Editing Tumor suppressor gene (section)

==Two-hit hypothesis==
Unlike [[oncogene]]s, tumor suppressor genes generally follow the [[two-hit hypothesis]], which states both alleles that code for a particular protein must be affected before an effect is manifested.<ref name=":1" /> If only one allele for the gene is damaged, the other can still produce enough of the correct protein to retain the appropriate function. In other words, mutant tumor suppressor alleles are usually [[Dominance relationship|recessive]], whereas mutant [[oncogene]] alleles are typically [[Dominance relationship|dominant]]{{cn|date=March 2025}}.[[Image:Models of tumour suppression.svg|right|thumb|Models of tumor suppression]] [[File:Two-hit.jpg|thumb|Illustration of two-hit hypothesis]]

Proposed by [[Alfred G. Knudson|A.G. Knudson]] for cases of retinoblastoma.<ref name=":1">{{cite journal | vauthors = Knudson AG | title = Mutation and cancer: statistical study of retinoblastoma | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 68 | issue = 4 | pages = 820–823 | date = April 1971 | pmid = 5279523 | pmc = 389051 | doi = 10.1073/pnas.68.4.820 | doi-access = free | bibcode = 1971PNAS...68..820K }}</ref> He observed that 40% of U.S cases were caused by a mutation in the germ-line. However, affected parents could have children without the disease, but the unaffected children became parents of children with retinoblastoma.<ref name=":0">{{Cite web|url=https://www.nature.com/scitable/topicpage/tumor-suppressor-ts-genes-and-the-two-887/|title=Tumor Suppressor (TS) Genes and the Two-Hit Hypothesis {{!}} Learn Science at Scitable|website=www.nature.com|language=en|access-date=2019-10-06}}</ref> This indicates that one could inherit a mutated germ-line but not display the disease. Knudson observed that the age of onset of retinoblastoma followed [[Rate equation#Second order reactions|2nd order kinetics]], implying that two independent genetic events were necessary. He recognized that this was consistent with a recessive mutation involving a single gene, but requiring bi-allelic mutation. Hereditary cases involve an inherited mutation and a single mutation in the normal allele.<ref name=":0" /> Non-hereditary retinoblastoma involves two mutations, one on each allele.<ref name=":0" /> Knudson also noted that hereditary cases often developed bilateral tumors and would develop them earlier in life, compared to non-hereditary cases where individuals were only affected by a single tumor.<ref name=":0" />

There are exceptions to the two-hit rule for tumor suppressors, such as certain mutations in the [[p53 (protein)|p53 gene product]].  p53 mutations can function as a [[dominant negative]], meaning that a mutated p53 protein can prevent the function of the natural protein produced from the non-mutated allele.<ref>{{cite journal | vauthors = Baker SJ, Markowitz S, Fearon ER, Willson JK, Vogelstein B | title = Suppression of human colorectal carcinoma cell growth by wild-type p53 | journal = Science | volume = 249 | issue = 4971 | pages = 912–915 | date = August 1990 | pmid = 2144057 | doi = 10.1126/science.2144057 | bibcode = 1990Sci...249..912B }}</ref> Other tumor-suppressor genes that do not follow the two-hit rule are those that exhibit [[haploinsufficiency]], including PTCH in [[medulloblastoma]] and NF1 in [[neurofibroma]].  Another example is [[p27 (gene)|p27]], a cell-cycle inhibitor, that when one allele is mutated causes increased carcinogen susceptibility.<ref>{{cite journal | vauthors = Fero ML, Randel E, Gurley KE, Roberts JM, Kemp CJ | title = The murine gene p27Kip1 is haplo-insufficient for tumour suppression | journal = Nature | volume = 396 | issue = 6707 | pages = 177–180 | date = November 1998 | pmid = 9823898 | pmc = 5395202 | doi = 10.1038/24179 | bibcode = 1998Natur.396..177F }}</ref>