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Human Molecular Genetics Pages 515-521  

Distinct mutation patterns of breast cancer-associated alleles of the HRAS1 minisatellite locus
Introduction
Results
   Repeat pattern variation of common alleles of the HRAS1 minisatellite
   Clustered mutations in rare alleles of the HRAS1 minisatellite
   Lack of hypermutation in common alleles of the HRAS1 minisatellite
Discussion
Materials And Methods
   Patients and DNA
   HRAS1 genotyping
   HRAS1 allele sequencing
Acknowledgements
References

Distinct mutation patterns of breast cancer-associated alleles of the HRAS1 minisatellite locus

Distinct mutation patterns of breast cancer-associated alleles of the HRAS1 minisatellite locus

Shaofeng Ding, Garry P. Larson, Kimberly Foldenauer, Guoxiang Zhang and Theodore G. Krontiris*

Division of Molecular Medicine, Beckman Research Institute of the City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA

Received November 9, 1998; Revised and Accepted December 12, 1998

DDBJ/EMBL/GenBank accession nos AF105318-AF105321

DNA sequence analysis of 130 alleles of the HRAS1 minisatellite has demonstrated that breast cancer-associated variants arise as a consequence of both replication errors and gene conversions. Unlike mutations at other variable number of tandem repeats (VNTRs), high-risk variants of the HRAS1 minisatellite do not demonstrate positional polarity. Instead, most mutations occur at three hotspots, with replication errors confined to one hotspot, gene conversions to a second and a mixed pattern of mutation at the third. DNA sequence analysis of 66 low-risk a1 alleles revealed no evidence for hypermutation. Therefore, while the HRAS1 minisatellite may serve as a reporter for a broad-based group of mutational mechanisms, these results are consistent with a direct pathogenetic contribution by high-risk alleles as the biological basis underlying cancer association of this VNTR.

INTRODUCTION

The HRAS1 minisatellite locus is composed of four common alleles (a1-a4) and dozens of rare variants; molecular genetic analysis has supported the conclusion that each rare allele is derived from the common allele nearest in size (1-3). The minisatellite consists of the tandem repetition of a 28 bp consensus unit; site-specific differences in DNA sequence occur from repeat unit to repeat unit (4,5). The variant alleles are strongly associated with an increased risk of many different types of malignancy, including breast cancer (6-9). In all instances examined to date, the variant alleles have been germline, not somatic, alterations that have usually been present in other family members. In the past, we have documented only one newly arisen rare allele among >400 informative meioses typed over the course of our studies (data not shown).

We undertook a comprehensive DNA sequence analysis of the variation present in high- and low-risk alleles of the HRAS1 minisatellite locus for several reasons. First, we expected that a detailed description of the repeat structure of these alleles would offer important clues about the mutation process and whether it resembled that described for other human and mouse minisatellite loci. Second, we wished to determine if the pattern of mutation would provide evidence that the variants were themselves pathogenetic, rather than the manifestation and reporter of a distal mutator locus. Finally, we hoped to identify any potential hotspots for mutation within the minisatellite, as well as recurring patterns of insertion and deletion, since this knowledge would aid subsequent studies on the mechanism underlying the disease association previously described.

RESULTS

Repeat pattern variation of common alleles of the HRAS1 minisatellite

To explore nucleotide variation within each HRAS1 variable number of tandem repeats (VNTR) repeat unit and, ultimately, the interspersion pattern of these repeats within the minisatellite, we utilized fluorescent DNA sequencing of PCR-amplified, gel-purified alleles from siblings with breast cancer and from cancer-free controls. Thus, we avoided the limitations of other PCR-based approaches aimed at identifying repeat patterns in minisatellite alleles, such as MVR-PCR (10), that only score repeats demonstrating a high degree of homology to specific primer sets. To characterize VNTR variation patterns between common a1 and a2 alleles and rare alleles in this size class, we employed a direct sequencing strategy. For larger alleles, we cloned the PCR product and produced an array of smaller subclones by directed deletion.

Two regions showed the majority of variation. The first was within the body of the minisatellite; positions 19 and 27 of the repeat unit showed G or C substitutions. A color code (Fig. 1) has been assigned to each of the observed combinations of these positional variants, e.g. red for 19C27C, and is used throughout the text and subsequent figures to summarize our sequencing results. The second source of variation was at the 5[prime] and 3[prime] termini of the minisatellite, where the repeat units showed more extensive, but recurring, sequence differences (Fig. 1). Many of these variants were restricted to particular progenitor alleles, such as variant 7 (green-striped; the first repeat of all a1 class alleles) or variant 9 (brown-striped; the second repeat of all a1 and a2 class alleles) (Fig. 1). Several unique internal repeat units were described, including a yellow motif (19G27G) restricted to the a3/a4 class and a 40 bp repeat unit unique to all a4-derived alleles that arose from deletion of 16 bases and fusion of two adjacent repeats (DD). The deletion created a TaqI restriction site previously reported by others (11,12); we confirmed the presence of the site by digestion of PCR fragments. Overall, 15 repeat unit variants were observed; and these served as the basis for establishing both the lineage relationships of mutant alleles and the source of donor sequences in gene conversion events (see below).


Figure 1. HRAS1 minisatellite 28 bp consensus sequence variation. DNA sequence analysis of a1-a4 alleles of the HRAS1 minisatellite showed 15 distinct variants of the 28 bp consensus sequence. Each repeat pattern was assigned a color-coded cell (see also Figs 2 and 4). Patterns 1-6, where variation occurred primarily at positions 18, 19 and 27 of the 28 bp consensus, appeared in the body of the VNTR. Patterns 4 and 6 occurred only in a3 and a4 class alleles and in certain rare alleles (see text). Each a4-derived allele had repeat pattern 15 (DD), which was formed by a 16 bp joint deletion in two adjacent repeats. Eight other repeat patterns, with polymorphic sites in addition to positions 18, 19 and 27, constituted the 5[prime] and 3[prime] termini of the repeat array.

The interspersion pattern of repeats clearly distinguished common alleles from one another (Fig. 2, columns a1, a2, a3 and a4). We confirmed the existence of two major classes of the a1 allele (3), designated a1A and a1B, that have an identical interspersion pattern except for a red (19C27C) insertion after repeat unit 16 and a brown (19G27C) deletion of unit 26 in a1B (see also Fig. 4). Two major variants of the a3 progenitor were also found, distinguished by a yellow insertion after repeat unit 12 and a complex event involving a red unit deletion in or near the unit 48-51 hotspot described in more detail below. The class bearing yellow units could be subdivided further into two variants by subsequent red to green variation of repeat unit 43.


Figure 2. Repeat unit variation of common and rare HRAS1 minisatellite alleles. Each column is a false-color representation of the complete DNA sequence of one HRAS1 minisatellite allele. Every 28 bp repeat unit of the minisatellite is represented by a color-coded cell; the key is given in Figure 1. The interspersed, adjacent columns of labeled cells indicate the repeat unit numbers. Independent alleles demonstrating identical or related mutation events are grouped together; samples sharing the same five-digit sample number (e.g. 10032LH and 10032MM) are siblings. Insertions and deletions are highlighted by a solid black border; deletions are open boxes. Boxes labeled ‘DD’ represent the deleted, fused repeat variant described in Figure 1. Alleles are named by the number of repeat units by which they exceed the nearest smaller common allele. For example, a1.15 is 15 repeat units larger than a1.

Lineage relationships among the common alleles themselves were inferred from both unique repeat units and interspersion patterns. Thus, a3 and a4 were clearly the most closely related, sharing unique yellow and black (18G19G27G) repeat motifs, a unique second repeat at the 5[prime] end and multiple patterns of repeats internally (e.g. the green-red-yellow-blue motif that is a common donor fragment; see below). The a2 allele was, in most respects, distinguishable from the other three types. In this regard, it is interesting to note that a2 was absent in population studies of the Japanese, marking it perhaps as an evolutionarily distinct addition to the locus in European Caucasians (13).

Clustered mutations in rare alleles of the HRAS1 minisatellite

Our previous molecular genetic analysis (1,2) and MVR-PCR (3) suggested that rare alleles were variants derived from common progenitor alleles closest in size. Complete DNA sequencing has corroborated this work and provided several additional findings (Fig. 2). For each class of rare alleles (e.g. sizes between a1 and a2, a2 and a3, etc.), overall differences in interspersion patterns strongly suggested the origin of variants. Note in Figure 2 the ease of distinguishing a1-related alleles, a1.1-a1.4, from the a2-associated alleles, a1.13 and a1.14. Both a1A and a1B alleles were seen to be progenitors. Similar relationships to progenitors could be found for the other mutations.

A closer examination of specific rare alleles indicated that multiple mechanisms may have operated in the genesis of mutations. In many instances, deletions or duplications reminiscent of replication errors were observed. Examples include a brown-green-blue duplication immediately after the same three-unit motif at repeat no. 16 in a2.3 and the 13-unit duplication in a2.13. In both instances, the mutations represented motifs present uniquely in the a2 progenitor. Multiple instances of smaller deletions or insertion/duplications were found (see, for example, the a1.13 alleles, a3.1, a3.14 and a4.1).

Interallelic exchanges, in the form of insertions without alteration of flanking units, were also evident. Most prominent among these were 15 independent mutant alleles that demonstrated insertions between units 14 and 15 (blue and green) of both a1A and a1B progenitors. At least four different motifs were detected at this hotspot; many of the 15 alleles are shown in Figure 2. The most frequent donor sequence was a green-red-yellow-blue motif that occurred once in a3 and four times in a4. Thus, the origins of these mutations were probably exchanges between both a1A and a1B and either a3 or a4. The green-brown-brown-red insertion of a1.4 (sample 10086MB) could represent either a local a1A duplication or an a1A/a1A exchange. Other interallelic exchanges are indicated in Figures 2 and 3.


Figure 3. Composite map of mutation sites in the common, progenitor alleles of the HRAS1 minisatellite locus. The common alleles are depicted by four horizontal arrays of numbers, with each number representing the corresponding repeat unit in the allele. A mutation event is depicted at the site of the first repeat unit altered by the mutation; for example, each of the Xs over unit 15 in the a1 allele represents an insertion beginning immediately after unit 14. O, deletion/duplication; X, insertion; C, complex events involving both insertions and deletions. Three mutational hotspots are enclosed in rectangles. The arrows indicate size differences between alleles.


Figure 4. Lack of hypermutability in a1 repeat unit interspersion patterns. PCR-amplified a1 alleles from cancer-free (top; groups 1 and 2) and breast cancer (bottom; groups 3 and 4) patients were sequenced and repeat patterns assembled as described in Figures 1 and 2. Individuals in groups 1 and 3 had one common allele in addition to a1; individuals in groups 2 and 4 had one rare allele.

Among all rare alleles sequenced, only three point mutations occurred at positions outside the polymorphic sites noted in Figure 1. One was detected at the 3[prime] terminus of an a1.15 allele (10002 ANS). The other two were found at the 5[prime] and 3[prime] termini of the same a0.26 allele (10017 TF).

Several observations suggested that individual repeat unit variants might possess an increased propensity for mutation. Eight of 11 deletions or insertion/duplications of one unit involved a red unit (19C27C). The yellow repeat motif that was present frequently in a3- or a4-derived transfers to a1 was also responsible for the insertional rearrangement leading to the a3 variant allele.

Positional polarity, the hallmark of mutation at other minisatellite loci, was completely absent at HRAS1 (Fig. 3). A non-random clustering of mutational sites was present in all four progenitors. For example, units 15-19 showed multiple independent rearrangements in a1-, a2- and a4-derived variant alleles (18 independent occurrences). Units 25-26 showed multiple independent rearrangements in a2-, a3- and a4-derived variant alleles (six independent occurrences). Units 48-51 showed multiple independent short insertion/duplications and deletion rearrangements in a3- and a4-derived alleles (five independent occurrences). In a1-derived variant alleles, interallelic exchange was the predominant mechanism at repeat unit 15.

Lack of hypermutation in common alleles of the HRAS1 minisatellite

An excess number of rare HRAS1alleles in cancer patients may reflect the existence of mutator alleles at a distinct repair locus, as has been described for microsatellite instability (14,15). In the case of minisatellites, however, such instability may not only be manifested as a variation in the size of new alleles. The mutation events affecting minisatellites may also convert individual repeat units without altering the total number of repeats; see, for example, the red-to-green (19C27C to 19C27G) conversion in repeat unit 21 of the a1.4 allele in sample 10030EK (Fig. 2). Therefore, an examination of a1 alleles, which may be sequenced rapidly in their entirety, for the presence of mutations akin to short gene conversion events serves as one test of hypermutability.

To pursue this, we purified and sequenced 66 a1 alleles from cancer-free controls (Fig. 4, groups 1 and 2) and breast cancer patients (Fig. 4, groups 3 and 4). Cases and controls were subdivided further into individuals bearing only common alleles, one of which was a1 (Fig. 4, groups 1 and 3), or those bearing the a1 alleles in combination with a rare allele (Fig. 4, groups 2 and 4). Our expectation was that an overall increase in genome instability in cancer patients bearing rare alleles would be accompanied by variations in a1 repeat unit structure. Such variation should be absent or diminished in cancer-free controls lacking a rare allele.

Our results provided no evidence for minisatellite hypermutability. In addition to the major a1A and a1B variants, only a third minor polymorphic class bearing a blue for red exchange in repeat 23 (Fig. 4) was identified. No other differences, such as unique repeats or altered repeat interspersion patterns, were observed.

DISCUSSION

Because we analyzed rare alleles of breast cancer patients, rather than newly arising mutations in gametes or nuclear families, our results were potentially the convergent outcomes of two distinct influences: the mechanism(s) of HRAS1 minisatellite mutation and selection bias because of breast cancer pathogenicity of rare alleles. Although discriminating effects due solely to one or another of these influences was difficult, a number of important conclusions were possible.

The mutation pattern of high-risk alleles of the HRAS1 minisatellite showed several notable similarities to and differences from mutations observed at other VNTR loci. Most prominent among the similarities was the appearance of many mutations involving inter-allelic exchange by a gene conversion process that did not alter flanking sequences of the recipient allele. In all instances, the origin of donor sequences could be clearly established. The deletion/duplication mutations we described, suggesting replication errors, have also been established previously. In principle, these ostensibly different pathways could both represent replication errors in which two distinct sources of information were employed in repair: intrastrand or sister chromatid-based corrections would appear primarily as deletions/duplications, while corrections obtained with material from homologs would appear as gene conversions.

The most prominent difference in the mutational pattern at the HRAS1 VNTR was the complete absence of positional polarity of mutations. Other minisatellites, such as MS32 (16) and CEB1 (17), accumulate mutations on one end (MS32) or one half (CEB1) of the repeat array. In contrast, most mutations of the HRAS1 minisatellite occurred roughly in the middle (a1 and a2) or middle third (a3 and a4) of the repeat array (Fig. 3). In fact, the 5[prime] region of the VNTR up to unit 14 in a1 and unit 16 in a2, a3, and a4 was completely devoid of mutational events, as were the 16 3[prime]-terminal units of a3 and the 35 3[prime]-terminal units of a4. Instead of mutational polarity, we demonstrated the existence of several mutational hotspots. Multiple, independent, inter-allelic exchanges were observed between repeat units 14 and 15 in the a1 progenitor. A cluster of deletion/duplication events occurred between units 48 and 52 in a3 and a4. Three progenitors (a2, a3 and a4) showed clustering of multiple mutation types between units 24 and 27.

While the lack of polarity and the appearance of hotspots conceivably could represent a completely distinct mutation mechanism for the HRAS1 minisatellite, this is unlikely, especially since the types of mutations occurring at the hotspots have been observed before at other VNTRs. Although the HRAS1 minisatellite may well serve as a reporter of mutator loci influencing both replication fidelity and recombination (mismatch repair genes being the principal candidates), the differences described above between mutation events at HRAS1 and other VNTRs suggested that we ascertained only a subset of all possible mutations by virtue of their presence in breast cancer patients. The implication of this conclusion is that the breast cancer-associated alleles may themselves contribute to the disease process. In support of this interpretation, we found no evidence for hypermutability in our examination of a1 ‘reporter’ alleles (Fig. 4).

The mechanism by which high-risk alleles contribute to cancer risk remains to be elucidated. We have shown that HRAS1 minisatellite repeat units are capable of binding constitutively expressed members of the rel/NF-[kappa]B family of transcription factors (18). A tandem array of such factors might have destabilizing effects on human chromatin. We now predict that such effects, whether on gene expression or chromosome fragility, will be governed by the exact nature of the repeat interspersion pattern.

MATERIALS AND METHODS

Patients and DNA

The Eastern Cooperative Oncology Group (ECOG) provided Caucasian patients affected with breast cancer. All index case diagnoses were confirmed by examination of pathology reports. Leukocyte DNAs were purified by a modified salt extraction procedure (19). Cancer-free controls were from our own DNA archives (6,7). After HRAS1 minisatellite genotyping, only heterozygous patients were utilized for the sequencing study. We sequenced 66 a1 alleles from cases and controls, as well as 10 a2 alleles, five a3 alleles and three a4 alleles. Thirty two rare alleles smaller than a2 were selected for sequencing, as well as 14 rare alleles larger than a2. Several rare alleles were sequenced independently from isolates obtained from sibling pairs or trios.

HRAS1 genotyping

The HRAS1 minisatellite was PCR amplified with 0.4 µ[Mgr] of the primers MG04 (5[prime]-TET-GAGCTAGCAGGGCATGCCGC-3[prime]) and MG06 (5[prime]-AGCACGGTGTGGAAGGAGCC-3[prime]) in a 50 µl reaction containing 50 ng of genomic DNA, 20 mM Tris-HCl (pH 8.3), 6% glycerol, 5 mM (NH4)2SO4, 5% dimethylsulfoxide (DMSO), 1.1 M Betaine, 2.5 mM MgCl2 , 1 mM dithiothreitol (DTT), 0.2 m[Mgr] dNTPs and 2.6 U of Expand Long Template PCR System (Boehringer Mannheim, Indianapolis, IN). The following thermal cycling conditions were used: one cycle of 96°C for 2 min, then 10 cycles of 30 s at 95°C, 30 s at 58°C and 6 min at 68°C, followed by 17 cycles of 30 s at 95°C, 30 s at 58°C and 6 min with a 20 s auto segment extension at 68°C. PCR products (2 µl) were co-electrophoresed on 5% native Long Ranger gels in the presence of an FAM-labeled HRAS1 a1-a4 common allelic reference ladder and GS2500 molecular weight marker (Perkin Elmer/ABI, Foster City, CA) on an Applied Biosystems (Foster City, CA) 377 DNA Sequencer (total volume 3.5 µl). The gel was run for 15 h at 800 V. Data were analyzed by using GeneScan software (v.2.1; Perkin Elmer/ABI). Genotypes were determined by comparison of the TET-labeled patient DNAs with the reference ladder and GS2500 molecular weight marker. Utilizing this methodology, single VNTR repeat resolution was achieved for all common and rare alleles.

HRAS1 allele sequencing

HRAS1 alleles were amplified preparatively by PCR of 300 ng of genomic DNA using an MG04 biotinylated primer (MG04Bio) in conjunction with MG06 as described above. Amplified alleles were purified via agarose gel electrophoresis and extracted using a QIAEX II gel extraction kit (Qiagen, Santa Clarita, CA). Single-stranded biotinylated alleles were purified using capture on streptavidin-coated magnetic beads (Kilobase binder; Dynal, Oslo, Norway) followed by alkaline elution of the non-biotinylated strand. Sequencing primers were nested internally to the PCR primers. The upper primer, U22, was 5[prime]-AGCAGGGCATGCCGCTGGCTGG-3[prime]; the lower primer, L24, was 5[prime]-GGGCTCCTGGCCTCGGGAAGTCTA-3[prime]. Double-stranded, non-biotinylated DNA was employed routinely for sequencing a1 class alleles and the 5[prime] and 3[prime] termini of a3 and a4 alleles using dRhodamine dye terminator Taq FS cycle sequencing chemistry (Perkin Elmer/ABI). For a2 alleles, ~20 ng of biotinylated single-stranded DNA was sequenced in the solid phase with dRhodamine dye terminator cycle sequencing chemistry (Amersham, Arlington Heights, IL). The eluted, non-biotinylated strand was neutralized with 0.2 M HCl and 1.0 M Tris-HCl (pH 8.0), then sequenced with dRhodamine Dye Terminator Taq FS cycle sequencing chemistry. Sequencing conditions were as described by the manufacturer.

For sequencing of a3 and a4 allele classes, nested deletions were prepared from cloned DNA. Purified alleles were given a 3[prime] dA overhang by incubation with Taq DNA polymerase and dATP at 72°C for 10 min, then cloned into the pCR2.1 TA plasmid vector (Invitrogen, Carlsbad, CA) and transformed into SURE cells (Stratagene, La Jolla, CA). The plasmid DNAs were extracted using a Plasmid Mini kit (Qiagen) and then digested with KpnI and XhoI. For each allele, 2.5 µg (25 µl) of digested, plasmid DNA was treated with exonuclease III (150 U/pmol susceptible 3[prime] ends) at 37°C to create unidirectional deletions from the 5[prime] (XhoI) overhang by removing 3 µl aliquots at 1 min intervals. After removal of the 5[prime] single-stranded overhang by S1 nuclease treatment, the 3[prime] overhang was repaired with the Klenow fragment of Escherichia coli DNA polymerase I to create blunt ends. The deleted plasmids were recircularized by T4 DNA ligase and retransformed into SURE cells. Deleted clones, differing by 250-300 bp intervals and spanning the inserted allele, were identified by gel electrophoresis of minipreparations of DNA and then sequenced using M13 forward and reverse primers. The entire sequence of the DNA of the a3- or a4-derived alleles was then obtained by alignment of sequences from the overlapping set of the deleted clones.

ACKNOWLEDGEMENTS

This work was supported by a grant from the US Public Health Service (CA45052) and funds from the Beckman Research Institute of the City of Hope.

REFERENCES

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19. Larson, G.P., Zhang, G., Ding, S., Foldenauer, K., Udar, N., Gatti, R.A., Neuberg, D., Lunetta, K.L., Ruckdeschel, J.C., Longmate, J., Flanagan, S. and Krontiris, T.G. (1998) An allelic variant at the ATM locus is implicated in breast cancer susceptibility. Genet. Testing, 1, 165-170.

*To whom correspondence should be addressed. Tel: +1 626 359 8111 ext. 4297; Fax: +1 626 301 8862; Email: tkrontir@coh.org

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J. N. Weitzel, S. Ding, G. P. Larson, R. A. Nelson, A. Goodman, E. C. Grendys, H. G. Ball, and T. G. Krontiris
The HRAS1 Minisatellite Locus and Risk of Ovarian Cancer
Cancer Res., January 1, 2000; 60(2): 259 - 261.
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