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[Cancer Research 63, 1722-1723, April 2003]
© 2003 American Association for Cancer Research

Letters to the Editor

Correspondence re: Welzel et al., Cancer Res., 61: 1629–1636.1

Sandrine Roulland, Pierre Lebailly and Pascal Gauduchon

Laboratoire de Cancérologie Expérimentale, Centre François Baclesse, 14076 CAEN cedex O5, France

Letter

In a recent issue of Cancer Research, Welzel et al. reported the presence of T-nucleotide2 insertions in t(11;14) junctions of MCL, in addition to N-nucleotides (1) . The authors analyzed both direct and reciprocal BCL-1/JH and DH/BCL-1 from 23 positive MCLs on 93 patients. They found that 19% (7 of 37) of the BCL-1/JH junctions with inserts of more than five nucleotides contained error-prone copies (T-nucleotides) from the surrounding BCL-1 or JH regions. Hence, in contrast to previous assumptions (2) , the formation of t(11;14) junctions might not only involve illegitimate V(D)J-mediated recombination but also a template-dependent, error-prone DNA synthesis. Similarly to t(11;14), the chromosomal translocation t(14;18) (q32;q21), which juxtaposes the BCL-2 gene with the immunoglobulin heavy chain locus, is classically assumed to result from a mistake in the normal mechanism of V(D)J recombination (3) . t(14;18) is a hallmark of follicular lymphoma and has also been detected at low frequency in peripheral lymphocytes of healthy individuals (4 , 5) .

We performed a detailed analysis of de novo insertions in the direct breakpoint of 36 BCL-2/JH junctions obtained from 12 of 33 healthy individuals for which DNA sequencing was achieved. The presence of T-nucleotides, defined as short sequences of at least five nucleotides inserted in the breakpoint, with sufficient homology to the adjacent flanking sequences to exclude their concomitant presence by chance alone, was investigated using the statistical approach used by Welzel et al (1) .

We found highly significant templated nucleotides in 6 of 36 (16%) BCL-2/JH junctions (Table 1)Citation . The homologies were 6–18 nucleotides in length and presented mismatches with the original sequence (mutations, deletions, and insertions) in three cases. Template sequences belonged more frequently to the JH gene segment (four of six) than the BCL-2 gene (two of six). In one sample (111), the BCL-2/JH insertion presented highly significant homologies with nucleotides that could either belong to the BCL-2 gene or the JH gene segment. The BCL-2 11-bp sequence 5'-ACCCAGA-GCCC-3' was found in reverse complement orientation with one nucleotide insertion. The JH 11-bp sequence 5'-GGACGTCTGGG-3' was found in the direct orientation with one nucleotide mutation. The rate of T-nucleotides found in healthy individuals appeared similar to that observed in MCL (16% versus 19%) (1) . However, as only direct breakpoints were analyzed in our study, this rate might be underestimated. A paper from the same group reported that >30% of the BCL-2/JH junctions (reciprocal and direct) found in follicular lymphomas also contained T-nucleotides insertions (6) .


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  		Table 1 Highly significant T-nucleotides found in BCL-2/JH junctions of healthy individuals

 
Hence, the unusual mechanism that leads to T-nucleotide insertions into BCL-1 and BCL-2/JH junctions, respectively, found in MCL and follicular lymphoma (1 , 6) seems also implicated in the genesis of BCL-2/JH rearrangements in healthy individuals. Additional investigations on a larger population of subjects will be helpful to characterize the mechanisms and environmental or individual factors that influence the formation of such T-nucleotide insertions.

ACKNOWLEDGMENTS

We thank Dr. B. Nadel for providing us the statistical method for the identification of T-nucleotides.

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 grants from the Ligue Nationale contre le Cancer (Comite de la Manche), Association pour la Recherche sur le Cancer (ARC), Conseil General du Calvados. S. R. is supported by fellowships from this committee and the Conseil Regional de Basse-Normandie. Back

2 The abbreviations used are: T-nucleotide; templated nucleotide; MCL, mantle cell lymphoma. Back

Received 10/11/02. Accepted 2/ 3/03.

REFERENCES

  1. Welzel N., Trang L., Marculescu R., Mitterbauer G., Chott A., Pott C., Kneba M., Du M., Kusec R., Drach J., Raderer M., Mannhalter C., Lechner K., Nadel B., Jaeger U. Templated nucleotide addition and immunoglobulin JH-gene utilization in t(11;14) junctions: implications for the mechanism of translocation and the origin of mantle cell lymphoma. Cancer Res., 61: 1629-1636, 2001.[Abstract/Free Full Text]
  2. Tsujimoto Y., Jaffe E., Cossman J., Gorham J., Nowell P. C., Croce C. M. Clustering of breakpoints on chromosome 11 in human B-cell neoplasms with the t(11;14) chromosome translocation. Nature, 315: 340-343, 1985.[Medline]
  3. Tsujimoto Y., Gorham J., Cossman J., Jaffe E., Croce C. M. The t(14;18) chromosome translocations involved in B-cell neoplasms result from mistakes in VDJ joining. Science (Wash. DC), 229: 1390-1393, 1985.[Abstract/Free Full Text]
  4. Fuscoe J. C., Setzer R. W., Collard D. D., Moore M. M. Quantification of t(14;18) in the lymphocytes of healthy adult humans as a possible biomarker for environmental exposures to carcinogens. Carcinogenesis, 17: 1013-1020, 1996.[Abstract/Free Full Text]
  5. Liu Y., Hernandez A. M., Shibata D., Cortopassi G. A. BCL2 translocation frequency rises with age in humans. Proc. Natl. Acad. Sci. USA, 91: 8910-8914, 1994.[Abstract/Free Full Text]
  6. Jäger U., Bocskor S., Le T., Mitterbauer G., Bolz I., Chott A., Kneba M., Mannhalter C., Nadel B. Follicular lymphomas’ BCL-2/IgH junctions contain templated nucleotide insertions: novel insights into the mechanism of t(14;18) translocation. Blood, 95: 3520-3529, 2000.[Abstract/Free Full Text]
Response

Reply

Natascha Welzel, Bertrand Nadel and Ulrich Jaeger

Department of Medicine I, Division of Hematology, A-1090, University of Vienna, Austria

Roulland et al. have investigated 33 healthy individuals for BCL2/JH translocations. Analyzing 36 breakpoints, they found 6 (16%) junctions displaying T-nucleotides as described by our group (1 , 2) . This is the first confirmation of our data by another lab. Roulland et al. have extended our observations in follicular and MCLs to t(14;18) junctions in normal subjects. This indicates that the mechanism of translocation is similar in both instances. We appreciate this interesting work by our French colleagues.

REFERENCES

  1. Jäger U., Böcskör S., Le T., Mitterbauer G., Bolz I., Chott A., Kneba M., Mannhalter C., Nadel B. Follicular lymphomas BCL-2/IgH junctions contain templated nucleotide insertions: novel insights into the mechanism of t(14;18) translocation. Blood, 95: 3520-3529, 2000.
  2. Welzel N., Le T., Marculescu R., Mitterbauer G., Chott A., Pott C., Kneba M., Du M. Q., Kusec R., Drach J., Raderer M., Mannhalter C., Lechner K., Nadel B., Jaeger U. Templated nucleotide additions and immunoglobulin JHgene utilization in (11;14) junctions: implications for the mechanism of translocation and the origin of mantle cell lymphoma. Cancer Res., 61: 1629-1636, 2001.




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