184:, the resulting cancer cells have the potential to diverge in sequence and gain new traits. This intratumoral heterogeneity creates a tumor mass with different genomic backgrounds as well as unique cellular traits and drug susceptibilities. Several research groups have shown that heterogeneity and genomic instability are heavily correlated with poor patient outcomes and aggressive cancers. Chang-Min Choi et al. examined the survival of individuals with adenocarcinoma of the lung. Those individuals with higher rates of chromosome instability were associated with worse 5-year survival curves. This was similarly observed in a colorectal study by Walther et al. These more aggressive heterogenous tumors also provide unique difficulties for treatment regimens. To support this hypothesis, Duesberg et al. tested drug susceptibility on cell lines with and without aneuploidy. While the diploid cell lines remained drug sensitive, the aneuploid lines showed marked increases in mutation rates, drug resistance, and unintended morphological changes to cell phenotypes. As the importance of
160:. When Aurora B was partially inhibited by a small molecule drug, Cimini et al. observed lagging chromatids at increasing frequency. Similarly, mutations to the gene Stag2 have been associated with increased aneuploidy in cancers. Stag2 encodes a cohesin protein responsible for holding sister chromatids together pre-anaphase. Imaging of cells with Stag2
86:
originating from both spindle poles of the dividing cell. The merotelic attachments can occur in two ways: centrosome spindle attachments from both poles on the same chromatid kinetochore or the formation of a third centrosome whose microtubule spindles attach to a chromatid kinetochore. Because
843:
Choi, Chang-Min; Seo, Kwang Won; Jang, Se Jin; Oh, Yeon-Mok; Shim, Tae-Sun; Kim, Woo Sung; Lee, Dong-Soon; Lee, Sang-Do (2009-04-01). "Chromosomal instability is a risk factor for poor prognosis of adenocarcinoma of the lung: Fluorescence in situ hybridization analysis of paraffin-embedded tissue
103:
has the capacity to persist in the daughter cell but with abnormal replication and maintenance machinery. This allows for the accumulation of mutations, increasing the potential for future miss-segregation events. In total these events cause problematic aneuploid cells with increased genomic
460:
Cosenza, Marco R.; Cazzola, Anna; Rossberg, Annik; Schieber, Nicole L.; Konotop, Gleb; Bausch, Elena; Slynko, Alla; Holland-Letz, Tim; Raab, Marc S.; Dubash, Taronish; Glimm, Hanno; Poppelreuther, Sven; Herold-Mende, Christel; Schwab, Yannick; Krämer, Alwin (2017-08-22).
139:
The increasing importance of genomic instability on cancer progression has been emphasized in recent years. There are many ways to cause aneuploidy, however the genomic predispositions for these events are less well understood. In regards to the merotelic
116:, referring to the increased frequency in sequence mutation, chromosome rearrangement, and aneuploidy. The instability allows a cancerous growth to increasingly diverge from normal cell growth and division, with the potential to gain new traits such as
188:
in cancer prognosis/treatment continues, identifying the causes and consequences of mechanisms such as anaphase lag will be critical to understanding how cancer develops as well as developing better multi-target therapies.
51:. Whether the cell survives depends on which sister chromatid was lost and the background genomic state of the cell. The passage of abnormal numbers of chromosomes will have unique consequences with regards to
91:, it cannot migrate to the mass of segregated chromatids at either pole. If the migration is significantly delayed the reformation of nuclei will begin to occur without a full complement of chromosomes. This
47:
with unique repercussions. In either case, anaphase lag will cause one daughter cell to receive a complete set of chromosomes while the other lacks one paired set of chromosomes, creating a form of
721:
Solomon, David A.; Kim, Taeyeon; Diaz-Martinez, Laura A.; Fair, Joshlean; Elkahloun, Abdel G.; Harris, Brent T.; Toretsky, Jeffrey A.; Rosenberg, Steven A.; Shukla, Neerav (2011-08-19).
952:
Lee, Alvin J X; Endesfelder, David; Rowan, Andrew J; Walther, Axel; Birkbak, Nicolai J; Futreal, P Andrew; Downward, Julian; Szallasi, Zoltan; Tomlinson, Ian P M (2011-03-01).
515:
Chen, Guangbo; Mulla, Wahid A.; Kucharavy, Andrei; Tsai, Hung-Ji; Rubinstein, Boris; Conkright, Juliana; McCroskey, Scott; Bradford, William D.; Weems, Lauren (2015-02-12).
124:
165:
1011:"Explaining the high mutation rates of cancer cells to drug and multidrug resistance by chromosome reassortments that are catalyzed by aneuploidy"
104:
instability. This has important implications in the development and persistence of cancers as well as debilitating developmental diseases.
206:
415:"Merotelic kinetochore orientation versus chromosome mono-orientation in the origin of lagging chromosomes in human primary cells"
1082:
305:
Gordon, David J.; Resio, Benjamin; Pellman, David (March 2012). "Causes and consequences of aneuploidy in cancer".
786:
McGranahan, Nicholas; Burrell, Rebecca A.; Endesfelder, David; Novelli, Marco R.; Swanton, Charles (2012-06-01).
131:, as such the potential heterogeneity within these cells makes diagnosis and treatment increasingly difficult.
905:
666:"Aurora Kinase Promotes Turnover of Kinetochore Microtubules to Reduce Chromosome Segregation Errors"
231:
356:
Redli, Patrick M.; Gasic, Ivana; Meraldi, Patrick; Nigg, Erich A.; Santamaria, Anna (2016-10-10).
889:"Association between chromosomal instability and prognosis in colorectal cancer: a meta-analysis"
210:
900:
1087:
218:
63:
There are two notable mechanisms that cause
Anaphase Lag, each of which are characterized by
144:
attachments associated with anaphase lag, several genes have been implicated. Aurora B is a
1022:
734:
621:
Cimini, Daniela (2008-09-01). "Merotelic kinetochore orientation, aneuploidy, and cancer".
8:
463:"Asymmetric Centriole Numbers at Spindle Poles Cause Chromosome Missegregation in Cancer"
185:
181:
113:
1026:
738:
986:
953:
934:
820:
787:
763:
722:
703:
549:
516:
413:
Cimini, Daniela; Fioravanti, Daniela; Salmon, E. D.; Degrassi, Francesca (2002-02-01).
390:
357:
338:
282:
249:
35:
and the daughter cells will lose some genetic information. It is one of many causes of
1058:
1053:
1040:
1010:
991:
973:
926:
918:
869:
861:
825:
807:
768:
750:
695:
687:
646:
638:
603:
595:
554:
536:
492:
484:
442:
434:
395:
377:
330:
322:
287:
269:
28:
938:
707:
1097:
1092:
1048:
1030:
981:
965:
910:
853:
815:
799:
758:
742:
677:
630:
585:
544:
528:
474:
426:
385:
369:
342:
314:
277:
261:
92:
969:
857:
87:
the chromatid is being pulled in two opposing directions or away from the correct
479:
462:
75:
responsible for chromatid separation. Merotelic attachments occur when a single
634:
1015:
Proceedings of the
National Academy of Sciences of the United States of America
664:
Cimini, Daniela; Wan, Xiaohu; Hirel, Christophe B.; Salmon, E.D. (2006-09-05).
590:
573:
532:
358:"The Ska complex promotes Aurora B activity to ensure chromosome biorientation"
152:, and has been shown to function as a checkpoint for the proper attachments of
682:
665:
414:
64:
1076:
1044:
1035:
977:
922:
865:
811:
754:
691:
642:
599:
540:
488:
438:
381:
326:
273:
20:
914:
746:
1062:
995:
930:
873:
829:
772:
699:
650:
607:
558:
496:
446:
399:
334:
291:
169:
157:
117:
100:
96:
83:
72:
68:
803:
430:
373:
265:
141:
79:
55:
and development as well as the progression and heterogeneity of cancers.
95:
formation is also seen for the lone lagging sister chromatid, forming a
788:"Cancer chromosomal instability: therapeutic and diagnostic challenges"
161:
121:
76:
36:
888:
164:
showed increased frequency of lagging anaphase chromatids; subsequent
153:
149:
128:
88:
52:
24:
723:"Mutational Inactivation of STAG2 Causes Aneuploidy in Human Cancer"
318:
785:
48:
32:
954:"Chromosomal Instability Confers Intrinsic Multi-Drug Resistance"
44:
40:
250:"Losing balance: the origin and impact of aneuploidy in cancer"
172:
cell lines reduced the occurrence of this genomic instability.
145:
31:. The chromosome or chromatid does not properly migrate during
459:
412:
27:
do not properly separate from each other because of improper
112:
One of the hallmarks of cancer formation and persistence is
720:
951:
886:
517:"Targeting the Adaptability of Heterogeneous Aneuploids"
887:
Walther, A.; Houlston, R.; Tomlinson, I. (2008-07-01).
623:
Biochimica et
Biophysica Acta (BBA) - Reviews on Cancer
1008:
514:
127:. Aneuploidy is a drastic divergence from the normal
1009:
Duesberg, P.; Stindl, R.; Hehlmann, R. (2000-12-19).
355:
663:
572:
Hanahan, Douglas; Weinberg, Robert A. (2011-03-04).
304:
248:Holland, Andrew J; Cleveland, Don W (June 2012).
1074:
247:
571:
842:
574:"Hallmarks of Cancer: The Next Generation"
175:
1052:
1034:
985:
904:
819:
762:
681:
589:
548:
478:
389:
281:
1075:
620:
120:, immune system evasion, and loss of
107:
510:
508:
506:
243:
241:
19:is a consequence of an event during
39:. This event can occur during both
13:
14:
1109:
503:
238:
134:
1002:
945:
880:
836:
779:
714:
657:
614:
565:
453:
406:
349:
298:
199:
1:
970:10.1158/0008-5472.CAN-10-3604
858:10.1016/j.lungcan.2008.07.016
192:
58:
480:10.1016/j.celrep.2017.08.005
7:
635:10.1016/j.bbcan.2008.05.003
362:The Journal of Cell Biology
10:
1114:
591:10.1016/j.cell.2011.02.013
533:10.1016/j.cell.2015.01.026
207:"Human Molecular Genetics"
156:spindles to the chromatid
1083:Chromosomal abnormalities
683:10.1016/j.cub.2006.07.022
1036:10.1073/pnas.97.26.14295
915:10.1136/gut.2007.135004
844:from Korean patients".
747:10.1126/science.1203619
419:Journal of Cell Science
307:Nature Reviews Genetics
176:Prognosis and treatment
226:Cite journal requires
804:10.1038/embor.2012.61
431:10.1242/jcs.115.3.507
374:10.1083/jcb.201603019
266:10.1038/embor.2012.55
1027:2000PNAS...9714295D
1021:(26): 14295–14300.
739:2011Sci...333.1039S
733:(6045): 1039–1043.
186:genomic instability
182:genomic instability
180:Consequent of this
114:genomic instability
108:Hallmark of cancer
676:(17): 1711–1718.
213:on June 29, 2007.
29:spindle formation
1105:
1067:
1066:
1056:
1038:
1006:
1000:
999:
989:
964:(5): 1858–1870.
949:
943:
942:
908:
906:10.1.1.1019.9550
884:
878:
877:
840:
834:
833:
823:
783:
777:
776:
766:
718:
712:
711:
685:
661:
655:
654:
618:
612:
611:
593:
569:
563:
562:
552:
512:
501:
500:
482:
473:(8): 1906–1920.
457:
451:
450:
410:
404:
403:
393:
353:
347:
346:
302:
296:
295:
285:
245:
236:
235:
229:
224:
222:
214:
209:. Archived from
203:
125:checkpoint genes
93:nuclear envelope
1113:
1112:
1108:
1107:
1106:
1104:
1103:
1102:
1073:
1072:
1071:
1070:
1007:
1003:
958:Cancer Research
950:
946:
885:
881:
841:
837:
784:
780:
719:
715:
670:Current Biology
662:
658:
619:
615:
570:
566:
513:
504:
458:
454:
411:
407:
354:
350:
319:10.1038/nrg3123
303:
299:
246:
239:
227:
225:
216:
215:
205:
204:
200:
195:
178:
166:gene correction
148:active in late
137:
110:
67:attachments of
61:
12:
11:
5:
1111:
1101:
1100:
1095:
1090:
1085:
1069:
1068:
1001:
944:
899:(7): 941–950.
879:
835:
798:(6): 528–538.
778:
713:
656:
613:
584:(5): 646–674.
564:
527:(4): 771–784.
502:
452:
425:(3): 507–515.
405:
348:
313:(3): 189–203.
297:
260:(6): 501–514.
237:
228:|journal=
197:
196:
194:
191:
177:
174:
136:
135:Genomic causes
133:
109:
106:
60:
57:
9:
6:
4:
3:
2:
1110:
1099:
1096:
1094:
1091:
1089:
1086:
1084:
1081:
1080:
1078:
1064:
1060:
1055:
1050:
1046:
1042:
1037:
1032:
1028:
1024:
1020:
1016:
1012:
1005:
997:
993:
988:
983:
979:
975:
971:
967:
963:
959:
955:
948:
940:
936:
932:
928:
924:
920:
916:
912:
907:
902:
898:
894:
890:
883:
875:
871:
867:
863:
859:
855:
851:
847:
839:
831:
827:
822:
817:
813:
809:
805:
801:
797:
793:
789:
782:
774:
770:
765:
760:
756:
752:
748:
744:
740:
736:
732:
728:
724:
717:
709:
705:
701:
697:
693:
689:
684:
679:
675:
671:
667:
660:
652:
648:
644:
640:
636:
632:
628:
624:
617:
609:
605:
601:
597:
592:
587:
583:
579:
575:
568:
560:
556:
551:
546:
542:
538:
534:
530:
526:
522:
518:
511:
509:
507:
498:
494:
490:
486:
481:
476:
472:
468:
464:
456:
448:
444:
440:
436:
432:
428:
424:
420:
416:
409:
401:
397:
392:
387:
383:
379:
375:
371:
367:
363:
359:
352:
344:
340:
336:
332:
328:
324:
320:
316:
312:
308:
301:
293:
289:
284:
279:
275:
271:
267:
263:
259:
255:
251:
244:
242:
233:
220:
212:
208:
202:
198:
190:
187:
183:
173:
171:
167:
163:
159:
155:
151:
147:
143:
132:
130:
126:
123:
119:
115:
105:
102:
98:
94:
90:
85:
81:
78:
74:
70:
66:
56:
54:
50:
46:
42:
38:
34:
30:
26:
23:where sister
22:
21:cell division
18:
1088:Cytogenetics
1018:
1014:
1004:
961:
957:
947:
896:
892:
882:
852:(1): 66–70.
849:
845:
838:
795:
792:EMBO Reports
791:
781:
730:
726:
716:
673:
669:
659:
629:(1): 32–40.
626:
622:
616:
581:
577:
567:
524:
520:
470:
467:Cell Reports
466:
455:
422:
418:
408:
368:(1): 77–93.
365:
361:
351:
310:
306:
300:
257:
254:EMBO Reports
253:
219:cite journal
211:the original
201:
179:
170:glioblastoma
158:kinetochores
138:
118:angiogenesis
111:
101:micronucleus
97:micronucleus
84:microtubules
82:attaches to
73:microtubules
69:kinetochores
62:
17:Anaphase lag
16:
15:
846:Lung Cancer
142:kinetochore
80:kinetochore
1077:Categories
193:References
162:knock-outs
122:cell cycle
77:centromere
59:Mechanisms
37:aneuploidy
25:chromatids
1045:0027-8424
978:0008-5472
923:0017-5749
901:CiteSeerX
866:0169-5002
812:1469-3178
755:0036-8075
692:0960-9822
643:0304-419X
600:0092-8674
541:0092-8674
489:2211-1247
439:0021-9533
382:0021-9525
327:1471-0064
274:1469-221X
168:in human
154:centriole
150:metaphase
129:karyotype
89:centriole
65:merotelic
53:mosaicism
1063:11121035
996:21363922
939:26360129
931:18364437
874:18814932
830:22595889
773:21852505
708:18117282
700:16950108
651:18549824
608:21376230
559:25679766
497:28834753
447:11861758
400:27697923
335:22269907
292:22565320
49:monosomy
33:anaphase
1098:Mitosis
1093:Meiosis
1023:Bibcode
987:3059493
821:3367245
764:3374335
735:Bibcode
727:Science
550:4328141
391:5057281
343:4956346
283:3367240
99:. The
71:to the
45:mitosis
41:meiosis
1061:
1051:
1043:
994:
984:
976:
937:
929:
921:
903:
872:
864:
828:
818:
810:
771:
761:
753:
706:
698:
690:
649:
641:
606:
598:
557:
547:
539:
495:
487:
445:
437:
398:
388:
380:
341:
333:
325:
290:
280:
272:
146:kinase
1054:18912
935:S2CID
704:S2CID
339:S2CID
1059:PMID
1041:ISSN
992:PMID
974:ISSN
927:PMID
919:ISSN
870:PMID
862:ISSN
826:PMID
808:ISSN
769:PMID
751:ISSN
696:PMID
688:ISSN
647:PMID
639:ISSN
627:1786
604:PMID
596:ISSN
578:Cell
555:PMID
537:ISSN
521:Cell
493:PMID
485:ISSN
443:PMID
435:ISSN
396:PMID
378:ISSN
331:PMID
323:ISSN
288:PMID
270:ISSN
232:help
43:and
1049:PMC
1031:doi
982:PMC
966:doi
911:doi
893:Gut
854:doi
816:PMC
800:doi
759:PMC
743:doi
731:333
678:doi
631:doi
586:doi
582:144
545:PMC
529:doi
525:160
475:doi
427:doi
423:115
386:PMC
370:doi
366:215
315:doi
278:PMC
262:doi
1079::
1057:.
1047:.
1039:.
1029:.
1019:97
1017:.
1013:.
990:.
980:.
972:.
962:71
960:.
956:.
933:.
925:.
917:.
909:.
897:57
895:.
891:.
868:.
860:.
850:64
848:.
824:.
814:.
806:.
796:13
794:.
790:.
767:.
757:.
749:.
741:.
729:.
725:.
702:.
694:.
686:.
674:16
672:.
668:.
645:.
637:.
625:.
602:.
594:.
580:.
576:.
553:.
543:.
535:.
523:.
519:.
505:^
491:.
483:.
471:20
469:.
465:.
441:.
433:.
421:.
417:.
394:.
384:.
376:.
364:.
360:.
337:.
329:.
321:.
311:13
309:.
286:.
276:.
268:.
258:13
256:.
252:.
240:^
223::
221:}}
217:{{
1065:.
1033::
1025::
998:.
968::
941:.
913::
876:.
856::
832:.
802::
775:.
745::
737::
710:.
680::
653:.
633::
610:.
588::
561:.
531::
499:.
477::
449:.
429::
402:.
372::
345:.
317::
294:.
264::
234:)
230:(
Text is available under the Creative Commons Attribution-ShareAlike License. Additional terms may apply.