Editing Neoplasm (section)

===Genome instability===
Cancers are known to exhibit [[genome instability]] or a mutator phenotype.<ref name="pmid22954224">{{cite journal |vauthors=Schmitt MW, Prindle MJ, Loeb LA | title = Implications of genetic heterogeneity in cancer | journal = Ann. N. Y. Acad. Sci. | volume = 1267 | issue = 1| pages = 110–6 |date=September 2012 | pmid = 22954224 | pmc = 3674777 | doi = 10.1111/j.1749-6632.2012.06590.x | bibcode = 2012NYASA1267..110S }}</ref> The protein-coding DNA within the nucleus is about 1.5% of the total genomic DNA.<ref name="pmid11237011">{{cite journal | vauthors = Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W | title = Initial sequencing and analysis of the human genome | journal = Nature | volume = 409 | issue = 6822 | pages = 860–921 | date = February 2001 | pmid = 11237011 | doi = 10.1038/35057062 | bibcode = 2001Natur.409..860L | display-authors = etal | url = https://deepblue.lib.umich.edu/bitstream/2027.42/62798/1/409860a0.pdf | doi-access = free | access-date = 2019-09-02 | archive-date = 2020-07-29 | archive-url = https://web.archive.org/web/20200729030748/https://deepblue.lib.umich.edu/bitstream/handle/2027.42/62798/409860a0.pdf;jsessionid=C72311E1AB91A832789410D56B35F9F1?sequence=1 | url-status = live }}</ref> Within this protein-coding DNA (called the [[exome]]), an average cancer of the breast or colon can have about 60 to 70 protein altering mutations, of which about 3 or 4 may be "driver" mutations, and the remaining ones may be "passenger" mutations.<ref name=Vogelstein /> However, the average number of DNA sequence mutations in the entire genome (including [[Noncoding DNA|non-protein-coding regions]]) within a breast cancer tissue sample is about 20,000.<ref name="pmid22492626">{{cite journal |vauthors=Yost SE, Smith EN, Schwab RB, Bao L, Jung H, Wang X, Voest E, Pierce JP, Messer K, Parker BA, Harismendy O, Frazer KA | title = Identification of high-confidence somatic mutations in whole genome sequence of formalin-fixed breast cancer specimens | journal = Nucleic Acids Res. | volume = 40 | issue = 14 | pages = e107 |date=August 2012 | pmid = 22492626 | pmc = 3413110 | doi = 10.1093/nar/gks299 }}</ref> In an average melanoma tissue sample (where melanomas have a higher [[exome]] mutation frequency<ref name=Vogelstein />) the total number of DNA sequence mutations is about 80,000.<ref name="pmid22622578">{{cite journal |vauthors=Berger MF, Hodis E, Heffernan TP, Deribe YL, Lawrence MS, Protopopov A, Ivanova E, Watson IR, Nickerson E, Ghosh P, Zhang H, Zeid R, Ren X, Cibulskis K, Sivachenko AY, Wagle N, Sucker A, Sougnez C, Onofrio R, Ambrogio L, Auclair D, Fennell T, Carter SL, Drier Y, Stojanov P, Singer MA, Voet D, Jing R, Saksena G, Barretina J, Ramos AH, Pugh TJ, Stransky N, Parkin M, Winckler W, Mahan S, Ardlie K, Baldwin J, Wargo J, Schadendorf D, Meyerson M, Gabriel SB, Golub TR, Wagner SN, Lander ES, Getz G, Chin L, Garraway LA|display-authors = 6 | title = Melanoma genome sequencing reveals frequent PREX2 mutations | journal = Nature | volume = 485 | issue = 7399 | pages = 502–6 |date=May 2012 | pmid = 22622578 | pmc = 3367798 | doi = 10.1038/nature11071 |bibcode = 2012Natur.485..502B }}</ref> This compares to the very low mutation frequency of about 70 new mutations in the entire genome between generations (parent to child) in humans.<ref name="pmid20220176">{{cite journal | vauthors = Roach JC, Glusman G, Smit AF, Huff CD, Hubley R, Shannon PT, Rowen L, Pant KP, Goodman N, Bamshad M, Shendure J, Drmanac R, Jorde LB, Hood L, Galas DJ|display-authors = 6| title = Analysis of genetic inheritance in a family quartet by whole-genome sequencing | journal = Science | volume = 328 | issue = 5978 | pages = 636–9 | date = April 2010 | pmid = 20220176 | pmc = 3037280 | doi = 10.1126/science.1186802 |bibcode = 2010Sci...328..636R}}</ref><ref name="pmid23001126">{{cite journal | vauthors = Campbell CD, Chong JX, Malig M, Ko A, Dumont BL, Han L, Vives L, O'Roak BJ, Sudmant PH, Shendure J, Abney M, Ober C, Eichler EE |display-authors = 6| title = Estimating the human mutation rate using autozygosity in a founder population | journal = Nat. Genet. | volume = 44 | issue = 11 | pages = 1277–81 | date = November 2012 | pmid = 23001126 | pmc = 3483378 | doi = 10.1038/ng.2418 }}</ref>

The high frequencies of mutations in the total nucleotide sequences within cancers suggest that often an early alteration in the field defects giving rise to a cancer (e.g. yellow area in the diagram in this section) is a deficiency in DNA repair. The large field defects surrounding colon cancers (extending to at about 10&nbsp;cm on each side of a cancer) were shown by Facista et al.<ref name=Facista /> to frequently have epigenetic defects in 2 or 3 DNA repair proteins ([[ERCC1]], XPF or [[PMS2]]) in the entire area of the field defect. Deficiencies in DNA repair cause increased mutation rates.<ref name=Narayanan /><ref name=Hegan /><ref name=Tutt /> A deficiency in DNA repair, itself, can allow DNA damages to accumulate, and error-prone [[DNA repair|translesion synthesis]] past some of those damages may give rise to mutations. In addition, faulty repair of these accumulated DNA damages may give rise to epimutations. These new mutations or epimutations may provide a proliferative advantage, generating a field defect. Although the mutations/epimutations in DNA repair genes do not, themselves, confer a selective advantage, they may be carried along as passengers in cells when the cells acquire additional mutations/epimutations that do provide a proliferative advantage.{{cn|date=May 2023}}