1096:'s huge banks of DNA-sequencing machines in motion to read every single letter of DNA in a tumor. By 2009, Stratton and his team had produced the first whole cancer genome sequences. These were detailed maps showing all the genetic changes and mutations that had occurred within two individual cancers—a melanoma from the skin and a lung tumor. The melanoma and lung cancer genomes were powerful proof that the fingerprints of specific culprits could be seen in cancers with one major cause. These tumors still contained many mutations that could not be explained by ultraviolet light or tobacco smoking. The detective work became a lot more complicated for cancers with complex, multiple or even completely unknown origins. By way of analogy, imagine a forensic scientist dusting for fingerprints at a murder scene. The forensic scientist might strike it lucky and find a set of perfect prints on a windowpane or door handle that match a known killer. However, they are much more likely to uncover a mish-mash of fingerprints belonging to a whole range of folk—from the victim and potential suspects to innocent parties and police investigators—all laid on top of each other on all sorts of surfaces. This is very similar to cancer genomes where multiple mutational patterns are commonly overlaid one over another making the data incomprehensible. Fortunately, a PhD student of Stratton's,
116:
39:
unique to the signer. Uniqueness allows the mutagen to be deduced from a cell's mutations Later, the phrase referred to a pattern of mutations characteristic of a tumor type, although usually not unique to the tumor type nor to a mutagen. If a tumor mutational signature matches a unique mutagen mutational signature, it is valid to deduce the carcinogen exposure or mutagenesis process that occurred in the patient's distant past. Increasingly refined tumor signatures are becoming assignable to mutagen signatures.
934:
cellular oxidative processes. Therefore even if all mutations in a tumor were caused by UV from sunlight, one quarter of the mutations are expected to not be UV signature mutations. A second carcinogen needn't be invoked to explain those mutations, but a second mutational process is required. Identification of a UV signature in a tumor of unknown primary site is clinically important as it suggests a diagnosis of metastatic skin cancer and has important treatment implications.
795:
425:
929:, causing a strong bias for C>T substitutions enriched on the untranscribed DNA strand. The regions of a tumor suppressor protein that are mutationally inactivated in sunlight-related skin cancers are the same as in cancers of organs not exposed to sunlight, but the nucleotide mutated is often shifted a few bases to a site where a CPD could form.
1109:
data. Subsequently, they applied this framework to more than seven thousand cancer genomes creating the first comprehensive map of mutational signatures in human cancer. Currently, more than one hundred mutational signatures have been identified across the repertoire of human cancer. In April 2022 58
924:
Signature 7 has a predominance of C>T substitutions at sites of adjacent pyrimidines (adjacent C or T), with a particularly diagnostic subset being the CC>TT dinucleotide mutation. This pattern arises because the major UV-induced DNA photoproducts join two adjacent pyrimidines; the photoproduct
933:
radiation exposure is therefore the proposed underlying mutagenic mechanism of this signature. UV also illustrates a subtlety in interpreting a tumor signature as a mutagen signature: only three-quarters of mutations induced by UV in the laboratory are UV signature mutations because UV also triggers
38:
The term is used for two distinct concepts, often conflated: mutagen signatures and tumor signatures. Its original use, mutagen signature, referred to a pattern of mutations made in the laboratory by a known mutagen and not made by other mutagens – unique to the mutagen as a human signature is
403:
There are six classes of base substitution: C>A, C>G, C>T, T>A, T>C, T>G. The G>T substitution is considered equivalent to the C>A substitution because it is not possible to differentiate on which DNA strand (forward or reverse) the substitution initially occurred. Both the
428:
The 96 mutation types concept from
Alexandrov et al. Considering the 5' flanking base (A, C, G, T), the 6 substitution classes (C>A, C>G, C>T, T>A, T>C, T>G) and 3' flanking base (A, C, G, T) leads to a 96 mutation types classification (4 x 6 x 4 = 96). The 16 possible mutation
407:
Taking the information from the 5' and 3' adjacent bases (also called flanking base pairs or trinucleotide context) lead to 96 possible mutation types (e.g. AA, AT, etc.). The mutation catalog of a tumor is created by categorizing each single nucleotide variant (SNV) (synonyms:
404:
C>A and G>T substitutions are therefore counted as part of the "C>A" class. For the same reason the G>C, G>A, A>T, A>G and A>C mutations are counted as part of the "C>G", "C>T", "T>A", "T>C" and "T>G" classes respectively.
925:
is typically the cyclobutane pyrimidine dimer (CPD). Specificity for C>T appears to be due to the million-fold acceleration of C deamination when it is part of a CPD, with the resulting uracil acting as T. CPDs are repaired via transcription-coupled
440:
The mutation catalog of the tumor is compared to a reference mutation catalogue, or mutational signatures reference dataset, such as the 21 Signatures of
Mutational Processes in Human Cancer from the Catalogue of Somatic Mutation In Cancer
122:
Diverse mutagenesis processes shape the somatic landscape of tumors. Deciphering the underlying patterns of cancer mutations allows to uncover relationships between these recurrent patterns of mutations and infer possible causal mutational
683:
is associated with high burden of
Signature 2 and Signature 13 mutations. This polymorphism is considered to be of moderate penetrance (two-fold above background risk) for breast cancer risk. The exact roles and mechanisms underlying
1100:
came up with a way of mathematically solving the problem. Alexandrov demonstrated that mutational patterns from individual mutagens found in a tumor can be distinguished from one another using a mathematical approach called
699:
Both
Signature 2 and Signature 13 feature cytosine to uracil substitutions due to cytidine deaminases. Signature 2 has a higher proportion of CN substitutions and Signature 13 a higher proportion of TN substitutions.
433:
Once the mutation catalog (e.g. counts for each of the 96 mutation types) of a tumor is obtained, there are two approaches to decipher the contributions of different mutational signatures to tumor genomic landscape:
771:
Signature 10 has a transcriptional bias and is enriched for C>A substitutions in the TpCpT context as well as T>G substitutions in the TpTpTp context. Signature 10 is associated with altered function of
558:
Some mutational signatures feature strong transcriptional-bias with substitutions preferentially affecting one of the DNA strands, either the transcribed or untranscribed strand (Signatures 5, 7, 8, 10, 12,
1105:. The newly disentangled patterns of mutations were termed mutational signatures. In 2013, Alexandrov and Stratton published the first computational framework for deciphering mutational signatures from
2381:
Alexandrov LB, Ju YS, Haase K, Van Loo P, Martincorena I, Nik-Zainal S, Totoki Y, Fujimoto A, Nakagawa H, Shibata T, Campbell PJ, Vineis P, Phillips DH, Stratton MR (November 2016).
982:) display transcriptional strand-bias and enrichment for C>A substitutions, but their respective composition and patterns (proportion of each mutation types) differ slightly.
2795:
Alexandrov L, Kim J, Haradhvala NJ, Huang MN, Ng AW, Boot A, Covington KR, Gordenin DA, Bergstrom E (2018-05-15). "The
Repertoire of Mutational Signatures in Human Cancer".
2487:
Olivier M, Hussain SP, Caron de
Fromentel C, Hainaut P, Harris CC (2004). "TP53 mutation spectra and load: a tool for generating hypotheses on the etiology of cancer".
1583:
Chuk MK, Chang JT, Theoret MR, Sampene E, He K, Weis SL, Helms WS, Jin R, Li H, Yu J, Zhao H, Zhao L, Paciga M, Schmiel D, Rawat R, Keegan P, Pazdur R (October 2017).
395:(e.g. single nucleotide variants, indels, structural variants) can be used individually or in combination to model mutational signatures in cancer.
2167:"Rapid deamination of cyclobutane pyrimidine dimer photoproducts at TCG sites in a translationally and rotationally positioned nucleosome in vivo"
1072:
at the Johns
Hopkins Oncology Center in Baltimore reviewed data showing that different types of cancer had their own unique suite of mutations in
1813:"Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer"
1417:
Kucab JE, Zou X, Morganella S, Joel M, Nanda AS, Nagy E, Gomez C, Degasperi A, Harris R, Jackson SP, Arlt VM, Phillips DH, Nik-Zainal S (2019).
2218:"The major mechanism of melanoma mutations is based on deamination of cytosine in pyrimidine dimers as determined by circle damage sequencing"
79:). More recently, mutational signatures profiling has proven successful in guiding oncological management and use of targeted therapies (e.g.
689:
351:
2332:
Mata, Douglas A.; Williams, Erik A.; Sokol, Ethan; Oxnard, Geoffrey R.; Fleischmann, Zoe; Tse, Julie Y.; Decker, Brennan (23 March 2022).
619:
494:
1153:
As DNA replication, maintenance and repair is not a linear process, some signatures are caused by overlapping mutagenesis mechanisms.
1092:
saw the potential for the technology to revolutionize our understanding of the genetic changes inside individual tumors, setting the
452:
320:(MMR) deficiency: The mismatch repair machinery recognizes and repairs erroneous base pair insertion, deletion or mis-incorporation.
416:) in one of the 96 mutation types and counting the total number of substitutions for each of these 96 mutation types (see figure).
1764:"Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors"
272:
230:
200:
63:
552:
types (e.g. Signature 1) while some others tend to associate with specific cancers (e.g. Signature 9 and lymphoid malignancies)
2273:
Ziegler A, Leffell DJ, Kunala S, Sharma HW, Gailani M, Simon JA, Halperin AJ, Baden HP, Shapiro PE, Bale AE, Brash DE (1993).
583:
Signature 5 has a predominance of T>C substitutions in the ApTpN trinucleotide context with transcriptional strand bias.
515:
deficiency leads to
Signature 3 substitution pattern, but also to increase burden of structural variants. In the absence of
54:. Mutational signatures have shown their applicability in cancer treatment and cancer prevention. Advances in the fields of
2438:
Rogozin IB, Goncearenco A, Lada AG, De S, Yurchenkod V, Nudelman G, Panchenko AR, Cooper DN, Pavlov YI (February 2018).
1012:
1996:"A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer"
1085:
999:
953:
926:
729:
524:
520:
501:
490:
391:
in order to create the tumor mutation catalog (mutation types and counts) of a specific tumor. Different types of
1093:
288:
2551:
2953:
814:
516:
512:
478:
384:
311:
303:
100:
1585:"FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma"
1358:
115:
1134:
1102:
979:
660:
Signature 2 and
Signature 13 are enriched for C>T and C>G substitutions and are thought to arise from
343:
809:
in colorectal cancer leads to enrichment for transversion mutations (G:C>T:A), which has been linked to
172:
to correct these replication errors leads to progressive accumulation of mutations through successive cell
2575:
Pleasance ED, Cheetham RK, Stephens PJ, McBride DJ, Humphray SJ, Greenman CD, et al. (January 2010).
810:
773:
721:
528:
409:
1945:
569:
366:
196:
1624:
O'Neil, Nigel J.; Bailey, Melanie L.; Hieter, Philip (26 June 2017). "Synthetic lethality and cancer".
2738:
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. (August 2013).
1357:
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. (August 2013).
2958:
2878:
2796:
2751:
2645:
2588:
2394:
2286:
2229:
2119:
2059:
1762:
Middlebrooks CD, Banday AR, Matsuda K, Udquim KI, Onabajo OO, Paquin A, et al. (November 2016).
1373:
1296:
826:
654:
653:
has also been found to cause unwanted host genome editing and may even participate to oncogenesis in
532:
486:
331:
1483:
Alexandrov LB, Jones PH, Wedge DC, Sale JE, Campbell PJ, Nik-Zainal S, Stratton MR (December 2015).
696:
complex is thought to be involved in host immune response to viral infections and lipid metabolism.
1897:"APOBEC3A and APOBEC3B Preferentially Deaminate the Lagging Strand Template during DNA Replication"
1672:"Homologous Recombination Deficiency and Platinum-Based Therapy Outcomes in Advanced Breast Cancer"
1129:
760:
725:
615:
544:
A brief description of selected mutational processes and their associated mutational signatures in
317:
307:
242:
96:
2632:
Pleasance ED, Stephens PJ, O'Meara S, McBride DJ, Meynert A, Jones D, et al. (January 2010).
2904:
1973:
1649:
1320:
661:
638:
347:
2896:
2847:
2777:
2720:
2671:
2614:
2527:
2492:
2469:
2420:
2363:
2314:
2255:
2198:
2147:
2085:
2025:
1965:
1944:
Rayner E, van Gool IC, Palles C, Kearsey SE, Bosse T, Tomlinson I, Church DN (February 2016).
1926:
1877:
1842:
1811:
Nik-Zainal S, Wedge DC, Alexandrov LB, Petljak M, Butler AP, Bolli N, et al. (May 2014).
1793:
1744:
1693:
1670:
Zhao EY, Shen Y, Pleasance E, Kasaian K, Leelakumari S, Jones M, et al. (December 2017).
1641:
1606:
1565:
1514:
1448:
1399:
1312:
1262:
1208:
1124:
1097:
596:
591:
Signature 3 displays high mutation counts of multiple mutation classes and is associated with
485:(up to 50 nucleotides) with overlapping microhomology at the breakpoints. In such tumors, DNA
76:
915:-induced DNA damage and repair mechanisms have been linked to specific molecular signatures.
2886:
2837:
2829:
2767:
2759:
2710:
2702:
2661:
2653:
2604:
2596:
2519:
2459:
2451:
2440:"DNA polymerase η mutational signatures are found in a variety of different types of cancer"
2410:
2402:
2353:
2345:
2304:
2294:
2245:
2237:
2188:
2178:
2137:
2127:
2075:
2067:
2015:
2007:
1957:
1916:
1908:
1869:
1832:
1824:
1783:
1775:
1734:
1724:
1683:
1633:
1596:
1555:
1545:
1504:
1496:
1438:
1430:
1389:
1381:
1304:
1252:
1244:
1198:
1190:
1177:
Forbes SA, Beare D, Boutselakis H, Bamford S, Bindal N, Tate J, et al. (January 2017).
1089:
1065:
945:
777:
733:
577:
466:
189:
157:
68:
59:
2818:"Substitution mutational signatures in whole-genome–sequenced cancers in the UK population"
2106:
Brash DE, Rudolph JA, Simon JA, Lin A, McKenna GJ, Baden HP, Halperin AJ, Pontén J (1991).
641:
enzymes respond to viral infections by editing viral genome, but the enzymatic activity of
2510:
Pfeifer GP, Hainaut P (2003). "On the origin of G --> T transversions in lung cancer".
1713:"Roles of APOBEC3A and APOBEC3B in Human Papillomavirus Infection and Disease Progression"
1106:
1077:
1069:
1016:
836:
576:
diagnosis. The underlying proposed biological mechanism is the spontaneous deamination of
246:
150:
84:
24:
2108:"A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma"
1534:"Advances in Targeted and Immunobased Therapies for Colorectal Cancer in the Genomic Era"
2882:
2755:
2649:
2592:
2398:
2290:
2233:
2123:
2063:
1377:
1300:
712:-mediated mutagenesis preferentially involve the lagging DNA strand during replication.
2842:
2817:
2772:
2739:
2715:
2690:
2666:
2633:
2609:
2576:
2464:
2439:
2415:
2382:
2358:
2333:
2250:
2217:
2193:
2166:
2080:
2047:
2020:
1995:
1921:
1896:
1837:
1812:
1788:
1763:
1739:
1712:
1560:
1533:
1509:
1484:
1443:
1418:
1394:
1257:
1232:
1203:
1178:
1119:
991:
462:
413:
388:
169:
161:
92:
72:
47:
2523:
2349:
1076:, which were likely to have been caused by different agents, such as the chemicals in
548:
will be included in the sections below. Some signatures are ubiquitous across diverse
451:
mutational signatures modelling can be accomplished using statistical methods such as
2947:
2908:
2309:
2274:
2142:
2107:
1895:
Hoopes JI, Cortez LM, Mertz TM, Malc EP, Mieczkowski PA, Roberts SA (February 2016).
840:
104:
80:
1324:
614:
types (e.g. breast, pancreatic, ovarian, prostate). This signature results from DNA
572:
in the NpG trinucleotide contexts and correlates with the age of patient at time of
2043:
1977:
1653:
1048:
error-prone synthesis signature has been linked to non-hematological cancers (e.g.
1020:
896:
868:
844:
822:
335:
280:
234:
62:, but such therapies historically focused on inhibition of oncogenic drivers (e.g.
55:
2455:
1688:
1671:
1601:
1584:
2706:
1912:
2689:
Alexandrov LB, Nik-Zainal S, Wedge DC, Campbell PJ, Stratton MR (January 2013).
2275:"Mutation hotspots due to sunlight in the p53 gene of non-melanoma skin cancers"
2011:
1860:
Yang B, Li X, Lei L, Chen J (September 2017). "APOBEC: From mutator to editor".
1081:
1053:
1049:
1036:
987:
The proposed underlying mechanism of
Signature 4 is the removal of DNA adducts (
971:
930:
908:
782:
362:
339:
268:
238:
220:
212:
207:
192:
165:
134:
51:
20:
2891:
2866:
1434:
442:
424:
1873:
876:
250:
216:
182:
32:
2634:"A small-cell lung cancer genome with complex signatures of tobacco exposure"
2132:
944:
Signature 11 was identified in tumors previously exposed to Temozolamide, an
2833:
2406:
2183:
1308:
392:
28:
2922:
2900:
2851:
2781:
2724:
2675:
2618:
2577:"A comprehensive catalogue of somatic mutations from a human cancer genome"
2531:
2496:
2473:
2424:
2367:
2299:
2259:
2241:
2202:
2089:
2029:
1969:
1930:
1881:
1846:
1797:
1748:
1697:
1645:
1610:
1569:
1518:
1452:
1403:
1266:
1212:
2691:"Deciphering signatures of mutational processes operative in human cancer"
2318:
2151:
1316:
1194:
794:
1946:"A panoply of errors: polymerase proofreading domain mutations in cancer"
852:
708:
702:
679:
673:
649:
643:
592:
359:
276:
224:
88:
2763:
2657:
2600:
2071:
1961:
1637:
1385:
19:
are characteristic combinations of mutation types arising from specific
2383:"Mutational signatures associated with tobacco smoking in human cancer"
2334:"Prevalence of UV Mutational Signatures Among Cutaneous Primary Tumors"
1550:
995:
988:
975:
967:
949:
912:
872:
864:
860:
848:
634:
504:, also features enrichment of 1bp indels in nucleotide repeat regions.
284:
264:
258:
173:
1248:
1056:
and could partly explain the increase TC dinucleotides substitutions.
1729:
693:
685:
665:
623:
611:
573:
549:
545:
482:
355:
254:
138:
43:
1828:
1779:
1500:
1284:
956:. A strong transcriptional strand-bias is present in this signature.
481:(HR) deficient tumour, is associated with increased burden of large
465:
provides insight into tumor biology and can offer opportunities for
120:
Conceptual workflow of somatic mutational signatures identification.
2801:
330:
Cytidine deaminase enzymes: This family of enzymes are part of the
887:
856:
831:
606:
600:
461:
Identifying the contributions of diverse mutational signatures to
423:
114:
1031:
881:
755:
749:
743:
737:
383:
Cancer mutational signatures analyses require genomic data from
1419:"A compendium of mutational signatures of environmental agents"
1283:
Hollstein M, Sidransky D, Vogelstein B, Harris CC (July 1991).
786:
exonuclease domain mutations are associated with Signature 10.
429:
types of the substitution class C>A are shown as an example.
1073:
847:, which if remains un-repaired, will lead to incorporation of
813:
Signature 18 described by Alexandrov et al (Signature 18 plot
1994:
Viel, A, Bruselles, A, Meccia, E, et al. (April 2017).
1023:
events. It is thought to result from error-prone polymerase
46:
provides insight into the biological mechanisms involved in
688:-mediated genome editing are not yet fully delineated, but
1711:
Warren C, Westrich J, Doorslaer K, Pyeon D (August 2017).
2552:"The DNA detectives who are hunting the causes of cancer"
948:. This signature is enriched for C>T substitutions on
2867:"Trove of tumour genomes offers clues to cancer origins"
2216:
Jin SG, Pettinga D, Johnson J, Li P, Pfeifer GP (2021).
1485:"Clock-like mutational processes in human somatic cells"
2165:
Cannistraro VJ, Pondugula S, Song Q, Taylor JS (2015).
2740:"Signatures of mutational processes in human cancer"
1359:"Signatures of mutational processes in human cancer"
1179:"COSMIC: somatic cancer genetics at high-resolution"
141:
Signatures 1 to 30) include, but are not limited to:
58:
have enabled the development and use of molecularly
2279:
Proceedings of the National Academy of Sciences USA
2112:
Proceedings of the National Academy of Sciences USA
1862:
Journal of Genetics and Genomics = Yi Chuan Xue Bao
489:are repaired by the imprecise repair mechanisms of
164:excises an incorrectly incorporated nucleotide via
1052:) and was hypothesized to contribute to YCG motif
137:mechanisms underlying mutational signatures (e.g.
622:). Signature 3 is associated with high burden of
455:to identify potential novel mutational processes.
2816:Degasperi, Andrea; et al. (21 April 2021).
1478:
1476:
1474:
1472:
1470:
1468:
1466:
1464:
1462:
1352:
1350:
1348:
1346:
1344:
1342:
1340:
1338:
1336:
1334:
825:mutations (G:C>T:A) has been associated with
724:mutational signatures have been associated with
1989:
1987:
1278:
1276:
863:glycosylase enzyme which excise the mismatched
2923:"Cancer: Huge DNA analysis uncovers new clues"
2545:
2543:
2541:
2048:"Base-excision repair of oxidative DNA damage"
803:in base excision repair and somatic signature.
568:Signature 1 features a predominance of C>T
257:cells are most impacted because of their high
314:mechanism for accurate repair of breakpoints.
8:
2101:
2099:
1665:
1663:
1172:
1170:
1226:
1224:
1222:
671:A germline deletion polymorphism involving
523:leads to large structural variants such as
497:(MMEJ) instead of high fidelity HR repair.
1110:new mutational signatures were described.
2890:
2841:
2800:
2771:
2714:
2665:
2608:
2463:
2414:
2357:
2308:
2298:
2249:
2192:
2182:
2141:
2131:
2079:
2019:
1920:
1836:
1787:
1738:
1728:
1687:
1600:
1559:
1549:
1508:
1442:
1393:
1256:
1202:
829:(BER) deficiency and linked to defective
1068:at the US National Cancer Institute and
895:, MutT homolog 1) to remove the damaged
793:
1166:
1146:
1084:light from the sun. With the advent of
626:with microhomology at the breakpoints.
508:Types of mutations: structural variants
215:radiation: UVB radiation causes direct
1532:Seow H, Yip WK, Fifis T (March 2016).
399:Types of mutations: base substitutions
188:Endogenous cellular (e.g. spontaneous
690:activation-induced cytidine deaminase
352:activation-induced cytidine deaminase
42:Deciphering mutational signatures in
35:pathways, and DNA enzymatic editing.
27:infidelity, exogenous and endogenous
7:
780:activity. Both germline and somatic
728:deficiency and found in tumors with
271:which are harmful to DNA, including
1011:Signature 9 has been identified in
952:bases due to transcription-coupled
620:homologous recombination deficiency
587:Homologous recombination deficiency
334:and are involved in the control of
87:deficient of diverse cancer types,
1019:and feature enrichment for T>G
891:(Nudix hydrolase 1, also known as
495:microhomology-mediated end joining
14:
2350:10.1001/jamanetworkopen.2022.3833
1007:Immunoglobulin gene hypermutation
903:Exposures to exogenous genotoxins
875:base pairing, therefore enabling
500:Signature 6, seen in tumors with
453:non-negative matrix factorization
168:enzymatic reaction. Inability of
1285:"p53 mutations in human cancers"
843:damage leads to the creation of
273:polycyclic aromatic hydrocarbons
231:Alkylating antineoplastic agents
201:DNA damage (naturally occurring)
2046:; O'Shea, VL; Kundu, S (2007).
1237:Photochemistry and Photobiology
998:) by the transcription-coupled
839:, in colorectal cancer. Direct
365:and therefore introduce C>T
358:protein family) actively cause
219:and is a known risk factor for
907:Selected exogenous genotoxins/
732:: Signature 6, 15, 20 and 26.
1:
2865:Ledford, Heidi (2022-04-21).
2524:10.1016/s0027-5107(03)00013-7
2456:10.1080/15384101.2017.1404208
1689:10.1158/1078-0432.CCR-17-1941
1602:10.1158/1078-0432.CCR-16-0663
978:chewing, gingivo-buccal oral
885:(Oxoguanine glycosylase) and
2707:10.1016/j.celrep.2012.12.008
2489:IARC Scientific Publications
1913:10.1016/j.celrep.2016.01.021
1013:chronic lymphocytic leukemia
776:, which result in deficient
2012:10.1016/j.ebiom.2017.04.022
267:: Tobacco contains several
2975:
2892:10.1038/d41586-022-01095-2
1435:10.1016/j.cell.2019.03.001
1086:next-generation sequencing
1000:nucleotide excision repair
954:nucleotide excision repair
927:nucleotide excision repair
919:Ultraviolet radiation (UV)
730:microsatellite instability
716:Mismatch repair deficiency
525:chromosomal translocations
521:non-homologous end joining
502:microsatellite instability
491:non-homologous end joining
473:Types of mutations: indels
1874:10.1016/j.jgg.2017.04.009
1094:Wellcome Sanger Institute
289:health effects of tobacco
2133:10.1073/pnas.88.22.10124
1676:Clinical Cancer Research
1589:Clinical Cancer Research
1233:"UV signature mutations"
855:during DNA replication.
517:homologous recombination
513:Homologous recombination
479:homologous recombination
385:cancer genome sequencing
312:homologous recombination
304:Homologous recombination
160:is the process by which
101:homologous recombination
2834:10.1126/science.abl9283
2407:10.1126/science.aag0299
2184:10.1074/jbc.M115.673301
1626:Nature Reviews Genetics
1538:OncoTargets and Therapy
1309:10.1126/science.1905840
1135:Whole genome sequencing
1103:blind source separation
980:squamous cell carcinoma
821:Somatic enrichment for
564:Age-related mutagenesis
344:endogenous retroviruses
2300:10.1073/pnas.90.9.4216
2242:10.1126/sciadv.abi6508
1950:Nature Reviews. Cancer
1183:Nucleic Acids Research
994:covalently bounded to
818:
774:DNA polymerase epsilon
759:genes cause defective
618:repair deficiency (or
529:chromosomal inversions
430:
420:Tumor mutation catalog
410:base-pair substitution
306:deficiency (HRD): DNA
124:
1042:Recently, polymerase
879:mechanisms involving
797:
610:mutations in several
570:transition (genetics)
539:Mutational signatures
477:Signature 3, seen in
427:
367:transition (genetics)
326:Enzymatic DNA editing
299:DNA repair deficiency
241:to DNA, which causes
197:transition (genetics)
128:Mechanisms – overview
118:
31:exposures, defective
17:Mutational signatures
974:) and Signature 29 (
827:base excision repair
790:Base excision repair
664:activity of the AID/
655:human papillomavirus
533:copy number variants
487:double-strand breaks
342:elements (including
332:innate immune system
245:and interferes with
2883:2022Natur.604..609L
2764:10.1038/nature12477
2756:2013Natur.500..415.
2658:10.1038/nature08629
2650:2010Natur.463..184P
2601:10.1038/nature08658
2593:2010Natur.463..191P
2550:Mosaic, Kat Arney.
2399:2016Sci...354..618A
2291:1993PNAS...90.4216Z
2234:2021SciA....7.6508J
2177:(44): 26597–26609.
2124:1991PNAS...8810124B
2072:10.1038/nature05978
2064:2007Natur.447..941D
1962:10.1038/nrc.2015.12
1638:10.1038/nrg.2017.47
1386:10.1038/nature12477
1378:2013Natur.500..415.
1301:1991Sci...253...49H
1195:10.1093/nar/gkw1121
1130:Pan-cancer analysis
761:DNA mismatch repair
726:DNA mismatch repair
616:double-strand break
387:with paired-normal
318:DNA mismatch repair
308:double-strand break
243:crosslinking of DNA
97:synthetic lethality
50:and normal somatic
1551:10.2147/OTT.S95101
1064:During the 1990s,
966:Both Signature 4 (
819:
662:cytidine deaminase
657:-related cancers.
639:cytidine deaminase
431:
348:cytidine deaminase
346:). These enzymes (
125:
23:processes such as
2512:Mutation Research
2393:(6312): 618–622.
2338:JAMA Network Open
2058:(7147): 941–950.
1774:(11): 1330–1338.
1682:(24): 7521–7530.
1595:(19): 5666–5670.
1429:(4): 821–36 e16.
1249:10.1111/php.12377
1231:Brash DE (2015).
1189:(D1): D777–D783.
1125:Genomic signature
1098:Ludmil Alexandrov
1035:gene)-associated
939:Alkylating agents
859:encodes the mutY
597:somatic (biology)
199:) mutations (see
77:colorectal cancer
2966:
2938:
2937:
2935:
2934:
2919:
2913:
2912:
2894:
2862:
2856:
2855:
2845:
2813:
2807:
2806:
2804:
2792:
2786:
2785:
2775:
2750:(7463): 415–21.
2735:
2729:
2728:
2718:
2686:
2680:
2679:
2669:
2644:(7278): 184–90.
2629:
2623:
2622:
2612:
2572:
2566:
2565:
2563:
2562:
2547:
2536:
2535:
2507:
2501:
2500:
2484:
2478:
2477:
2467:
2435:
2429:
2428:
2418:
2378:
2372:
2371:
2361:
2329:
2323:
2322:
2312:
2302:
2270:
2264:
2263:
2253:
2222:Science Advances
2213:
2207:
2206:
2196:
2186:
2162:
2156:
2155:
2145:
2135:
2103:
2094:
2093:
2083:
2040:
2034:
2033:
2023:
1991:
1982:
1981:
1941:
1935:
1934:
1924:
1907:(6): 1273–1282.
1892:
1886:
1885:
1857:
1851:
1850:
1840:
1808:
1802:
1801:
1791:
1759:
1753:
1752:
1742:
1732:
1730:10.3390/v9080233
1708:
1702:
1701:
1691:
1667:
1658:
1657:
1621:
1615:
1614:
1604:
1580:
1574:
1573:
1563:
1553:
1529:
1523:
1522:
1512:
1480:
1457:
1456:
1446:
1414:
1408:
1407:
1397:
1372:(7463): 415–21.
1363:
1354:
1329:
1328:
1280:
1271:
1270:
1260:
1228:
1217:
1216:
1206:
1174:
1154:
1151:
1090:Michael Stratton
1046:
1027:
1002:(NER) machinery.
946:alkylating agent
778:DNA proofreading
767:DNA proofreading
734:Loss of function
668:enzymes family.
578:5-methylcytosine
560:
553:
467:targeted therapy
412:or substitution
287:and others (see
233:: This group of
195:leads to C>T
190:5-methylcytosine
158:DNA proofreading
142:
111:General concepts
69:gain-of-function
60:targeted therapy
2974:
2973:
2969:
2968:
2967:
2965:
2964:
2963:
2954:Cancer genomics
2944:
2943:
2942:
2941:
2932:
2930:
2921:
2920:
2916:
2864:
2863:
2859:
2815:
2814:
2810:
2794:
2793:
2789:
2737:
2736:
2732:
2688:
2687:
2683:
2631:
2630:
2626:
2587:(7278): 191–6.
2574:
2573:
2569:
2560:
2558:
2549:
2548:
2539:
2509:
2508:
2504:
2491:(157): 247–70.
2486:
2485:
2481:
2437:
2436:
2432:
2380:
2379:
2375:
2331:
2330:
2326:
2272:
2271:
2267:
2215:
2214:
2210:
2164:
2163:
2159:
2118:(22): 10124–8.
2105:
2104:
2097:
2042:
2041:
2037:
1993:
1992:
1985:
1943:
1942:
1938:
1894:
1893:
1889:
1859:
1858:
1854:
1829:10.1038/ng.2955
1817:Nature Genetics
1810:
1809:
1805:
1780:10.1038/ng.3670
1768:Nature Genetics
1761:
1760:
1756:
1710:
1709:
1705:
1669:
1668:
1661:
1632:(10): 613–623.
1623:
1622:
1618:
1582:
1581:
1577:
1544:(9): 1899–920.
1531:
1530:
1526:
1501:10.1038/ng.3441
1489:Nature Genetics
1482:
1481:
1460:
1416:
1415:
1411:
1361:
1356:
1355:
1332:
1295:(5015): 49–53.
1282:
1281:
1274:
1230:
1229:
1220:
1176:
1175:
1168:
1163:
1158:
1157:
1152:
1148:
1143:
1116:
1107:cancer genomics
1070:Bert Vogelstein
1062:
1044:
1025:
1017:B-cell lymphoma
1009:
963:
941:
921:
905:
837:DNA glycosylase
792:
769:
718:
632:
589:
566:
557:
543:
541:
510:
475:
422:
401:
381:
376:
247:DNA replication
151:DNA replication
133:The biological
132:
130:
113:
85:mismatch repair
25:DNA replication
12:
11:
5:
2972:
2970:
2962:
2961:
2956:
2946:
2945:
2940:
2939:
2914:
2857:
2808:
2802:10.1101/322859
2787:
2730:
2681:
2624:
2567:
2537:
2518:(1–2): 39–43.
2502:
2479:
2450:(3): 348–355.
2430:
2373:
2344:(3): e223833.
2324:
2285:(9): 4216–20.
2265:
2208:
2157:
2095:
2035:
1983:
1936:
1887:
1868:(9): 423–437.
1852:
1803:
1754:
1703:
1659:
1616:
1575:
1524:
1495:(12): 1402–7.
1458:
1409:
1330:
1272:
1218:
1165:
1164:
1162:
1159:
1156:
1155:
1145:
1144:
1142:
1139:
1138:
1137:
1132:
1127:
1122:
1120:Gene signature
1115:
1112:
1061:
1058:
1015:and malignant
1008:
1005:
1004:
1003:
992:benzo(a)pyrene
984:
983:
962:
959:
958:
957:
940:
937:
936:
935:
920:
917:
904:
901:
791:
788:
768:
765:
717:
714:
631:
630:APOBEC enzymes
628:
588:
585:
565:
562:
540:
537:
509:
506:
474:
471:
463:carcinogenesis
459:
458:
457:
456:
446:
421:
418:
414:point mutation
400:
397:
389:DNA sequencing
380:
377:
375:
374:
373:
372:
371:
370:
323:
322:
321:
315:
296:
295:
294:
293:
292:
262:
228:
204:
179:
178:
177:
170:DNA polymerase
162:DNA polymerase
144:
129:
126:
112:
109:
93:PARP inhibitor
73:EGFR inhibitor
48:carcinogenesis
13:
10:
9:
6:
4:
3:
2:
2971:
2960:
2957:
2955:
2952:
2951:
2949:
2928:
2924:
2918:
2915:
2910:
2906:
2902:
2898:
2893:
2888:
2884:
2880:
2877:(7907): 609.
2876:
2872:
2868:
2861:
2858:
2853:
2849:
2844:
2839:
2835:
2831:
2827:
2823:
2819:
2812:
2809:
2803:
2798:
2791:
2788:
2783:
2779:
2774:
2769:
2765:
2761:
2757:
2753:
2749:
2745:
2741:
2734:
2731:
2726:
2722:
2717:
2712:
2708:
2704:
2701:(1): 246–59.
2700:
2696:
2692:
2685:
2682:
2677:
2673:
2668:
2663:
2659:
2655:
2651:
2647:
2643:
2639:
2635:
2628:
2625:
2620:
2616:
2611:
2606:
2602:
2598:
2594:
2590:
2586:
2582:
2578:
2571:
2568:
2557:
2553:
2546:
2544:
2542:
2538:
2533:
2529:
2525:
2521:
2517:
2513:
2506:
2503:
2498:
2494:
2490:
2483:
2480:
2475:
2471:
2466:
2461:
2457:
2453:
2449:
2445:
2441:
2434:
2431:
2426:
2422:
2417:
2412:
2408:
2404:
2400:
2396:
2392:
2388:
2384:
2377:
2374:
2369:
2365:
2360:
2355:
2351:
2347:
2343:
2339:
2335:
2328:
2325:
2320:
2316:
2311:
2306:
2301:
2296:
2292:
2288:
2284:
2280:
2276:
2269:
2266:
2261:
2257:
2252:
2247:
2243:
2239:
2235:
2231:
2227:
2223:
2219:
2212:
2209:
2204:
2200:
2195:
2190:
2185:
2180:
2176:
2172:
2168:
2161:
2158:
2153:
2149:
2144:
2139:
2134:
2129:
2125:
2121:
2117:
2113:
2109:
2102:
2100:
2096:
2091:
2087:
2082:
2077:
2073:
2069:
2065:
2061:
2057:
2053:
2049:
2045:
2039:
2036:
2031:
2027:
2022:
2017:
2013:
2009:
2005:
2001:
1997:
1990:
1988:
1984:
1979:
1975:
1971:
1967:
1963:
1959:
1955:
1951:
1947:
1940:
1937:
1932:
1928:
1923:
1918:
1914:
1910:
1906:
1902:
1898:
1891:
1888:
1883:
1879:
1875:
1871:
1867:
1863:
1856:
1853:
1848:
1844:
1839:
1834:
1830:
1826:
1823:(5): 487–91.
1822:
1818:
1814:
1807:
1804:
1799:
1795:
1790:
1785:
1781:
1777:
1773:
1769:
1765:
1758:
1755:
1750:
1746:
1741:
1736:
1731:
1726:
1722:
1718:
1714:
1707:
1704:
1699:
1695:
1690:
1685:
1681:
1677:
1673:
1666:
1664:
1660:
1655:
1651:
1647:
1643:
1639:
1635:
1631:
1627:
1620:
1617:
1612:
1608:
1603:
1598:
1594:
1590:
1586:
1579:
1576:
1571:
1567:
1562:
1557:
1552:
1547:
1543:
1539:
1535:
1528:
1525:
1520:
1516:
1511:
1506:
1502:
1498:
1494:
1490:
1486:
1479:
1477:
1475:
1473:
1471:
1469:
1467:
1465:
1463:
1459:
1454:
1450:
1445:
1440:
1436:
1432:
1428:
1424:
1420:
1413:
1410:
1405:
1401:
1396:
1391:
1387:
1383:
1379:
1375:
1371:
1367:
1360:
1353:
1351:
1349:
1347:
1345:
1343:
1341:
1339:
1337:
1335:
1331:
1326:
1322:
1318:
1314:
1310:
1306:
1302:
1298:
1294:
1290:
1286:
1279:
1277:
1273:
1268:
1264:
1259:
1254:
1250:
1246:
1242:
1238:
1234:
1227:
1225:
1223:
1219:
1214:
1210:
1205:
1200:
1196:
1192:
1188:
1184:
1180:
1173:
1171:
1167:
1160:
1150:
1147:
1140:
1136:
1133:
1131:
1128:
1126:
1123:
1121:
1118:
1117:
1113:
1111:
1108:
1104:
1099:
1095:
1091:
1087:
1083:
1079:
1078:tobacco smoke
1075:
1071:
1067:
1066:Curtis Harris
1059:
1057:
1055:
1051:
1047:
1040:
1038:
1034:
1033:
1028:
1022:
1018:
1014:
1006:
1001:
997:
993:
990:
986:
985:
981:
977:
973:
969:
965:
964:
960:
955:
951:
947:
943:
942:
938:
932:
928:
923:
922:
918:
916:
914:
910:
902:
900:
898:
894:
890:
889:
884:
883:
878:
874:
870:
866:
862:
858:
854:
850:
846:
842:
841:DNA oxidation
838:
834:
833:
828:
824:
816:
812:
808:
804:
802:
796:
789:
787:
785:
784:
779:
775:
766:
764:
762:
758:
757:
752:
751:
746:
745:
740:
739:
735:
731:
727:
723:
715:
713:
711:
710:
705:
704:
697:
695:
691:
687:
682:
681:
676:
675:
669:
667:
663:
658:
656:
652:
651:
646:
645:
640:
636:
629:
627:
625:
621:
617:
613:
609:
608:
603:
602:
598:
594:
586:
584:
581:
579:
575:
571:
563:
561:
555:
551:
547:
538:
536:
534:
530:
526:
522:
518:
514:
507:
505:
503:
498:
496:
492:
488:
484:
480:
472:
470:
468:
464:
454:
450:
447:
444:
439:
438:
437:
436:
435:
426:
419:
417:
415:
411:
405:
398:
396:
394:
390:
386:
378:
368:
364:
361:
357:
353:
349:
345:
341:
337:
333:
329:
328:
327:
324:
319:
316:
313:
309:
305:
302:
301:
300:
297:
290:
286:
282:
278:
274:
270:
266:
263:
260:
256:
252:
248:
244:
240:
236:
232:
229:
226:
222:
218:
214:
211:
210:
209:
205:
202:
198:
194:
191:
187:
186:
185:
184:
180:
175:
171:
167:
163:
159:
156:
155:
154:
152:
148:
147:
146:
145:
143:
140:
136:
127:
121:
117:
110:
108:
106:
105:breast cancer
102:
98:
94:
90:
86:
82:
81:immunotherapy
78:
75:treatment in
74:
71:mutation and
70:
67:
66:
61:
57:
53:
49:
45:
40:
36:
34:
30:
26:
22:
18:
2931:. Retrieved
2929:. 2022-04-21
2926:
2917:
2874:
2870:
2860:
2825:
2821:
2811:
2790:
2747:
2743:
2733:
2698:
2695:Cell Reports
2694:
2684:
2641:
2637:
2627:
2584:
2580:
2570:
2559:. Retrieved
2555:
2515:
2511:
2505:
2488:
2482:
2447:
2443:
2433:
2390:
2386:
2376:
2341:
2337:
2327:
2282:
2278:
2268:
2225:
2221:
2211:
2174:
2170:
2160:
2115:
2111:
2055:
2051:
2038:
2003:
2000:eBioMedicine
1999:
1956:(2): 71–81.
1953:
1949:
1939:
1904:
1901:Cell Reports
1900:
1890:
1865:
1861:
1855:
1820:
1816:
1806:
1771:
1767:
1757:
1720:
1716:
1706:
1679:
1675:
1629:
1625:
1619:
1592:
1588:
1578:
1541:
1537:
1527:
1492:
1488:
1426:
1422:
1412:
1369:
1365:
1292:
1288:
1243:(1): 15–26.
1240:
1236:
1186:
1182:
1149:
1063:
1043:
1041:
1030:
1024:
1021:transversion
1010:
906:
897:8-Oxoguanine
892:
886:
880:
869:8-Oxoguanine
845:8-Oxoguanine
830:
823:transversion
820:
806:
800:
798:
781:
770:
754:
748:
742:
736:
719:
707:
701:
698:
678:
672:
670:
659:
648:
642:
633:
605:
599:
590:
582:
567:
556:
542:
511:
499:
476:
460:
448:
432:
406:
402:
382:
379:Genomic data
336:retroviruses
325:
298:
281:nitrosamines
237:agents adds
235:chemotherapy
181:
149:
131:
119:
64:
56:oncogenomics
41:
37:
16:
15:
2959:Mutagenesis
2171:J Biol Chem
1082:ultraviolet
1054:mutagenesis
1050:skin cancer
1037:mutagenesis
972:lung cancer
931:Ultraviolet
909:carcinogens
851:instead of
783:POLE (gene)
445:) database.
363:deamination
340:transposons
269:carcinogens
239:alkyl group
221:skin cancer
213:Ultraviolet
208:carcinogens
193:deamination
166:exonuclease
135:mutagenesis
95:to exploit
52:mutagenesis
21:mutagenesis
2948:Categories
2933:2022-04-22
2561:2018-09-25
2444:Cell Cycle
1723:(8): 233.
1161:References
911:and their
877:DNA repair
805:Defective
637:family of
493:(NHEJ) or
369:mutations.
251:DNA repair
217:DNA damage
206:Exogenous/
183:Genotoxins
153:infidelity
123:processes.
103:deficient
33:DNA repair
2909:248323597
2044:David, SS
2006:: 39–49.
1141:Note list
970:smoking,
393:mutations
310:requires
29:genotoxin
2927:BBC News
2901:35449305
2852:35949260
2828:(6591).
2782:23945592
2725:23318258
2676:20016488
2619:20016485
2532:12714181
2497:15055300
2474:29139326
2425:27811275
2368:35319765
2260:34330711
2203:26354431
2090:17581577
2030:28551381
1970:26822575
1931:26832400
1882:28964683
1847:24728294
1798:27643540
1749:28825669
1698:29246904
1646:28649135
1611:28235882
1570:27099521
1519:26551669
1453:30982602
1404:23945592
1325:38527914
1267:25354245
1213:27899578
1114:See also
853:cytosine
799:Role of
709:APOBEC3B
703:APOBEC3A
680:APOBEC3B
674:APOBEC3A
650:APOBEC3B
644:APOBEC3A
593:germline
360:cytidine
277:acrolein
225:melanoma
89:platinum
2879:Bibcode
2843:7613262
2822:Science
2797:bioRxiv
2773:3776390
2752:Bibcode
2716:3588146
2667:2880489
2646:Bibcode
2610:3145108
2589:Bibcode
2465:5914734
2416:6141049
2395:Bibcode
2387:Science
2359:8943639
2319:8483937
2287:Bibcode
2251:8324051
2230:Bibcode
2194:4646317
2152:1946433
2120:Bibcode
2081:2896554
2060:Bibcode
2021:5478212
1978:9359891
1922:4758883
1838:4137149
1789:6583788
1740:5580490
1717:Viruses
1654:3422717
1561:4821380
1510:4783858
1444:6506336
1395:3776390
1374:Bibcode
1317:1905840
1297:Bibcode
1289:Science
1258:4294947
1204:5210583
1060:History
996:guanine
989:tobacco
976:tobacco
968:tobacco
961:Tobacco
950:guanine
913:mutagen
873:adenine
865:adenine
861:adenine
849:adenine
635:APOBEC3
449:De novo
285:cyanide
265:Tobacco
259:mitosis
174:mitosis
2907:
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2871:Nature
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815:R code
811:COSMIC
722:COSMIC
694:APOBEC
692:(AID)/
686:APOBEC
666:APOBEC
624:indels
612:cancer
574:cancer
550:cancer
546:cancer
483:indels
443:COSMIC
356:APOBEC
350:/CDA,
255:Cancer
223:(e.g.
139:COSMIC
44:cancer
2905:S2CID
2310:46477
2143:52880
1974:S2CID
1650:S2CID
1362:(PDF)
1321:S2CID
888:NUDT1
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857:MUTYH
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801:MUTYH
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601:BRCA1
261:rate.
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2848:PMID
2778:PMID
2721:PMID
2672:PMID
2615:PMID
2528:PMID
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2421:PMID
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2256:PMID
2199:PMID
2148:PMID
2086:PMID
2026:PMID
1966:PMID
1927:PMID
1878:PMID
1843:PMID
1794:PMID
1745:PMID
1694:PMID
1642:PMID
1607:PMID
1566:PMID
1515:PMID
1449:PMID
1423:Cell
1400:PMID
1313:PMID
1263:PMID
1209:PMID
1032:POLH
893:MTH1
882:OGG1
835:, a
756:PMS2
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706:and
677:and
647:and
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354:and
338:and
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