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[Cancer Research 61, 3432-3438, April 15, 2001]
© 2001 American Association for Cancer Research

Molecular Biology and Genetics

Gestational Age and Gender-specific In Utero V(D)J Recombinase-mediated Deletions1

Makoto Yoshioka, J. Patrick O’Neill, Pamela M. Vacek and Barry A. Finette2

Department of Pediatrics [M. Y., B. A. F.], Genetics Laboratory [P. O.], Vermont Cancer Center [P. O., B. A. F.], Departments of Medical Biostatistics [P. M. V.] and Microbiology and Molecular Genetics [B. A. F.], University of Vermont, Burlington, Vermont 05405


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Recent studies have brought to the forefront the importance of somatic mutations during human fetal development and malignant transformation in children, specifically leukemia. Therefore, a better understanding of the frequency and mutational spectrum of spontaneous in utero mutations is essential for understanding the genetic mechanisms associated with pediatric malignancies. Previously we reported that the frequency of somatic mutations during the late stages of fetal development was dependent on both gestational age and gender. Here we present the hypoxanthine-guanine phosphoribosyltransferase (HPRT) reporter gene mutational spectra analysis for 60 T-cell mutant isolates from the umbilical cord blood of preterm newborns to gain insight into background mutational events during the late stages of fetal development. Logistic regression analyses showed a significant increase in HPRT deletions mediated by V(D)J recombinase in preterm newborns compared with full-term newborns (P = 0.009). A comparative analysis of deletion mutations also revealed that V(D)J recombinase-mediated HPRT deletions increased with decreasing gestational age (P = 0.012) and were significantly higher in females than males of the same developmental status (P = 0.031). Developmental and gender-specific differences in HPRT deletions mediated by V(D)J recombinase provide insight into the gender-specific differences seen in infant leukemia.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Significant progress has been made toward understanding the molecular basis and clinical relevance of germinal mutations and inherited human diseases. In contrast, only recently has there been significant evidence demonstrating that somatic mutational events during fetal development also have direct clinical consequences for both pediatric and adult multifactorial diseases, especially cancer.

Recent studies have linked for the first time specific in utero genetic events and the development of cancer in children. Specifically, in utero somatic mutational events involving the MLL/AF4 (1 , 2) and TEL-AML1 (3 , 4) gene fusions in T cells and immunoglobulin heavy chain and T-cell receptor rearrangements in B cells (5) have been correlated with the subsequent development of infant and childhood leukemia.

Previously, we reported developmental and gender-specific differences in the in utero frequency of somatic mutations (Mf) at the HPRT3 reporter gene (6) . Specifically, the Mf of preterm newborns was higher compared with full-term newborns, with the mean Mf of female preterm newborns being inversely related to gestational age and significantly higher than that found for male preterm newborns (6) .

We report here a comparative analysis of the mutational spectra at the HPRT reporter gene mutations in T cells from this cohort. Statistical analyses revealed a significant increase of V(D)J recombinase-mediated HPRT deletions in preterm newborns compared with full-term infants. In addition, there was a significant increase in V(D)J recombinase-mediated deletions in both preterm and full-term female newborns compared with preterm and full-term male newborns. This gender-specific difference in V(D)J recombinase-mediated events may be relevant to understanding the higher incidence of infant leukemia observed among females.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Population.
Heparinized umbilical cord blood samples from 20 preterm newborns (gestation, <36 weeks; Ref. 6 ) and 33 full-term newborns (gestation, >=36 weeks; Ref. 7 ) were acquired from the labor and delivery unit of Fletcher Allen Hospital of the University of Vermont College of Medicine. Informed consents were obtained after the procedure was approved by the Committee on Human Research at the University of Vermont.

HPRT T-Cell Cloning Assay.
Determination of HPRT Mf and the isolation of mutant clones were described previously (6 , 7) . HPRT mutant isolates were expanded and stored at -80°C at either 1 x 104 cells for reverse transcription-PCR or 5 x 104 cells for genomic multiplex PCR before molecular analysis.

Molecular Analysis of HPRT Mutant Isolates.
The HPRT locus, located at Xq26, contains 9 exons, is 43 Kb in size, and has been completely sequenced. The coding sequence is 657-bp long. Molecular analyses of mutant cells both at the genomic and cDNA level have been well described (7, 8, 9) . HPRT mutations observed previously include: (a) base substitutions at more that 270 sites in all nine exons; (b) small deletions and insertions; (c) large structural alterations; (d) splice site changes in introns; and (e) specialized genetic events such as V(D)J recombinase-mediated deletions (9, 10, 11) .

Because the HPRT gene is located on the X-chromosome, molecular analysis at the DNA/RNA level is performed in different ways for mutant isolates from males and females (7) . Mutant isolates from males first were analyzed by multiplex genomic HPRT PCR to determine the presence or absence of the nine HPRT exons (8) . Mutant isolates from males showing no genomic alterations were characterized by reverse transcriptase-mediated production of HPRT cDNA, nested PCR amplification, and DNA sequencing of the amplified products (7) . The multiplex PCR primer pairs for exons 1–9 also permitted sequence analyses of both intron and exon segments involved in most splice-sequence mutations, reflected as exon exclusions or intron inclusions in cDNA. For mutant isolates from females, multiplex genomic PCR analysis was not performed because the inactive X chromosome precludes deletion determination. Therefore, HPRT mutant isolates from females first were analyzed with specific primers to screen for V(D)J recombinase-mediated exon 2–3 deletion mutants (11) . Then, those mutant isolates which showed no V(D)J recombinase-mediated deletions were analyzed by reverse transcription-PCR and DNA sequencing.

Statistical Analysis.
Logistic regression was used to assess the effects of gender and development on the proportions of the different types of mutations. Models with interaction terms were fitted to test whether the effects of gender and development were independent. In utero exposure to tobacco smoke was included in some models to determine whether the effects of development and gender were attributable to differences in transplacental exposure to tobacco smoke. Detailed information about maternal smoking and passive smoke exposure was unavailable for many preterm infants, so smoke exposure was represented as dichotomous variables (exposed or not exposed). All models included a random effect to account for the correlation between multiple mutations from the same newborn.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A summary of mutations at the HPRT locus for each mutant isolate, as well as sex and gestational age of the subjects, is shown in Table 1Citation Citation . A total of 66 mutant isolates representing 60 independent mutations from 20 preterm newborns and 85 mutant isolates representing 78 independent mutations from 33 full-term newborns were characterized. Independent mutations were defined as single HPRT mutational events corrected for in vivo clonal expansion of mutant isolates. Clonal expansion was evident in subjects PS21 (deletion exons 1–9); PS30 (C508->T); PS29 (deletion exon 2); PS5 (exclusion exons 2–6); MFS89 (deletion exons 1–9 and deletion exons 2–9); MFS36 (deletion exons 7–9); and MFS65 (G3->T). Mutational spectrum data for full-term infants was reported previously, except for those indicated in Table 1Citation (7) .


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  		Table 1 Molecular analysis of in utero HPRT mutations

 

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  		Table 1A Continued

 
Distribution Analyses of HPRT Mutations.
The distribution analysis for HPRT mutations during the late stages of fetal development is summarized in Table 2Citation and shown graphically in Fig. 1Citation .


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  		Table 2 Distribution analysis of in utero HPRT mutationsa

 


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  		Fig. 1. Distribution analysis of HPRT mutations in T cells from preterm and term infants.

 
Mutations were first designated as small alterations, large alterations, and uncharacterized, as defined previously (7) . A comparison between all mutations revealed a greater proportion of large alterations compared with small alterations for both preterm and full-term infants. This is consistent with previously reported HPRT mutational spectra in children from birth through 5 years of age (11) . Logistic regression analysis demonstrated that the proportions of small and large alterations were not significantly related to gestational age or gender.

Distribution analysis of small alterations revealed a higher proportion of transition mutations compared with transversion mutations in both preterm and full-term newborns. Logistic regression analysis of the proportions of transitions and transversions did not demonstrate a relationship with either development or gender.

There were two predominant large alterations observed: HPRT deletions of exons 2 and 3 mediated by V(D)J recombinase (V(D)J deletions) as defined previously (9 , 11) , and exon deletions not mediated by V(D)J recombinase (non-V(D)J deletions). Distribution analysis revealed a higher proportion of V(D)J deletions compared with non-V(D)J deletions among all preterm infants and term females, but not among term males. Notably, logistic regression analysis revealed that the proportion of V(D)J deletions to non-V(D)J deletions was significantly related to both development and gender. Specifically, the proportion of V(D)J deletions were significantly higher compared with non-V(D)J deletions in preterm infants than full-term infants of the same gender (OR, 3.5; P = 0.012) as well as higher in females compared with males of the same developmental status (OR, 4.1; P = 0.043). Similar results were obtained when development was represented as gestational age rather than being classified as preterm or full-term, with ORs indicating that the proportion of V(D)J deletions increased ~13% with each week of decreasing gestational age from birth (P = 0.038).

Previously, we have reported that transplacental exposure to tobacco smoke results in a significant increase in V(D)J-mediated HPRT deletions in healthy full-term infants (7) . In this study, an analysis of transplacental tobacco exposure was not related to any type of alteration in those preterm infants for whom exposure status was available.

Analysis of V(D)J Recombinase-mediated Breakpoints.
Characteristic V(D)J recombinase-mediated sequence signature markings for HPRT V(D)J deletions are summarized in Fig. 2Citation . A total of 10 V(D)J recombinase-mediated mutants from female preterm newborns and 21 V(D)J recombinase-mediated mutant isolates from male preterm newborns were characterized. All but two isolates from male subjects were Class I V(D)J deletion mutants, with the remaining mutant isolates being Class III V(D)J deletion mutants (9) . There were five mutant isolates from male subjects and two mutant isolates from female subjects that lacked the N nucleotides additions. The percentage of the breakpoint sequences lacking the N nucleotide in the V(D)J mutant isolates from preterm newborns (22.6%, 7 of 31) was higher than the percentage observed previously for full-term newborns (5.6%; 1 of 18; Ref. 7 ). In addition, two atypical V(D)J recombinase events were observed. The V(D)J deletion breakpoint sequence from PS7M11 contained a 14-base N nucleotide insertion with an unusually long 26-base nibbling at the 3' side of the breakpoint, whereas another mutation from subject PS7M20 contained a tandem direct repeat of a motif 5'-CACATCCCTTTCATG-3', which is separated by four bases upstream of the 5' breakpoint.



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  		Fig. 2. Breakpoint sequence analysis of HPRT V(D)J recombinase-mediated deletions in preterm infants. Intron 1 and 3 breakpoint regions for both Class I and III regions are shown. Bold nucleotides represent conserved genomic V(D)J RSSs associated with 12- or 23-bp spacer sequences. DNA sequences for Class I and III HPRT mutant clones show the hallmark signature markings of V(D)J recombinase-mediated events at breakpoint sites, including nibbling back, the presence of templated P nucleotides (underline), and the insertion of nongermline templated bases, N nucleotides (italics).

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study we observed a unique mutational spectra for large alterations during the late stages of fetal development that was not seen for small alterations (including single-bp transversions and transitions). The most significant finding is that the proportion of V(D)J recombinase-mediated HPRT deletions are significantly higher during fetal development compared with after birth, and that this genetic event is related to gestational age and gender. Specifically, 63% (54 of 86) of all large alterations found in preterm and full-term newborns are V(D)J-mediated HPRT deletions, with a significantly higher distribution of V(D)J deletions in females (84%) compared with males (57%). To the best of our knowledge, this is the first demonstration of a gender-specific mutational spectra in humans, especially one with potential clinical consequences. We hypothesize that the high frequency of V(D)J recombinase-mediated HPRT deletions observed are the consequence of aberrant V(D)J genomic recombination events occurring at a time of high V(D)J recombinase activity required for in utero T-cell maturation. The reason for the predominance of these V(D)J recombinase rearrangements in females is unclear. Yet our observations may still be relevant, because an increase in these aberrant V(D)J-mediated genomic rearrangements may be responsible for the higher incidence of infant leukemia among females (12) .

V(D)J recombinase-mediated rearrangements have been observed with cytogenetic alterations associated with T- and B-cell leukemia (13, 14, 15, 16) . In these studies, sequence analysis of translocation and deletion breakpoint sites in malignant clones demonstrated hallmark V(D)J recombinase signature markings that include palindromic bases (P nucleotides) and nucleotide nibbling and/or insertion of nontemplated bases (N nucleotides) at heptamer (CAC/TGTG)/nonamer (GGTTTTTGT) RSSs containing 12- and 23-bp spacers. Recently, chromosomal rearrangements involving the MLL (ALL-1, HRX-AF-9) gene at chromosome band 11q23 and the TEL-AML1 gene fusion in children with infant leukemia (<12 months of age) have been shown to have occurred in utero (3 , 17 , 18) . In addition, molecular analysis of Guthrie blood spots in monozygotic twins demonstrated clonal MLL fusion rearrangements that were subsequently identified in leukemic cells from these children, providing additional support to the hypothesis that in utero somatic mutational events are associated with the development of pediatric leukemia (1 , 19 , 20) . These and other studies in MLL-AF9 knockin mice (21) also demonstrate that other genetic events and environmental influences likely affect the length of the latent period for tumor development. For example, the expression of mutant isoforms of a transcription factor Ikaros has also been correlated with infant leukemia (22) . The etiology of a number of MLL rearrangements observed is not clear. Cell lines established from leukemia patients with t(4;11)(q21;q23) MLL translocations have showed the hallmarks of V(D)J recombinase at the chromosomal breakpoints, which include cryptic RSSs and random base insertions at chromosomal breakpoints (23) .

MLL rearrangements have also been associated with chemotherapy using topoisomerase II inhibitors (24 , 25) . These chemotherapeutic agents have been shown to increase the frequency of V(D)J recombinase-mediated HPRT deletions in the CCRF-CEM lymphoid cell line that constitutively expresses RAG1 and RAG2 (26) , therefore suggesting a link between DNA DSB repair and V(D)J recombinase-mediated rearrangements. In addition, some components of the DSB repair system are shared by V(D)J recombinase, including the catalytic subunit of DNA-dependent protein kinase (27) , Ku70 (28) , and Ku80 (29 , 30) . Breakpoints associated with some t(4;11) translocations involving MLL genes have recently been reported to display short tandem repeats, inversions, and short homologous sequences at the chromosomal breakpoints, suggesting a DNA repair mechanism (31 , 32) . Of interest, P nucleotide sequences were observed at some of these breakpoints, which may indicate that V(D)J recombinase activity may have also participated in these translocations.

In this report, 22.6% of V(D)J breakpoints in preterm newborns did not contain N nucleotide insertion compared with 5.6% in full-term newborns. A decrease in the insertion of N nucleotides has been associated with the early stages of murine B-cell (33) and {gamma}{delta} T-cell development (34) as well as in human T-cell development attributable to decreased in utero expression of terminal deoxytransferase. The lower frequency of in utero N nucleotides we observed is in agreement with these previous reports. In addition, V(D)J mutant, PS7M20, contained a tandem repeat (5'-CACATCCCTTTCATG-3'). Such tandem repeats were also observed at MLL breakpoint sites (31 , 32) .

Therefore, during in utero lymphoid development, a synergistic relationship may exist between components of the V(D)J recombinase and DSB repair systems that increases the frequency of aberrant genomic deletions and chromosome translocations that are responsible for the development of leukemia in infants and children.


   ACKNOWLEDGMENTS
 
We thank Holly Pasackow for obtaining preterm cord blood samples.


   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 Research was supported by Child Health and Human Development (NICHD) Grants 1K11HD01010 and 1R29HD35309, National Cancer Institute Grant 1KO1CA77737, and National Cancer Institute Grant P30CA22435 to the University of Vermont Cancer Center DNA Analysis Facility. Back

2 To whom requests for reprints should be addressed, at Department of Pediatrics, Medical Alumni Building, Burlington VT 05405. Phone: (802) 656-2296; Fax: (802) 656-2077; E-mail: finette{at}salus.med.uvm.edu Back

3 The abbreviations used are: HPRT, hypoxanthine-guanine phosphoribosyltransferase; Mf, mutation frequency; RSS, recombination signal sequences; OR, odds ratio; N nucleotides, nontemplated nucleotides; DSB, double-strand break. Back

Received 11/15/00. Accepted 2/13/01.


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 DISCUSSION
 REFERENCES
 

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Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online