A large proportion of epithelial cancers show the chromosome-instability phenotype, in which they have many chromosome abnormalities. This is thought to be the result of mutations that disrupt chromosome maintenance, but the causative mutations are not known. We identified cell lines known to have mutations that might cause chromosome instability, and examined their karyotypes. Two cell lines, the breast cancer line HCC1937 and the pancreatic cancer line CAPAN-1, that have mutations respectively in BRCA1 and BRCA2, had very abnormal karyotypes, with many structural and numerical chromosome changes and substantial variation between metaphases. However, two colorectal cancer lines with mutations in BUB1, a spindle checkpoint protein involved in chromosome segregation, had rather simple near-tetraploid karyotypes, with minimal loss or gain of chromosomes other than the endoreduplication event, and minimal structural change. Apart from tetraploidy, these karyotypes were typical of colorectal lines considered to be chromosomally stable. Two lines derived from the same tumour, DLD-1 and HCT-15, with bi-allelic mutation of CHK2, had karyotypes that were typical of near-diploid colorectal lines considered chromosomally stable. The karyotypes observed supported the proposed role for BRCA1 and BRCA2 mutations in chromosomal instability, but showed that the tested mutations in BUB1 and CHK2 did not result in karyotypes that would have been predicted if they were sufficient for chromosomal instability.    

1.
Abdel-Rahman WM, Katsura K, Rens W, Gorman PA, Sheer D, Bicknell D, Bodmer WF, Arends MJ, Wyllie AH, Edwards PA: Spectral karyotyping suggests additional subsets of colorectal cancers characterized by pattern of chromosome rearrangement. Proc natl Acad Sci, USA 98:2538–2543 (2001).
2.
Adelaide J, Huang H-E, Murati A, Alsop AE, Orsetti B, Mozziconacci M-J, Popovici C, Ginestier C, Letessier A, Basset C, Courtay-Cahen C, Jacquemier J, Theillet C, Birnbaum D, Edwards PA, Chaffanet M: A recurrent chromosome translocation breakpoint in breast and pancreatic cancer cell lines targets the Neuregulin/NRG1 gene. Genes Chromosomes Cancer 37:333–345 (2003).
3.
Bell DW, Varley JM, Szydlo TE, Kang DH, Wahrer DC, Shannon KE, Lubratovich M, Verselis SJ, Isselbacher KJ, Fraumeni JF, Birch JM, Li FP, Garber JE, Haber DA: Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science 286:2528–2531 (1999).
4.
Cahill DP, Lengauer C, Yu J, Riggins GJ, Willson JK, Markowitz SD, Kinzler KW, Vogelstein B: Mutations in mitotic checkpoint genes in human cancers. Nature 392:300–303 (1998).
5.
Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE: Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nature Genet 8:27–32 (1994).
6.
Chen J, Silver DP, Walpita D, Cantor SB, Gazdar AF, Tomlinson G, Couch FJ, Weber BL, Ashley T, Livingston DM, Scully R: Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. Mol Cell 2:317–328 (1998).
7.
Chen TR, Dorotinsky CS, McGuire LJ, Macy ML, Hay RJ: DLD-1 and HCT-15 cell lines derived separately from colorectal carcinomas have totally different chromosome changes but the same genetic origin. Cancer Genet Cytogenet 81:103–108 (1995).
8.
Davidson JM, Gorringe KL, Chin S-F, Orsetti B, Besret C, Courtay-Cahen C, Roberts I, Theillet C, Caldas C, Edwards PA: Molecular cytogenetic analysis of breast cancer cell lines. Br J Cancer 83:1309–1317 (2000).
9.
Dutrillaux B: Pathways of chromosome alteration in human epithelial cancers. Adv Cancer Res 67:59–82 (1995).
10.
Eshleman JR, Casey G, Kochera ME, Sedwick WD, Swinler SE, Veigl ML, Willson JK, Schwartz S, Markovitz SD: Chromosome number and structure both are markedly stable in RER colorectal cancers and are not destabilized by mutation of p53. Oncogene 17:719–725 (1998).
11.
Falck J, Mailand N, Syljuasen RG, Bartek J, Lukas J: The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 410:842–847 (2001).
12.
Galloway SM, Ivett JL: Chemically induced aneuploidy in mammalian cells in culture. Mutat Res 167:89–105 (1986).
13.
Gayther SA, Batley SJ, Linger L, Bannister A, Thorpe K, Chin S–F, Daigo Y, Russell P, Wilson A, Sowter HM, Delhanty JD, Ponder BA, Kouzarides T, Caldas C: Mutations truncating the EP300 acetylase in human cancers. Nature Genet 24:300–303 (2000).
14.
Ghadimi BM, Schrock E, Walker RL, Wangsa D, Jauho A, Meltzer PS, Ried T: Specific chromosomal aberrations and amplification of the AlB1 nuclear receptor coactivator gene in pancreatic carcinomas. Am J Pathol 154:525–536 (1999).
15.
Ghadimi BM, Sackett, DL, Difilippantonio MJ, Schrock E, Neumann T, Jauho A, Auer G, Ried T: Centrosome amplification and instability occurs exclusively in aneuploid, but not in diploid colorectal cancer cell lines, and correlates with numerical chromosomal aberrations. Genes Chrom Cancer 27:183–190 (2000).
16.
Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM, Yeo CJ, Jackson CE, Lynch HT, Hruban RH, Kern SE: Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res 56:5360–5364 (1996).
17.
Hirao A, Cheung A, Duncan G, Girard PM, Elia AJ, Wakeham A, Okada H, Sarkissian T, Wong JA, Sakai T, De Stanchina E, Bristow RG, Suda T, Lowe SW, Jeggo PA, Elledge SJ, Mak TW: Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia telangiectasia mutated (ATM)-dependent and an ATM-independent manner. Mol Cell Biol 22:6521–6532 (2002).
18.
Jallepalli PV, Lengauer C: Chromosome segregation and cancer: cutting through the mystery. Nature Rev 1:109–117 (2001).
19.
Kastan MB: Checking two steps. Nature 410:766–767 (2001).
20.
Kytola S, Rummukainen J, Nordgren A, Karhu R, Farnebo F, Isola J, Larsson C: Chromosomal alterations in 15 breast cancer cell lines by comparative genomic hybridization and spectral karyotyping. Genes Chrom Cancer 28:308–317 (2000).
21.
Lee H, Trainer AH, Friedman LS, Thistlethwaite FC, Evans MJ, Ponder BA, Venkitaraman AR: Mitotic checkpoint inactivation fosters transformation in cells lacking the breast cancer susceptibility gene, Brca2. Mol Cell 4:1–10 (1999).
22.
Lee SB, Kim SH, Bell DW, Wahrer DC, Schiripo TA, Jorczak MM, Sgroi DC, Garber JE, Li FP, Nichols KE, Varley JM, Godwin AK, Shannon KM, Harlow E, Haber DA: Destabilization of CHK2 by a missense mutation associated with Li-Fraumeni syndrome. Cancer Res 61:8062–8067 (2001).
23.
Lengauer C, Kinzler KW, Vogelstein B: Genetic instability in colorectal cancers. Nature 386:623–627 (1997).
24.
Lengauer C, Kinzler KW, Vogelstein B: Genetic instabilities in human cancers. Nature 396:643–649 (1998).
25.
Moynahan ME, Pierce AJ, Jasin M: BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell 7:263–272 (2001).
26.
Musacchio A, Hardwick KG: The spindle checkpoint: structural insights into dynamic signalling. Nat Rev Mol Cell Biol 3:731–741 (2002).
27.
O’Connor PM, Jackman J, Bae I, Myers TG, Fan S, Mutoh M, Scudiero DA, Monks A, Sausville EA, Weinstein JN, Friend S, Fornace AJ Jr, Kohn KW: Characterization of the p53 tumor suppressor pathway in cell lines of the National Cancer Institute anticancer drug screen and correlations with the growth-inhibitory potency of 123 anticancer agents. Cancer Res 57:4285–4300 (1997).
28.
Özdag H, Batley SJ, Forsti A, Iyer NG, Daigo Y, Boutell J, Arends MJ, Ponder BA, Kouzarides T, Caldas C: Mutation analysis of CBP and PCAF reveals rare inactivating mutations in cancer cell lines but not in primary tumours. Br J Cancer 87:1162–1165 (2002).
29.
Patel KJ, Yu VP, Lee H, Corcoran A, Thistlethwaite FC, Evans MJ, Colledge WH, Friedman LS, Ponder BA, Venkitaraman AR: Involvement of Brca2 in DNA Repair. Mol Cell 1:347–357 (1998).
30.
Polyak K, Waldman T, He T-C, Kinzler KW, Vogelstein B: Genetic determinants of p53-induced apoptosis and growth arrest. Genes Dev 10:1945–1952 (1996).
31.
Popovici C, Basset C, Bertucci F, Orsetti B, Adelaide J, Mozziconacci MJ, Conte N, Murati A, Ginestier C, Charafe-Jauffret E, Ethier SP, Lafage-Pochitaloff M, Theillet C, Birnbaum D, Chaffanet M: Reciprocal translocations in breast tumor cell lines: cloning of a t(3;20) that targets the FHIT gene. Genes Chrom Cancer 35:204–218 (2002).
32.
Redston MS, Caldas C, Seymour AB, Hruban RH, da Costa L, Yeo CJ, Kern SE: p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res 54:3025–3033 (1994).
33.
Roschke AV, Stover K, Tonon G, Schaffer AA, Kirsch IR: Stable karyotypes in epithelial cancer cell lines despite high rates of ongoing structural and numerical chromosomal instability. Neoplasia 4:19–31 (2002).
34.
Rowan AJ, Lamium H, Ilyas M, Wheeler J, Straub J, Papadopoulou A, Bicknell D, Bodmer WF, Tomlinson IPM: APC mutations in sporadic colorectal tumors: A mutational “hotspot” and interdependence of the “two hits”. Proc natl Acad Sci, USA 97:3352–3357 (2000).
35.
Schröck E, du Manoir S, Veldman T, Schoell B, Wienberg J, Ferguson-Smith MA, Ledbetter DH, Bar-Am I, Soenksen D, Garini Y, Ried T: Multicolor spectral karyotyping of human chromosomes. Science 273:494–497 (1996).
36.
Schutte M, Seal S, Barfoot R, Meijers-Heijboer H, Wasielewski M, Evans DG, Eccles D, Meijers C, Lohman F, Klijn J, Van Den Ouweland A, Futreal PA, Nathanson KL, Weber BL, Easton DF, Stratton MR, Rahman N: Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility. Am J hum Genet 72:1023–1028 (2003).
37.
Scully R, Ganesan S, Vlasakova K, Chen J, Socolovsky M, Livingston DM: Genetic analysis of BRCA1 function in a defined tumor cell line. Mol Cell 4:1093–1099 (1999).
38.
Sirivatanauksorn V, Sirivatanauksorn Y, Gorman PA, Davidson JM, Sheer D, Moore PS, Scarpa A, Edwards PA, Lemoine NR: Non-random chromosomal rearrangements in pancreatic cancer cell lines identified by spectral karyotyping. Intl J Cancer 91:350–358 (2001).
39.
Sodha N, Houlston RS, Williams R, Yuille MA, Mangion J, Eeles RA: A robust method for detecting CHK2/RAD53 mutations in genomic DNA. Hum Mutat 19:173–177 (2002).
40.
Tighe A, Johnson VL, Albertella M, Taylor SS: Aneuploid colon cancer cells have a robust spindle checkpoint. EMBO Rep 2:609–614 (2001).
41.
Tomlinson GE, Chen TT, Stastny VA, Virmani AK, Spillman MA, Tonk V, Blum JL, Schneider NR, Wistuba II, Shay JW, Minna JD, Gazdar AF: Characterization of a breast cancer cell line derived from a germ-line BRCA1 mutation carrier. Cancer Res 58:3237–3242 (1998).
42.
Venkitaraman AR: Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108:171–182 (2002).
43.
Warren CD, Brady DM, Johnston RC, Hanna JS, Hardwick KG, Spencer FA: Distinct chromosome segregation roles for spindle checkpoint proteins. Mol Biol Cell 13:3029–3041 (2002).
44.
Wheeler JMD, Beck NE, Kim HC, Tomlinson IPM, Mortensen NJMcC, BodmerWF: Mechanisms of inactivation of mismatch repair genes in human colorectal cancer cell lines: The predominant role of hMLH1. Proc natl Acad Sci, USA 96:10296–10301 (1999).
45.
Willson JK, Bittner GN, Oberley TD, Meisner LF, Weese JL: Cell culture of human colon adenomas and carcinomas. Cancer Res 47:2704–2713 (1987).
46.
Wu X, Webster SR, Chen J: Characterization of tumor-associated Chk2 mutations. J biol Chem 276:2971–2974 (2001).
47.
Xu X, Weaver Z, Linke SP, Li C, Gotay J, Wang XW, Harris CC, Ried T, Deng CX: Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol Cell 3:389–395 (1999).
48.
Xu X, Qiao W, Linke SP, Cao L, Li WM, Furth PA, Harris CC, Deng CX: Genetic interactions between tumor suppressors Brca1 and p53 in apoptosis, cell cycle and tumorigenesis. Nature Genet 28:266–271 (2001).
49.
Yu VP, Koehler M, Steinlein C, Schmid M, Hanakahi LA, van Gool AJ, West SC, Venkitaraman AR: Gross chromosomal rearrangements and genetic exchange between nonhomologous chromosomes following BRCA2 inactivation. Genes Dev 14:1400–1406 (2000).
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