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MLL rearrangements in infant leukemia: Is there a higher frequency in females?
Leukemia Research Vol. 21, No. 8, pp. 193-795, 1997. 0 1997 Ekevier Science Ltd. All riehts resewed
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CONCISE REPORT MLL REARRANGEMENTS IN INFANT LEUKEMIA: IS THERE A HIGHER FREQUENCY IN FEMALES? Julie A. Ross and Leslie L. Robison Division of Pediatric Epidemiology & Clinical Research, University of Minnesota, Box 422, 420 Delaware St. SE., Minneapolis, MN 55455 U.S.A. (Received 4 January 1997. Accepted 4 January 1997) Abstract-Unlike childhood leukemia diagnosed at later ages, where there is an excess risk in males, there is a notable female predominance in infant leukemia. Since abnormalities involving the MLL gene are frequent in infants with leukemia, we asked whether there are gender differences with respect to MLL gene status. Data were combined from seven published molecular studies that examined MLL abnormalities in infants with leukemia. Of 239 cases with conclusive information, there was a female predominance in cases with an MU abnormality (female:male ratio 1.3); this was in marked contrast to cases with normal germline MU (female:male ratio, 0.7). These potential gender-dependent MLL frequencies should be explored in large populations of infant leukemia and, if confirmed, future investigations could be directed toward potential etiologic mechanisms. 0 1997 Elsevier Science Ltd Key words: Infants, leukemia,
1 lq23, gender,
etiology.
Introduction
in the first 6 months of life [2]. There is also a notable female predominance in infant leukemia, whereas in the older age groups there is a well-documented male excess
Infant leukemia is extremely rare and accounts for only about 5% of all childhood leukemias in the United States [l]. Leukemias that occur in the first year of life, however, are noted by several distinct biological characteristics that suggest a different etiology than children who develop leukemia at older ages (reviewed in [2]). Infants with acute leukemia demonstrate an approximately equal frequency of both lymphoid (ALL) and myeloid (AML) morphology compared to the distribution at later ages, in which the ratio of ALL cases to AML is about 4: 1. Infants with ALL usually present with a pre-pre-B cell phenotype and a poorer prognosis than older children, and often there is coexpression of myeloid antigens [2, 31. Further, leukemia cells in infants (both ALL and AML) frequently manifest an abnormality involving the MLL gene at chromosome band llq23, typically associated with a translocation [4]. Reports suggest as high as 7%80% of infant leukemias demonstrate MLL rearrangements with various partner chromosomes. These MU abnormalities are age-dependent with the highest frequency occurring
[1,21. It is unclear why female infants experience a higher risk of leukemia. We have recently postulated that an elevated risk in females could indicate that there is either a genetic or hormonal event associated with being female that confers a higher risk, or, that male infants more often die in utero as a result of a leukemogenic event [3]. We speculated that it may be informative to examine whether gender differences exist with respect to the presence or absence of llq23 abnormalities, since the presence of an MLL abnormality in infant leukemia likely indicates a different etiology than its absence [2,5]. To date, there have been seven independent studies that have examined MLL abnormalities using combinations of cytogenetic and molecular techniques in infants with leukemia, for a total of 265 cases (Table 1) [6-121. Several of these studies have explored the presence or absence of an MLL abnormality by sex and have reported no statistically significant differences. Taken separately, however, each of these studies was comprised of a relatively small number of cases and may have lacked sufficient statistical power to examine this question.
Correspondence to: Dr J. A. Ross, Division of Pediatric Epidemiology & Clinical Research, University of Minnesota Cancer Center, Box 422, 420 Delaware St. S.E., Minneapolis, MN 55455, U.S.A. (Tel.: 612 626 2902; Fax: 612 626 4842). 793
J. A. RossandL. L. Robison
194
Table 1. Studies which have examined infant leulcemiasfor ML.L abnorrnalines using molecular t&miques Year 1993 1993 1994 1994 1994 1995 1996
Reference
Total number of infants Number R*/avail.t
Chen et al. [6] Cimino et al. [7] Pui et al. [8] Rub&z et al. [9] Sorensener al. [lo] Martinez-Climent et al. [ 1l] Taki et al. [12]
Total
AU, AML
Femaless Number R/avail.
Males1 Number R/avail.
30 15 30 96 26 26 42
21130 12m 19128 78196 15126 14119 32142
30,o 13,2 30,o 96,0 0,26 0,26 215
9/11 6/8 10/13 42148 6/8 10113 lW23
6/11 617 9115 36148 519 416 14/19
265
191/256
190.59
101024 Odds ratio = 1.98,
80/l 15
p < 0.05
*R = rearrangementof the h4LL gene. ?A few caseshad unavailable material for molecular analysis of the MLL gene. Thus, cytogenetically normal casesor caseswho had other cytogenetic abnormalities, but were not investigated further with molecular probes,were not included in the totals. $In someinstancesgender was not discernible from the publication; thus, somecasescould not be included in the genderspecific columns. $Representsthe risk of having an MLL abnormality among female infants compared with male infants.
Materials and Methods In this report, we combined data from previously published studies to examine the patterns of MLL abnormalities with respect to gender. If individual sex data were not published, it was impossible to determine gender for a few cases if cytogenetic data were also unavailable [6,8, 10, 111. Further, infants who lacked cytogenetic evidence of llq23 rearrangements in their leukemia cells and were not studied further for molecular evidence of MLL abnormalities were not included in the totals. Of the 265 infant cases examined among these seven studies, 239 had conclusive information regarding the child’s sex and the presence or absence of a MLL abnormality. Results In this combined group, there was a female predominance of MLL abnormalities (female:male ratio, 1.3) (Table 1). In contrast, there was an under representation of females who had normal germline MLL (femalemale ratio, 0.7). Overall, there was an approximate 1.9-fold increased risk of having an MLL abnormality among female infants compared to male infants (p < 0.05). Discussion and Conclusion It is unclear why being female would be associated with an increased frequency of MLL abnormalities. As noted previously, however, the highest percentage of MLL abnormalities in infant leukemia occurs in the first few months of life [2]. Although not testable in this series, the over representation of females in the MLL
abnormal group might also be related to a younger age at diagnosis. It is striking that the gender distribution of infant cases with normal germline MLL more closely follows the pattern seen in childhood leukemia overall, where there is a male predominance of about 1.2 [2]. In particular, based on the expected overall 1.2 male: female distribution of childhood leukemia, these combined data suggest an approximate 8% excess of female cases in the rearranged MLL group and a 2% deficit of female cases in the normal MLL gene group. Thus, it is possible that the reported higher incidence of infant leukemia in females may be accounted for, in part, by the higher frequency of female cases with MLL abnormalities. It is important to note the limitations of this combined analysis. In particular, there may be unrecognized case selection factors that are possibly sex-specific in some of these studies, including which children had diagnostic bone marrow samples available for molecular analyses. Ideally, the relationship among gender, age at diagnosis, and MLL abnormalities should be explored in a study of infant leukemia that utilizes a large number of cases from the pediatric cooperative clinical trials groups. If this relationship is confirmed, molecular and epidemiological investigations into potential etiological mechanisms may be warranted. Acknowledgement-Supported by the University of Minnesota Children’s Cancer Research Fund.
References 1. Gurney, J. G., Severson, R. K., Davis, S. and Robison, L. L., Incidence of cancer in children in the United States. Cancer, 1995, 75, 2186-2195.
MU rearrangementsin infant leukemia 2. Ross, J. A., Davies, S. M., Potter, J. D. and Robison, L. L., Epidemiology of childhood leukemia with a focus on infants. Epidemiology Review, 1994, 16, 243-272. 3. Ross, J. A., Potter, J. D., Shu, X.-O., Reaman, G. H., Lampkin, B. and Robison, L. L., Evaluating the relationships among maternal reproductive history, birth characteristics, and infant leukemia. A report from the Children’s Cancer Group. Annals of Epidemiology, 7, 172-179. 4. Ford, A. M., Ridge, S. A., Cabrera, M. E., Mahmoud, H., Steel, C. M., Chan, L. C. and Greaves, M., In utero rearrangements in the trithorax-related oncogene in infant leukemias. Nature, 1993, 363, 358-360. 5. Ross, J. A., Potter, J. D. and Robison, L. L., Infant leukemia, topoisomerase II inhibitors, and the MLL gene. Journal of the National Cancer Institute, 1994, 86, 16781680. 6. Chen, C.-S., Sorensen, P. H. B., Domer, P. H., Reaman, G. H., Korsmeyer, S. J., Heerema, N. A., Hammond, G. D. and Kersey, J. H., Molecular rearrangements on chromosome llq23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome. Blood, 1993,81, 2386-2393. 7. Cimino, G., Lo Coca, F., Biondi, A., Elia, L., Luciano, A., Croce, C. M., Masera, G., Mandelli, R. and Canaani, E., ALL-l gene at chromosome llq23 is consistently altered in acute leukemia of early infancy. Blood, 1993, 82, 544546. 8. Pui, C.-H., Behm, F. G., Downing, J. R., Hancock, M. L.,
795
Shurtleff, S. A., Ribeiro, R. C., Head, D. R., Mahmoud, H. H., Sandlund, J. T., Furman, W. L., Roberts, W. M., Crist, W. M. and Raimondi, S. C., llq23/MLL rearrangement confers a poor prognosis in infants with acute lymphoblastic leukemia. Journal of Clinical Oncology, 1994, 12, 909-91s. 9. Rub&z, J. E., Link, M. P., Shuster, J. J., Carroll, A. J., Hakami, N., Frankel, L. E., Pullen, D. J. and Cleary, M. L., Frequency and prognostic significance of HRX rearrangements in infant acute lymphoblastic leukemia: a Pediatric Oncology Group Study. Blood, 1994, 84, 570-573. 10. Sorensen, P. H. B., Chen, C.-S., Smith, F. O., Arthur, D. C., Domer, P. H., Bernstein, I. D., Korsmeyer, S. J., Hammond, G. D. and Kersey, J. H., Molecular rearrangements of the MLL gene are present in most cases of infant acute myeloid leukemia and are strongly correlated with monocytic or myelomonocytic phenotypes. Journal of Clinical Investigation, 1994, 93, 429-437. 11. Martinez-Climent, J. A., Thirman, M. J., Esponosa, R., Le Beau, M. M. and Rowley, J. D., Detection of llq23/MLL rearrangements in infant leukemias with fluorescence in situ hybridization and molecular analysis. Leukemia, 1995, 9, 1299-1304. 12. Taki, T., Ida, K., Bessho, F., Hanada, R., Kikuchi, A., Yamamato, K., Sako, M., Tsuchida, M., Seto, M., Ueda, R. and Hayashi, Y., Frequency and clinical significance of the MLL gene rearrangements in infant acute leukemia. Leukemia, 1996, 10, 1303-1307.
Pergamon
Ptintedin GreatBritain
0145-‘2126/97
$17.00 + 0.00
PII: SO1452126(9T)OOOSl-9
CONCISE REPORT MLL REARRANGEMENTS IN INFANT LEUKEMIA: IS THERE A HIGHER FREQUENCY IN FEMALES? Julie A. Ross and Leslie L. Robison Division of Pediatric Epidemiology & Clinical Research, University of Minnesota, Box 422, 420 Delaware St. SE., Minneapolis, MN 55455 U.S.A. (Received 4 January 1997. Accepted 4 January 1997) Abstract-Unlike childhood leukemia diagnosed at later ages, where there is an excess risk in males, there is a notable female predominance in infant leukemia. Since abnormalities involving the MLL gene are frequent in infants with leukemia, we asked whether there are gender differences with respect to MLL gene status. Data were combined from seven published molecular studies that examined MLL abnormalities in infants with leukemia. Of 239 cases with conclusive information, there was a female predominance in cases with an MU abnormality (female:male ratio 1.3); this was in marked contrast to cases with normal germline MU (female:male ratio, 0.7). These potential gender-dependent MLL frequencies should be explored in large populations of infant leukemia and, if confirmed, future investigations could be directed toward potential etiologic mechanisms. 0 1997 Elsevier Science Ltd Key words: Infants, leukemia,
1 lq23, gender,
etiology.
Introduction
in the first 6 months of life [2]. There is also a notable female predominance in infant leukemia, whereas in the older age groups there is a well-documented male excess
Infant leukemia is extremely rare and accounts for only about 5% of all childhood leukemias in the United States [l]. Leukemias that occur in the first year of life, however, are noted by several distinct biological characteristics that suggest a different etiology than children who develop leukemia at older ages (reviewed in [2]). Infants with acute leukemia demonstrate an approximately equal frequency of both lymphoid (ALL) and myeloid (AML) morphology compared to the distribution at later ages, in which the ratio of ALL cases to AML is about 4: 1. Infants with ALL usually present with a pre-pre-B cell phenotype and a poorer prognosis than older children, and often there is coexpression of myeloid antigens [2, 31. Further, leukemia cells in infants (both ALL and AML) frequently manifest an abnormality involving the MLL gene at chromosome band llq23, typically associated with a translocation [4]. Reports suggest as high as 7%80% of infant leukemias demonstrate MLL rearrangements with various partner chromosomes. These MU abnormalities are age-dependent with the highest frequency occurring
[1,21. It is unclear why female infants experience a higher risk of leukemia. We have recently postulated that an elevated risk in females could indicate that there is either a genetic or hormonal event associated with being female that confers a higher risk, or, that male infants more often die in utero as a result of a leukemogenic event [3]. We speculated that it may be informative to examine whether gender differences exist with respect to the presence or absence of llq23 abnormalities, since the presence of an MLL abnormality in infant leukemia likely indicates a different etiology than its absence [2,5]. To date, there have been seven independent studies that have examined MLL abnormalities using combinations of cytogenetic and molecular techniques in infants with leukemia, for a total of 265 cases (Table 1) [6-121. Several of these studies have explored the presence or absence of an MLL abnormality by sex and have reported no statistically significant differences. Taken separately, however, each of these studies was comprised of a relatively small number of cases and may have lacked sufficient statistical power to examine this question.
Correspondence to: Dr J. A. Ross, Division of Pediatric Epidemiology & Clinical Research, University of Minnesota Cancer Center, Box 422, 420 Delaware St. S.E., Minneapolis, MN 55455, U.S.A. (Tel.: 612 626 2902; Fax: 612 626 4842). 793
J. A. RossandL. L. Robison
194
Table 1. Studies which have examined infant leulcemiasfor ML.L abnorrnalines using molecular t&miques Year 1993 1993 1994 1994 1994 1995 1996
Reference
Total number of infants Number R*/avail.t
Chen et al. [6] Cimino et al. [7] Pui et al. [8] Rub&z et al. [9] Sorensener al. [lo] Martinez-Climent et al. [ 1l] Taki et al. [12]
Total
AU, AML
Femaless Number R/avail.
Males1 Number R/avail.
30 15 30 96 26 26 42
21130 12m 19128 78196 15126 14119 32142
30,o 13,2 30,o 96,0 0,26 0,26 215
9/11 6/8 10/13 42148 6/8 10113 lW23
6/11 617 9115 36148 519 416 14/19
265
191/256
190.59
101024 Odds ratio = 1.98,
80/l 15
p < 0.05
*R = rearrangementof the h4LL gene. ?A few caseshad unavailable material for molecular analysis of the MLL gene. Thus, cytogenetically normal casesor caseswho had other cytogenetic abnormalities, but were not investigated further with molecular probes,were not included in the totals. $In someinstancesgender was not discernible from the publication; thus, somecasescould not be included in the genderspecific columns. $Representsthe risk of having an MLL abnormality among female infants compared with male infants.
Materials and Methods In this report, we combined data from previously published studies to examine the patterns of MLL abnormalities with respect to gender. If individual sex data were not published, it was impossible to determine gender for a few cases if cytogenetic data were also unavailable [6,8, 10, 111. Further, infants who lacked cytogenetic evidence of llq23 rearrangements in their leukemia cells and were not studied further for molecular evidence of MLL abnormalities were not included in the totals. Of the 265 infant cases examined among these seven studies, 239 had conclusive information regarding the child’s sex and the presence or absence of a MLL abnormality. Results In this combined group, there was a female predominance of MLL abnormalities (female:male ratio, 1.3) (Table 1). In contrast, there was an under representation of females who had normal germline MLL (femalemale ratio, 0.7). Overall, there was an approximate 1.9-fold increased risk of having an MLL abnormality among female infants compared to male infants (p < 0.05). Discussion and Conclusion It is unclear why being female would be associated with an increased frequency of MLL abnormalities. As noted previously, however, the highest percentage of MLL abnormalities in infant leukemia occurs in the first few months of life [2]. Although not testable in this series, the over representation of females in the MLL
abnormal group might also be related to a younger age at diagnosis. It is striking that the gender distribution of infant cases with normal germline MLL more closely follows the pattern seen in childhood leukemia overall, where there is a male predominance of about 1.2 [2]. In particular, based on the expected overall 1.2 male: female distribution of childhood leukemia, these combined data suggest an approximate 8% excess of female cases in the rearranged MLL group and a 2% deficit of female cases in the normal MLL gene group. Thus, it is possible that the reported higher incidence of infant leukemia in females may be accounted for, in part, by the higher frequency of female cases with MLL abnormalities. It is important to note the limitations of this combined analysis. In particular, there may be unrecognized case selection factors that are possibly sex-specific in some of these studies, including which children had diagnostic bone marrow samples available for molecular analyses. Ideally, the relationship among gender, age at diagnosis, and MLL abnormalities should be explored in a study of infant leukemia that utilizes a large number of cases from the pediatric cooperative clinical trials groups. If this relationship is confirmed, molecular and epidemiological investigations into potential etiological mechanisms may be warranted. Acknowledgement-Supported by the University of Minnesota Children’s Cancer Research Fund.
References 1. Gurney, J. G., Severson, R. K., Davis, S. and Robison, L. L., Incidence of cancer in children in the United States. Cancer, 1995, 75, 2186-2195.
MU rearrangementsin infant leukemia 2. Ross, J. A., Davies, S. M., Potter, J. D. and Robison, L. L., Epidemiology of childhood leukemia with a focus on infants. Epidemiology Review, 1994, 16, 243-272. 3. Ross, J. A., Potter, J. D., Shu, X.-O., Reaman, G. H., Lampkin, B. and Robison, L. L., Evaluating the relationships among maternal reproductive history, birth characteristics, and infant leukemia. A report from the Children’s Cancer Group. Annals of Epidemiology, 7, 172-179. 4. Ford, A. M., Ridge, S. A., Cabrera, M. E., Mahmoud, H., Steel, C. M., Chan, L. C. and Greaves, M., In utero rearrangements in the trithorax-related oncogene in infant leukemias. Nature, 1993, 363, 358-360. 5. Ross, J. A., Potter, J. D. and Robison, L. L., Infant leukemia, topoisomerase II inhibitors, and the MLL gene. Journal of the National Cancer Institute, 1994, 86, 16781680. 6. Chen, C.-S., Sorensen, P. H. B., Domer, P. H., Reaman, G. H., Korsmeyer, S. J., Heerema, N. A., Hammond, G. D. and Kersey, J. H., Molecular rearrangements on chromosome llq23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome. Blood, 1993,81, 2386-2393. 7. Cimino, G., Lo Coca, F., Biondi, A., Elia, L., Luciano, A., Croce, C. M., Masera, G., Mandelli, R. and Canaani, E., ALL-l gene at chromosome llq23 is consistently altered in acute leukemia of early infancy. Blood, 1993, 82, 544546. 8. Pui, C.-H., Behm, F. G., Downing, J. R., Hancock, M. L.,
795
Shurtleff, S. A., Ribeiro, R. C., Head, D. R., Mahmoud, H. H., Sandlund, J. T., Furman, W. L., Roberts, W. M., Crist, W. M. and Raimondi, S. C., llq23/MLL rearrangement confers a poor prognosis in infants with acute lymphoblastic leukemia. Journal of Clinical Oncology, 1994, 12, 909-91s. 9. Rub&z, J. E., Link, M. P., Shuster, J. J., Carroll, A. J., Hakami, N., Frankel, L. E., Pullen, D. J. and Cleary, M. L., Frequency and prognostic significance of HRX rearrangements in infant acute lymphoblastic leukemia: a Pediatric Oncology Group Study. Blood, 1994, 84, 570-573. 10. Sorensen, P. H. B., Chen, C.-S., Smith, F. O., Arthur, D. C., Domer, P. H., Bernstein, I. D., Korsmeyer, S. J., Hammond, G. D. and Kersey, J. H., Molecular rearrangements of the MLL gene are present in most cases of infant acute myeloid leukemia and are strongly correlated with monocytic or myelomonocytic phenotypes. Journal of Clinical Investigation, 1994, 93, 429-437. 11. Martinez-Climent, J. A., Thirman, M. J., Esponosa, R., Le Beau, M. M. and Rowley, J. D., Detection of llq23/MLL rearrangements in infant leukemias with fluorescence in situ hybridization and molecular analysis. Leukemia, 1995, 9, 1299-1304. 12. Taki, T., Ida, K., Bessho, F., Hanada, R., Kikuchi, A., Yamamato, K., Sako, M., Tsuchida, M., Seto, M., Ueda, R. and Hayashi, Y., Frequency and clinical significance of the MLL gene rearrangements in infant acute leukemia. Leukemia, 1996, 10, 1303-1307.