JC and BK virus in childhood ALL: negative territory

There is considerable interest in determining whether common ALL (cALL) in childhood may have an infectious etiology. In particular,  a hypothesis that delayed exposure to an infectious agent  might increase the risk  of cALL has been proposed by Mel Greaves.  As reported previously in C3, Malcolm Smith [Immunotherapy 20:89-100, 1997] speculated that the polyoma virus, JC, might be an etiological candidate for this infectious agent. JC virus infects B-cells and has been shown to be oncogenic in animal models. MacKenzie et al [Br J Cancer 81:898-99, 1999] evaluated childhood cALL samples for both JC and BK virus (a related polyoma virus) to determine whether viral sequences might be detectable. Using pretreatment samples from 15 patients who fulfilled the diagnostic criteria of cALL, no positive results were found, suggesting no direct involvement of JC or BK virus in cALL. However, as the authors note, this does not rule out the possibility of an indirect role that these viruses might play in leukemogenesis, nor does it negate the potential for involvement in a minority of cases. 

COMMENT: This was a simple, but elegant study that tested an important hypothesis. Although JC virus cannot be ruled out completely in childhood cALL, it does suggest that it is unlikely to play a significant role. If an infectious agent is directly responsible for the most common type of childhood leukemia, it remains elusive. Julie A. Ross 

Does 6-MP Cause Cancer?

The association of alkylating agents and topoisomerase-II inhibitors with secondary cancers has been widely explored.  However, it has been generally believed that the antimetabolites, such as 6-mercaptopurine, are less carcinogenic. Two recent papers suggest that this interpretation may be overly optimistic.  Relling et al. [Lancet 1999; 354:34] from St. Jude's Children's Medical Center have described an unusually high frequency of brain tumors seen among children enrolled on the St. Jude's ALL treatment protocol, Total Therapy Study XII. In previous studies, malignant brain tumors have been reported to occur with a 10-20 year cumulative incidence of about 0.5 to 2% among patients with ALL.  The strongest risk factor for development of malignant brain tumors in patients with ALL seems to be cranial radiation.  In this St. Jude's study, the incidence of brain tumors among children receiving cranial radiation was 12.8% (6 of 52) compared with no cases seen in 101 patients treated on the same study who did not receive radiotherapy. Of note, in this protocol, intensive systemic antimetabolite therapy was continued before and during radiation therapy.  Of the 6 children who developed a brain tumor, 4 were shown to have erythrocyte concentrations of thioguanine nucleotide metabolites higher than the 70th percentile for the entire cohort, and 3 were shown to have a genetic defect in thiopurine methyltransferase (TPMT).  The 8-year cumulative incidence of brain tumors among children with defective vs. wild type TPMT was 42.9% vs. 8.3% (p=0.008). 

A second paper by Thomsen et al. [Cancer 1999; 86:1080] looked at the frequency of secondary leukemias in patients enrolled in the Nordic Society for Pediatric Hematology and Oncology ALL-92 Study.  One of the goals of the study was to intensify antimetabolite exposure by increasing dose to produce leukopenia.  543 patients (97% of all eligible patients in the Nordic countries) were enrolled on study, and 439 had TPMT activity measured.  Five children subsequently developed AML, all of whom had TPMT measured.  Patients who developed secondary leukemia had significantly lower TPMT activity compared with the remaining patients (p=0.03).  In the 55 patients with a TPMT activity <14 units/ml of red blood cells, five year risk of secondary AML was 9% compared with 1% for the remaining patients (p=0.002). 

COMMENT: These data suggest that antimetabolites such as 6-MP do contribute to overall risk of carcinogenicity of chemotherapy regimens and that risk is modified by genetic susceptibility.  In studies such as those described, additional agents such as alkylating agents, topoisomerase-II inhibitors and radiation therapy were given in conjunction with the 6-MP.  However, the data relating to TPMT activity provide important evidence that the exposure to 6-MP contributed to risk of carcinogenesis. The combination of agents administered together may be important however, perhaps with 6-MP inducing mutations and exposure to other agents impeding repair of those lesions. Continuing close monitoring of occurrence of secondary leukemias is important as dose intensification of therapy continues to be an important goal for treating children with chemotherapy.  Stella M. Davies 

Editors' Note: Overleaf, the last in our series that highlight selected tables from the NCI's childhood cancer monograph. 

STATE OF THE EPIDEMIOLOGY REPORT: CENTRAL NERVOUS SYSTEM TUMORS 
From: JG Gurney, MA Smith, GR Bunin, CNS and Miscellaneous Intracranial and Intraspinal Neoplasms, in: LAG Ries, MA Smith, JG Gurney, M Linet, T Tamra, JL Young, GR Bunin (eds), Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995, National Cancer Institute, SEER Program. NIH Pub. No. 99-4649, Bethesda, MD, 1999. Below is a compilation of selected risk factors reported to be associated with CNS tumors. For ‘known risk factors',  there is compelling evidence that the factor is strongly associated with the cancer (does not mean that all individuals with the factor develop cancer).  Specific citations are available at: http://www-seer.ims.nci.nih.gov/Publications/PedMono. A copy of the book can also be ordered from this website. 

Selected Risk Factors for Childhood Brain Tumors

C3 Quarterly Newsletter
Children's Cancer Research Fund
Epidemiology Research Unit
Division of Pediatric Epidemiology
Clinical Research
University of Minnesota
420 Delaware St. SE, Box 422
Minneapolis, MN 55455
pedsepi@umn.edu

Editors: 
Stella M. Davies, MD, PhD, and Julie A. Ross, PhD