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[Cancer Research 60, 4349-4352, August 15, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Genomic Instability at the BUB1 Locus in Colorectal Cancer, but not in Non-Small Cell Lung Cancer1

Ross G. Jaffrey, Stuart C. Pritchard, Caroline Clark, Graeme I. Murray, James Cassidy, Keith M. Kerr, Marianne C. Nicolson and Howard L. McLeod2

Departments of Medicine and Therapeutics [R. G. J., S. C. P., J. C., M. C. N., H. L. M.], Medical Genetics [C. C.], and Pathology [G. I. M., K. M. K.], Institute of Medical Sciences, University of Aberdeen, and Grampian University Hospital Trust [G. I. M., J. C., K. M. K, M. C. N.], Aberdeen AB25 2ZD, Scotland


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Genomic instability is observed in the majority of human tumors. Dysregulation of the mitotic spindle checkpoint is thought to be one of the mechanisms that facilitate aneuploidy in tumor cells. Mutations in the mitotic spindle checkpoint kinase BUB1 cause a dominant negative disruption of the spindle, leading to chromosome instability in cancer cell lines. However, little is known about chromosome 2q14, the genomic region containing BUB1, in human tumors. The BUB1 locus was evaluated in 32 colorectal cancer (CRC) and 20 non-small cell lung cancer (NSCLC) primary tumors using a panel of seven microsatellite repeats for 2q, two CA repeats in BUB1, and gene mutation analysis. The 2q locus was allelically stable in NSCLC but relatively unstable in colorectal primary tumors (20 of 32 tumors, 62.5%). In addition, 14.5% of CRC patients displayed instability within BUB1. Previously described BUB1 mutations and polymorphisms were rare (<1%) in the CRC or NSCLC tumors. Our data demonstrate 2q and BUB1 allelic instability in CRC and indicate that mutations in BUB1 are rare causes of chromosome instability in CRC or NSCLC. Additional investigations may shed light on the mechanistic impact of the mitotic spindle checkpoint pathway in colorectal tumor initiation and progression.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Genomic instability is a common feature of human cancer and is thought to be an important contributor to the malignant phenotype (1 , 2) . At least two categories of instability have been described: (a) CIN;3 and (b) MIN (3) . CIN is characterized by an alteration in chromosome number and is commonly detected as aneuploidy. For example, aneuploidy is observed in 70% of NSCLCs (4) and 50–70% of CRCs (5, 6, 7) . However, the influence of CIN in tumor development is a poorly understood phenomenon (8) . Attention has focused on the genes involved in the formation and control of the mitotic spindle checkpoint as likely candidates for CIN evolution because loss of the spindle checkpoint is a common feature of aneuploidy in yeast cells (9, 10, 11) .

Alterations in the mitotic spindle checkpoint kinase gene BUB1, which is located at chromosome 2q14, have been associated with CIN in human CRC. BUB1 is required for the normal mitotic delay in response to spindle disruption (12) . Cells lacking BUB1 can escape apoptosis, continuing cell cycle progression (13) . As the deformed mitotic spindle progresses, daughter cells receive abnormal chromosome complements, thus becoming aneuploid. Two BUB1 mutations were recently identified among 19 human CRC cell lines: (a) mutation at the 5' splice donor site for exon 4 (G->A); and (b) a missense mutation in exon 13 (C1413A; Ref. 13 ). These mutations in BUB1 appear to act in a dominant negative manner, leading to CIN and aneuploidy (13) . Additional SNPs in BUB1 have also been described recently (14, 15, 16) .

Little data exist on BUB1 in human tumors. In this study, NSCLC and colorectal tumors were used as models for evaluation of the BUB1 locus because both tumor types have a high incidence of CIN (1 , 2 , 4, 5, 6) . The BUB1 locus on chromosome 2q was assessed for genomic instability using a panel of microsatellite markers. In addition, two CA dinucleotide repeats in BUB1 were cloned and evaluated in the 32 CRC and 20 NSCLC samples. Lastly, the BUB1 gene was assessed to determine the frequency of two mutations and three polymorphisms described previously. (13, 14, 15, 16) .


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Tumor Samples.
DNA was extracted from primary surgical resection samples of 32 consecutive colorectal adenocarcinomas (7 Dukes’ stage A, 12 Dukes’ stage B, and 13 Dukes’ stage C samples) and 20 consecutive NSCLCs (13 adenocarcinomas and 7 squamous carcinomas, all stage II). DNA was prepared from frozen tumor and adjacent normal tissue using the Nucleon extraction kit (Anachem-Scotlab, Luton, United Kingdom).

Cell Lines.
HT29, BE, CACO2, DLD-1, and LOVO CRC cell lines were cultured in 50% DMEM and 50% Ham’s F-10 medium (Life Technologies, Inc., Paisley, United Kingdom). H630, H630-R10, and RKO CRC cell lines were cultured in RPMI 1640 (Life Technologies, Inc.); both media were supplemented with 10% fetal bovine serum, 2 mM L-glutamine, and 100 units of penicillin/streptomycin (Life Technologies, Inc.). Cells were grown in a 37°C incubator with 5% CO2. All cell lines were passaged once a week using trypsin-EDTA and split 1:10, with a subsequent medium change every 3–4 days. BE, CACO2, H630, H630-R10, and HT29 are CIN-positive cell lines.4

Characterization of BUB1 Mutations.
The previously reported BUB1 mutations were evaluated by directly sequencing PCR products from tumor DNA using previously published flanking intronic primers (13 , 14) . PCR products were purified using Centricon 100 microconcentrator columns (Amicon, Stonehouse, United Kingdom). Both strands of the amplified fragment were sequenced directly on an automated DNA sequencer (ABI 377) using a rhodamine-based dideoxy-terminator mix (Applied Biosystems, Foster City, CA). Each sequence was compared with the known sequence of the BUB1 cDNA (AF046078).

2q Instability Analysis.
Seven pairs of oligonucleotide primers for microsatellite markers from the long arm of chromosome 2 were obtained from Research Genetics (Huntsville, AL) and used to evaluate allelic instability near the BUB1 locus: (a) D2S2269; (b) D2S298; (c) IL1A (2q13); (d) D2S176 (2q11.2); (e) D2S1895; (f) D2S1896; and (g) D2S1897. Each primer set was used to amplify the repeat and short flanking sequences from template DNA by the PCR, as described previously (17) . The products were labeled directly with [{alpha}-32P]dCTP (Amersham, Buckinghamshire, United Kingdom) during the amplification reaction, followed by electrophoretic separation in 6% polyacrylamide gels and detection by autoradiography.

BUB1 Dinucleotide Repeats.
A bacterial artificial chromosome containing BUB1 was a gift from C. Lengauer, D. Cahill, and B. Vogelstein (14) . DNA was digested with the restriction endonuclease SacI (Promega, Southampton, United Kingdom) and subcloned into SacI-digested plasmid vector pGEM 3Zf(+) (Promega). This library was transformed into competent JM109 Escherichia coli cells (Promega) and screened on nylon membranes using a {gamma}-32P-labeled CA12 oligonucleotide probe. Positive colonies were further screened by PCR using a primer specific to the 3' end of exons 3–25 (14) and T7/SP6 primers specific to the vector sequences. These products were subjected to fluorescence dideoxy sequencing to identify the sequence flanking a 12-CA repeat in intron 19, (BUBCA19, GenBank accession number AF264055). A second 20-CA repeat, (BUBCA18, GenBank accession number AF264056), was also identified within a 4-kb fragment containing exons 16, 17, and 18. Primers were then designed to amplify a 119-bp product containing the BUBCA19 repeat (BUBCA19F, 5'-TTACAGATACAACTCCCTATTGG-3'; BUBCA19R, 5'-GTTTCTCTATGAAGTTGATGG-3') and a 175-bp product containing the BUBCA18 repeat (BUBCA18F, 5'-GTAGACTCAGGGCTTTGGTTC-3'; BUBCA18R, 5'-CAAAGGAGTGATTTAGGAGAC-3'). Instability of the repeats was evaluated as described above, with an annealing temperature of 56°C.

Sequencing of BUBCA18 LOH Samples.
The BUB1 coding region (excluding exon 1) was sequenced as described above in the two patients with BUBCA18 LOH, using previously described primers for exons 2–25 (14) .

MIN Status.
Each colorectal normal tissue/tumor paired DNA sample was also screened for mismatch repair deficiency using a 5-loci clinical panel: (a) Bat26; (b) Bat40; (c) DP1; (d) D2S123; (e) D17S250; and (f) D13S160 (18) . Mismatch deficiency was scored according to the guidelines of the International Collaborative Group on Hereditary Nonpolyposis Colorectal Carcinoma (18) . A MIN-positive tumor was defined as having instability in two or more markers. NSCLC samples were not evaluated for MIN.

BUB1 SNP Analysis.
A previously described SNP (G394A) in exon 4 from the BUB1 mutation sequencing experiments (14) was evaluated. RFLP analysis was performed on two additional BUB1 polymorphisms described previously in exons 3 (G157T) and 17 (C1993G; Ref. 14 ). A 146-bp fragment of BUB1 exon 3 that contained the polymorphism was amplified by using forward primer 5'-CCATATTTTCTAGATACATACAG-3' and reverse primer 5'-CTGATGAATCTTGGGTCATTG-3'. A 136-bp fragment of exon 17 was similarly amplified using forward primer 5'-CTCTAATTTTTGAATCTTTCAG-3' and reverse primer 5'-CAGAACCAAATAAACCCTCA C-3'. A 50-µl PCR reaction containing 50 ng of genomic DNA, 25 µM each deoxynucleotide triphosphate, 10 µM each primer, 5x reaction buffer (Promega), and 1 unit (5 units/µl) of Taq (Promega) was used in a thermocycler. After denaturing for 2 min at 95°C, the DNA was amplified for 35 cycles at 94°C for 30 s, 55°C for 40 s, and 72°C for 40 s, followed by a 5-min extension at 72°C. A control reaction containing all but the DNA was included in every PCR experiment. Five µl of each PCR product were run on a 1% agarose gel to ensure the expected bp products were generated. Ten µl of the PCR products were digested for 1 h at 37°C with 10 units of ApoI (exon 3) or at 50°C with 20 units of NlaIV (exon 17; New England Biolabs, Beverly, MA). The restriction digest products were separated on a 2.5% agarose gel.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Instability Analysis of 2q.
Allelic instability was observed in one or more of the seven microsatellite markers on chromosome 2q in 20 of 32 colorectal tumors (62.5%; Fig. 1Citation ). This consisted of LOH in 6 cases and MIN in 14 cases, including five patients who also met the criteria for mismatch repair deficiency. The BUBCA18 repeat revealed instability in 4 of 32 CRC patients (12.5%), two of whom showed LOH (6.25%; Fig. 2Citation ) whereas the BUBCA19 repeat revealed MIN in two patients (6.25%). The BUB1 coding region (excluding exon 1) was sequenced in the two patients with BUBCA18 LOH and in three control subjects. An apparent homozygous G200C transition in exon 3 was observed. However, the C allele was present in all control subjects, suggesting that it is the wild-type allele. The NSCLC patients did not show instability at any locus in the chromosome 2q microsatellite panel, including the BUB1 intronic repeats.



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  		Fig. 1. Schematic representation of LOH and MIN distribution on chromosome 2 in CRC and NSCLC. Tumor numbers are shown at the top, and markers are shown to the left and right. All microsatellite markers map between 2q11 and 2q14, including the BUBCA18 and BUBCA19 at 2q14.

 


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  		Fig. 2. MIN analysis with BUBCA18 in CRC samples. In each case, Lane N shows the DNA from normal colon, and Lane T shows DNA from the colonic tumor of the same patient. Patient 16 reveals heterozygosity for the marker. Patient 17 shows an allelic shift in the tumor (MIN). Patients 3 and 32 reveal allelic loss in the form of LOH.

 
BUB1 Mutations.
The whole of exon 4 (198 bp) and 192 bp of flanking intronic sequence were sequenced in the 20 NSCLC tumor samples, 32 CRC tumor samples, and 8 colorectal cell lines. No known or novel mutations were identified when compared with those found in cDNA from normal lymphocyte controls or in the original sequence (AF046078). Similarly, when exons 12 (129 bp) and 13 (111 bp) and 222 bp of intronic sequence were sequenced in all tissue and cell line samples, no known or novel mutations were seen.

BUB1 SNPs.
The exon 4 polymorphism (G394A) was not detected in any of the sequenced CRC or NSCLC samples. One NSCLC patient was heterozygous for G157T on exon 3 on RFLP analysis, but this SNP was not observed in the 32 CRC tumors. All of the 32 colorectal tumors, 8 CRC cell lines, and 20 NSCLC tumors had wild-type C at nucleotide 1993 in exon 17.


   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
CIN, in the form of aneuploidy, appears to play a major role in human tumor development. Aneuploidy is common to most tumor types and occurs as an early event in cancer progression (3) . Despite the fact that CIN is a relatively common phenotype, its mechanistic basis is unclear. One of the molecular mechanisms thought to be involved in CIN is the disruption of the mitotic spindle checkpoint. In particular, BUB1 has recently been implicated in colorectal tumorigenesis (13) . In this study, we evaluated genetic instability in the 2q region containing the mitotic spindle checkpoint gene BUB1.

Chromosome 2q is unstable at one or more loci in 62.5% of our CRC cases, with 15.6% demonstrating instability at dinucleotide repeats within the BUB1 gene. The high incidence of genomic instability in CRCs could have wide-ranging implications. Previous studies have shown that instability leads to alterations in short repeat sequences within the coding region of genes such as TGFßIIR, hMSH3, E2F4, hMSH6, BAX, and BRCA2 (19) . Furthermore, shortening of the microsatellite sequence within the promoter has been linked to the down-regulation of genes such as MMP9 (20) . Instability in coding regions, including introns, appears to be able to significantly influence gene transcription through direct or indirect mechanisms (21 , 22) . Therefore, localized 2q instability in CRC may have functional significance. Altered BUB1, through instability, is a possible mechanistic basis for CIN acquisition.

NSCLC had no instability at chromosome 2q with any of the evaluated markers. Previous investigation of chromosome 2q in NSCLC revealed allelic loss in 25% of primary tumors (23) . However, the majority of this instability was localized to the distal region of the chromosome, which was not evaluated in the current study (23) . Based on our mutational characterization of BUB1 in primary NSCLC tumors, it is unlikely that the aneuploidy seen in NSCLC stems from a mutant BUB1 disruption of the mitotic spindle checkpoint.

The genomic instability of this region may have repercussions for the function of BUB1. LOH in the BUBCA18 marker at BUB1 was observed in 2 of 32 CRC patients. BUB1 sequencing of these two CRC patients revealed no new mutations, polymorphisms, or sequence variants to satisfy a hypothesis of functional inactivation of the remaining allele. Alternatively, silencing of gene promoter activity through methylation or other epigenetic events (24, 25, 26) may influence the remaining BUB1 allele. Because the promoter sequence of the BUB1 gene is unknown, we could not evaluate this event in our study.

Previously published mutations in exons 4 and 13 were screened in 32 CRC tumors, 8 CRC cell lines, and 20 NSCLC tumors. No alterations were seen in any of the tumors or cell lines. This suggests that the described BUB1 mutations are not signature mutations for BUB1-mediated CIN.

The previously described BUB1 mutations and SNPs were low-frequency events in CRC and NSCLC (<1%). This does not rule out the involvement of BUB1 in CRC, because frequent instability was seen in the 2q region. More comprehensive analysis of the 2q region may prove valuable for detecting novel developmental mechanisms of CRC. In addition, other components of the mitotic spindle checkpoint have been implicated in CIN, including MAD2 and BUBR1 (13 , 14 , 27) . Comprehensive evaluation of the members of this pathway may accelerate understanding of the complex and subtle mechanisms involved in cellular chromosome catastrophe.


   Acknowledgments
 
The Aberdeen Colorectal Initiative Steering Committee is Jim Cassidy, Howard L. McLeod, Graeme I. Murray, Neva Haites, Julian Little, and William T. Melvin. The support of the surgeons and staff of Wards 32, 49, and 50 of the Grampian University Trust Hospital is greatly appreciated. We thank Christoph Lengauer and Dan Cahill for their input into these studies and the manuscript.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by the Grampian University Hospital Trust, a University of Aberdeen Development Trust Colorectal Cancer Initiative grant, and the Aberdeen Lung Cancer Group. Back

2 To whom requests for reprints should be addressed, at Washington University School of Medicine, Campus Box 8069, St. Louis, MO 63110. Phone: (314) 747-5183; Fax: (314) 747-2797; E-mail: hmcleod{at}imgate.wustl.edu Back

3 The abbreviations used are: CIN, chromosome instability; CRC, colorectal cancer; MIN, microsatellite instability; NSCLC, non-small cell lung cancer; SNP, single-nucleotide polymorphism; LOH, loss of heterozygosity. Back

4 R. G. Jaffrey, S. Marsh, and H. L. McLeod, Prediction of CIN status in human cancer, manuscript in preparation. Back

Received 5/15/00. Accepted 6/29/00.


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 Results
 Discussion
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