogramming of energy metabolism and evasion of immune destruction.<ref name=Han2000/><ref name=Han2011/>

=== Epigenetics ===
{{Main|Cancer epigenetics}}
[[File:Diagram Damage to Cancer Wiki 300dpi.svg|thumb|upright=1.35|The central role of DNA damage and epigenetic defects in DNA repair genes in carcinogenesis]]

The classical view of cancer is a set of diseases driven by progressive [[Genetics|genetic]] [[abnormalities]] that include mutations in tumor-suppressor genes and [[oncogene]]s, and in [[chromosome|chromosomal]] abnormalities. A role for [[Epigenetics|epigenetic alterations]] was identified in the early 21st century.<ref>{{cite journal |vauthors=Baylin SB, Ohm JE |s2cid=2514545 |title=Epigenetic gene silencing in cancer – a mechanism for early oncogenic pathway addiction? |journal=Nature Reviews. Cancer |volume=6 |issue=2 |pages=107–16 |date=February 2006 |pmid=16491070 |doi=10.1038/nrc1799}}</ref>

[[Epigenetics|Epigenetic]] alterations are functionally relevant modifications to the genome that do not change the nucleotide sequence. Examples of such modifications are changes in [[DNA methylation]] (hypermethylation and hypomethylation), [[histone modification]]<ref>{{cite journal |vauthors=Kanwal R, Gupta S |title=Epigenetic modifications in cancer |journal=Clinical Genetics |volume=81 |issue=4 |pages=303–11 |date=April 2012 |pmid=22082348 |pmc=3590802 |doi=10.1111/j.1399-0004.2011.01809.x}}</ref> and changes in chromosomal architecture (caused by inappropriate expression of proteins such as [[HMGA2]] or [[HMGA1]]).<ref>{{cite journal |vauthors=Baldassarre G, Battista S, Belletti B, Thakur S, Pentimalli F, Trapasso F, Fedele M, Pierantoni G, Croce CM, Fusco A |title=Negative regulation of BRCA1 gene expression by HMGA1 proteins accounts for the reduced BRCA1 protein levels in sporadic breast carcinoma |journal=Molecular and Cellular Biology |volume=23 |issue=7 |pages=2225–38 |date=April 2003 |pmid=12640109 |pmc=150734 |doi=10.1128/MCB.23.7.2225-2238.2003}}/</ref> Each of these alterations regulates gene expression without altering the underlying [[DNA sequence]]. These changes may remain through [[cell division]]s, endure for multiple generations, and can be considered as equivalent to mutations.

Epigenetic alterations occur frequently in cancers. As an example, one study listed protein coding genes that were frequently altered in their [[methylation]] in association with colon cancer. These included 147 hypermethylated and 27 hypomethylated genes. Of the hypermethylated genes, 10 were hypermethylated in 100% of colon cancers and many others were hypermethylated in more than 50% of colon cancers.<ref name="Sch">{{cite journal |vauthors=Schnekenburger M, Diederich M |title=Epigenetics Offer New Horizons for Colorectal Cancer Prevention |journal=Current Colorectal Cancer Reports |volume=8 |issue=1 |pages=66–81 |date=March 2012 |pmid=22389639 |pmc=3277709 |doi=10.1007/s11888-011-0116-z}}</ref>

While epigenetic alterations are found in cancers, the epigenetic alterations in DNA repair genes, causing reduced expression of DNA repair proteins, may be of particular importance. Such alterations may occur early in the progression to cancer and are a possible cause of the [[Genome instability|genetic]] instability characteristic of cancers.<ref>{{cite journal |vauthors=Jacinto FV, Esteller M |title=Mutator pathways unleashed by epigenetic silencing in human cancer |journal=Mutagenesis |volume=22 |issue=4 |pages=247–53 |date=July 2007 |pmid=17412712 |doi=10.1093/mutage/gem009|doi-access=free }}</ref><ref>{{cite journal |vauthors=Lahtz C, Pfeifer GP |title=Epigenetic changes of DNA repair genes in cancer |journal=Journal of Molecular Cell Biology |volume=3 |issue=1 |pages=51–8 |date=February 2011 |pmid=21278452 |pmc=3030973 |doi=10.1093/jmcb/mjq053}}</ref><ref>{{cite journal |vauthors=Bernstein C, Nfonsam V, Prasad AR, Bernstein H |title=Epigenetic field defects in progression to cancer |journal=World Journal of Gastrointestinal Oncology |volume=5 |issue=3 |pages=43–49 |date=March 2013 |pmid=23671730 |pmc=3648662 |doi=10.4251/wjgo.v5.i3.43 |doi-access=free }}</ref>

Reduced expression of DNA repair genes disrupts DNA repair. This is shown in the figure at the 4th level from the top. (In the figure, red wording indicates the central role of DNA damage and defects in DNA repair in the progression to cancer.) When DNA repair is deficient DNA damage remains in cells at a higher than usual level (5th level) and causes increased frequencies of mutation and/or epimutation (6th level). Mutation rates increase substantially in cells defective in [[DNA mismatch repair]]<ref>{{cite journal |vauthors=Narayanan L, Fritzell JA, Baker SM, Liskay RM, Glazer PM |title=Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2 |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=94 |issue=7 |pages=3122–27 |date=April 1997 |pmid=9096356 |pmc=20332 |doi=10.1073/pnas.94.7.3122|bibcode=1997PNAS...94.3122N |doi-access=free }}</ref><ref>{{cite journal |vauthors=Hegan DC, Narayanan L, Jirik FR, Edelmann W, Liskay RM, Glazer PM |title=Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6 |journal=Carcinogenesis |volume=27 |issue=12 |pages=2402–08 |date=December 2006 |pmid=16728433 |pmc=2612936 |doi=10.1093/carcin/bgl079}}</ref> or in [[homologous recombination]]al repair (HRR).<ref>{{cite journal |vauthors=Tutt AN, van Oostrom CT, Ross GM, van Steeg H, Ashworth A |title=Disruption of Brca2 increases the spontaneous mutation rate in vivo: synergism with ionizing radiation |journal=EMBO Reports |volume=3 |issue=3 |pages=255–60 |date=March 2002 |pmid=11850397 |pmc=1084010 |doi=10.1093/embo-reports/kvf037}}</ref> Chromosomal rearrangements and aneuploidy also increase in HRR defective cells.<ref>{{cite journal |vauthors=German J |title=Bloom's syndrome. I. Genetical and clinical observations in the first twenty-seven patients |journal=American Journal of Human Genetics |volume=21 |issue=2 |pages=196–227 |date=March 1969 |pmid=5770175 |pmc=1706430}}</ref>

Higher levels of DNA damage cause increased mutation (right side of figure) and increased epimutation. During repair of DNA double strand breaks, or repair of other DNA damage, incompletely cleared repair sites can cause epigenetic gene silencing.<ref>{{cite journal |vauthors=O'Hagan HM, Mohammad HP, Baylin SB |title=Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island |journal=PLOS Genetics |volume=4 |issue=8 |pages=e1000155 |date=August 2008 |pmid=18704159 |pmc=2491723 |doi=10.1371/journal.pgen.1000155 | veditors = Lee JT |doi-access=free }}</ref><ref>{{cite journal |vauthors=Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A, Messina S, Iuliano R, Fusco A, Santillo MR, Muller MT, Chiariotti L, Gottesman ME, Avvedimento EV |title=DNA damage, homology-directed repair, and DNA methylation |journal=PLOS Genetics |volume=3 |issue=7 |pages=e110 |date=July 2007 |pmid=17616978 |pmc=1913100 |doi=10.1371/journal.pgen.0030110 |doi-access=free }}</ref>

Deficient expression of DNA repair proteins due to an inherited mutation can increase cancer risks. Individuals with an inherited impairment in any of 34 DNA repair genes (see article [[DNA repair-deficiency disorder]]) have increased cancer risk, with some defects ensuring a 100% lifetime chance of cancer (e.g. p53 mutations).<ref>{{cite journal |vauthors=Malkin D |title=Li-fraumeni syndrome |journal=Genes & Cancer |volume=2 |issue=4 |pages=475–84 |date=April 2011 |pmid=21779515 |pmc=3135649 |doi=10.1177/1947601911413466}}</ref> Germline DNA repair mutations are noted on the figure's left side. However, such [[germline]] mutations (which cause highly penetrant cancer syndromes) are the cause of only about 1 percent of cancers.<ref>{{cite journal |vauthors=Fearon ER |title=Human cancer syndromes: clues to the origin and nature of cancer |journal=Science |volume=278 |issue=5340 |pages=1043–50 |date=November 1997 |pmid=9353177 |doi=10.1126/science.278.5340.1043|bibcode=1997Sci...278.1043F }}</ref>

In sporadic cancers, deficiencies in DNA repair are occasionally caused by a mutation in a DNA repair gene but are much more frequently caused by epigenetic alterations that reduce or silence expression of DNA repair genes. This is indicated in the figure at the 3rd level. Many studies of heavy metal-induced carcinogenesis show that such heavy metals cause a reduction in expression of DNA repair enzymes, some through epigenetic mechanisms. DNA repair inhibition is proposed to be a predominant mechanism in heavy metal-induced carcinogenicity. In addition, frequent epigenetic alterations of the DNA sequences code for small RNAs called [[microRNA]]s (or miRNAs). miRNAs do not code for proteins, but can "target" protein-coding genes and reduce their expression.

Cancers usually arise from an assemblage of mutations and epimutations that confer a selective advantage leading to clonal expansion (see [[Neoplasm#Field defects in progression to cancer|Field defects in progression to cancer]]). Mutations, however, may not be as frequent in cancers as epigenetic alterations. An average cancer of the breast or colon can have about 60 to 70 protein-altering mutations, of which about three or four may be "driver" mutations and the remaining ones may be "passenger" mutations.<ref>{{cite journal |vauthors=Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz LA, Kinzler KW |title=Cancer genome landscapes |journal=Science |volume=339 |issue=6127 |pages=1546–58 |date=March 2013 |pmid=23539594 |pmc=3749880 |doi=10.1126/science.1235122|bibcode=2013Sci...339.1546V }}</ref>

=== Metastasis ===
{{Main|Metastasis}}
[[Metastasis]] is the spread of cancer to other locations in the body. The dispersed tumors are called metastatic tumors, while the original is called the primary tumor. Almost all cancers can metastasize.<ref name=metastasis/> Most cancer deaths are due to cancer that has metastasized.<ref name="What is Metastasized Cancer"/>

Metastasis is common in the late stages of cancer and it can occur via the blood or the [[lymphatic system]] or both. The typical steps in metastasis are local [[Invasion (cancer)|invasion]], [[intravasation]] into the blood or lymph, circulation through the body, [[extravasation]] into the new tissue, proliferation and [[angiogenesis]]. Different types of cancers tend to metastasize to particular organs, but overall the most common places for metastases to occur are the [[lung]]s, [[liver]], brain and the [[bone]]s.<ref name=metastasis/>

=== Metabolism ===
{{Main|Tumor metabolome}}

Normal cells typically generate only about 30% of energy from [[glycolysis]],<ref name="pmid23226794">{{cite journal | vauthors = Zheng J | title=Energy metabolism of cancer: Glycolysis versus oxidative phosphorylation (Review) | journal=[[Oncology Letters]] | volume=4 | issue=6 | pages=1151–1157 | year=2012  | doi = 10.3892/ol.2012.928 | pmc= 3506713 | pmid=23226794}}</ref> whereas most cancers rely on glycolysis for energy production ([[Warburg effect (oncology)|Warburg effect]]).<ref name="pmid20181022">{{cite journal | vauthors = Seyfried TN, Shelton LM | title=Cancer as a metabolic disease | journal=Nutrition & Metabolism | volume=7 | page=7 | year=2010  | doi = 10.1186/1743-7075-7-7 | pmc= 2845135 | pmid=20181022 | doi-access=free }}</ref><ref name="pmid31781842">{{cite journal | vauthors = Weiss JM | title=The promise and peril of targeting cell metabolism for cancer therapy | journal=[[Cancer Immunology, Immunotherapy]] | volume=69 | issue=2 | pages=255–261 | year=2020  | doi = 10.1007/s00262-019-02432-7 | pmc= 7004869 | pmid=31781842}}</ref> But a minority of cancer types rely on [[oxidative phosphorylation]] as the primary energy source, including [[lymphoma]], [[leukemia]], and [[endometrial cancer]].<ref name="pmid33028168">{{cite journal | vauthors = Farhadi P, Yarani R, Dokaneheifard S, Mansouri K  | title = The emerging role of targeting cancer metabolism for cancer therapy | journal = [[Tumor Biology]] | volume = 42 | issue = 10 | page = 1010428320965284 | year = 2020 | doi = 10.1177/1010428320965284 | pmid = 33028168 | s2cid = 222214285 | doi-access = free }}</ref> Even in these cases, however, the use of glycolysis as an energy source rarely exceeds 60%.<ref name=pmid23226794/> A few cancers use [[glutamine]] as the major energy source, partly because it provides nitrogen required for [[nucleotide]] (DNA, RNA) synthesis.<ref name="pmid26771115">{{cite journal | vauthors=Pavlova NN, Thompson CB | title=The Emerging Hallmarks of Cancer Metabolism | journal=[[Cell Metabolism]] | volume=23 | issue=1 | pages=27–47 | year=2016  | doi = 10.1016/j.cmet.2015.12.006 | pmc= 4715268 | pmid=26771115}}</ref> [[Cancer stem cell]]s often use oxidative phosphorylation or glutamine as a primary energy source.<ref name="pmid32670883">{{cite journal | vauthors=Yadav UP, Singh T, Kumar P, Mehta K | title=Metabolic Adaptations in Cancer Stem Cells | journal=[[Frontiers in Oncology]] | volume=10 | page=1010 | year=2020  | doi = 10.3389/fonc.2020.01010 | pmc= 7330710 | pmid=32670883| doi-access=free }}</ref>