HIV and pediatric cancer

The risk of cancer is raised at least a hundredfold among both adults and children with the human immunodeficiency virus (HIV).  While the risk factors for HIV-related malignancy among adults have been characterized, a recent case-control study is one of a few to examine risk in children[Pollock BH et al. JAMA 2003; 289(18): 2393-2399]. The investigators identified forty-three HIV+ children with new diagnoses of cancer in Pediatric Oncology Group member institutions; seventy-four controls, individually matched on duration of HIV infection, were chosen from the same institutions.  The researchers collected blood to determine the extent of HIV infection, viral load and CD4 cell count, and to examine serological evidence of infection with Epstein Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus 6 (HHV-6).  Demographic and other information was obtained from parents, patient examination, or from medical records. As in adults with HIV, non-Hodgkin lymphoma (NHL) was the most common malignancy (32/43). The other cancers were 8 leiomyosarcomas, 4 ALLs, and one each of Hodgkin disease, hepatoblastoma, and Schwannoma. Cases were not significantly different than controls in regards to age (p = 0.10), sex (p = 0.60), race (p = 0.30), route of HIV infection (p = 0.13), or prior zidovudine use (p = 0.31). There was also no difference in CMV and HHV-6 seroprevalence (p = 0.11 and 0.61, respectively). There were significant associations of both CD4 cell count less than 200/microliter (p = 0.02) and EBV load >= 50 copies/100,000 peripheral blood mononuclear cells (p = 0.02), but these were not independent.  There was significant (p = 0.03) interaction between these factors such that the association of high EBV load (OR = 11.33; 95% CI: 2.09-65.66) was present among children with CD4 cell count >200/microliter, but not among children with low CD4 cell count (OR = 1.12; 95% CI: 0.13-9.62).

COMMENT: A previous Children’s Cancer Group study [see C3 Vol 9 no 4] by Granovsky et al [J Clin Oncol 1998; 16:1729-35] reported a similar pattern of malignancies in children infected with HIV. As Pollock et al note, prospective studies will be needed to elucidate the temporal relationship between HIV-related cancer, immunosuppression, and EBV load. Since blood was collected at the time of cancer diagnosis, rather than at some earlier point in time, it was not possible to determine which factors preceded the others.

 GATA1 in Down syndrome neonates with TMD

GATA1 is needed for normal growth and maturation of red blood cells and megakaryoctyes. Wechsler J, et al [Nature Genet 2002; 32:148-52] reported acquired mutations in the transcription factor, GATA1, in DNA samples of six patients with Down syndrome and AML but the mutation was not found in controls. All of these mutations resulted in a premature translation termination that results in an inactivation of the GATA1 domain encoded by exon 2. While these GATA1 mutations were demonstrated in patients with Down syndrome who already had developed AML, it was unclear whether they also could be found in patients who manifest transient myeloid disorder (TMD),  which is found in about 10% of young infants with Down syndrome. In a study by Groet J et al [Lancet 2003; 361:1617-20], GATA1 mutations in exon 2 were examined in 10 infants (mean age 8.2 days) with TMD and Down syndrome, 6 patients with AML and Down syndrome, 3 remission samples, 6 patients with ALL and Down syndrome, 27 children with Down syndrome no leukemia, and 16 other control samples (adult marrow or blood, umbilical cord blood). Interestingly, the investigators found GATA1 mutations in 7/10 patients with TMD and 4/6 patients with AML.  No reported mutations were found in any of the other samples and controls examined, including the children with Down syndrome and ALL. Further, the range of mutations found in the TMD patients and AML patients did not differ. Importantly, most of the patients with TMD and a GATA1 mutation spontaneously regressed without treatment, suggesting that GATA1 mutation is not sufficient to cause AML.

COMMENT: While the investigators acknowledge that other GATA1 mutations could exist in intronic sequences, the GATA1 mutations in exon 2 observed here are in accord with those described by Wechsler and colleagues. As with the observations regarding the TEL-AML1 rearrangement found in approximately 1% of neonatal cord bloods [see C3, Vol 13, No 3], this study demonstrates the potential importance of the fetal environment in inducing genetic mutations, regardless of whether they eventually result in leukemia. It will be important to consider how to design epidemiologic studies that could address exposures that may be associated with these types of mutations (see related article by Ravetto et al below). 

MPO in hepatoblastoma- radical discovery?

Hepatoblastoma (HB) is the most common form of liver cancer in children.  Due to its rarity there are few case-control studies of HB and its etiology is correspondingly obscure. Beckwith-Wiedemann syndrome, familial adenoma-tous polyposis, and low birth weight are the only known risk factors. A new study [Pakakasama S et. al. 2003; Int J Cancer 106: 205-207] suggests that expression of a certain enzyme may also play a role in the genesis of HB. The neutrophil enzyme myeloperoxidase (MPO) produces free oxygen radicals, which promote carcinogenesis in a number of ways in the course of their action. MPO also oxidizes foreign substances in the body, converting carcinogens to active form.  The substitution of an alanine (A) for a guanine (G) at position –463 in the promoter region of the MPO gene substantially reduces expression of the enzyme. These investigators examined the frequency of this polymorphism in 48 children with HB and 180 controls, all Caucasian. Overall the results indicated that the A allele, which had a frequency of 14.6% in cases and 25.3% in controls, reduced the risk of HB (OR=0.51; 95% CI=0.27-0.93). 

COMMENT: Previous studies have linked the A/A MPO genotype with reduced risk of lung cancer.  A large case-control study is currently being designed by Children’s Oncology Group investigators that will, among other hypotheses, examine and possibly confirm an association of MPO genotype with HB.  Also, they will collect information on potentially toxic exposures and test their interaction with MPO genotype. 

Diagnostic x-rays and fusion transcripts in premies

Given the interest in understanding whether certain exposures might cause childhood cancer, there are a growing number of investigations that are evaluating biological markers of exposure (such as gene mutations, chromosomal translocations, etc) associated with specific exposures of interest. In a recent study by Ravetto et al [Arch Dis Child Fetal Neonatal Ed 2003; 88:F237-F244], serial peripheral blood samples were collected at birth from 42 preterm infants (23-30 weeks) following exposure to diagnostic x-rays at intervals of two weeks until discharge. The mean number of x-rays was 6.9 with a maximum absorbed dose of 0.32 mGy over an 8 week period. The investigators were interested in determining whether leukemia-associated fusion transcripts for TEL-AML1, MLL-AF4, or BCR-ABL were present following exposure. Cord blood samples from 100 full-term infants served as controls. No preterm infants demonstrated any of these rearrangements following x-ray exposure, although one preterm infant had a BCR-ABL transcript prior to x-ray exposure. Two healthy controls had the TEL-AML1 transcript.

COMMENT: This was an interesting study as it is known that fetal exposure to x-rays is associated with an increased risk of leukemia. Since these preterm infants are equivalent to second/third trimester fetal stage, it was reasonable to ask whether diagnostic x-rays to these infants are associated with the occurrence of these fusion transcripts. The authors acknowledge the relatively small sample size and the possibility that the small amount of blood taken (< 0.5 ml) at each draw may have precluded them from detecting fusion gene transcripts. Nevertheless, this study is a good example of the types of studies that are needed to further explore the causes and importance of these reported mutations in children with leukemia. 

No to O2?

Supplementary oxygen is commonly used during newborn resuscitation for conditions such as asphyxia. A 1995 case-control study from Sweden [Cnattingius S. et al. 1995; JNCI 87: 908-914] first reported an association of oxygen supplementation with lymphatic leukemia   The researchers have now described another case-control study (in which many cases overlap) that examines oxygen exposure in more detail [Naumburg E. et al. 2003; Acta Paediatrica 91: 1328-1333]. Cases of lymphatic leukemia (< 15 years) were gathered from the Swedish Cancer Registry; after excluding 11 children with Down syndrome and 34 without available medical charts, 578 children were available for study. Controls were randomly selected from the Swedish Birth registry and individually matched to cases on gender and date of birth. Data were abstracted from children’s medical charts on the use, dose, and duration of supplementary oxygen. Administration of 100% oxygen by mask immediately after birth was significantly associated with leukemia (OR=2.87; 95%CI:1.21-6.82).  The association grew with the duration of exposure, with the ORs comparing <2 minutes and 3-10 minutes of oxygen exposure by mask to no exposure being 2.00 (95% CI: 0.50-8.00) and 3.54 (95%CI:1.16-10.80), respectively. Notably, the association between oxygen exposure and leukemia was apparent only among children diagnosed at ? 5 years. They also examined oxygen treatment during the first two weeks of life by both duration and dose. The ORs comparing receipt of oxygen for <24 hours and 25+ hours to no oxygen were 0.77 (95% CI: 0.34-1.76) and 1.99 (95% CI: 0.50-7.95), respectively. Too few children received treatment with high percentages (> 50%) of oxygen to accurately characterize an association of dosage with leukemia.

COMMENT: This study had a solid population base and, through the use of centralized records, little possibility of selection bias. However, it did not independently confirm the earlier observation of an association between neonatal oxygen supplementation and leukemia, since the case series overlapped (numbers not provided). Further, a small number of infants were given oxygen by mask (20 cases, 7 controls), so the analyses need to be interpreted cautiously. The dose-response relationship observed, however, can be compelling evidence that an association might be causal. There is also some biological plausibility, since oxygen administration increases levels of DNA-damaging free radicals and is known to cause a number of conditions in the neonate including retinopathy of prematurity. These findings deserve further investigation. Ideally, these studies would also explore the role of genetic polymorphisms in genes with functional significance in the detoxification of free radicals, which could conceivably modify possible associations. 

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