Announcement: New C.O.G. Epidemiology Committee

As many of you know, four national childhood cancer research and treatment groups have recently been merged to form the Children’s Oncology Group (C.O.G.). C.O.G. develops and coordinates clinical trials conducted at over 235 hospitals and cancer centers throughout the United States and Canada, as well as at sites in Europe and Australia. It has been estimated that member-institutions of C.O.G. treat more than 90% of children diagnosed with cancer in the continental United States [Ross et al, Cancer 77:201-207, 1996].  In the formation of C.O.G., scientific, disease, and discipline committees have been restructured and new leadership has been established. 

The new C.O.G. Epidemiology (Epi) Steering Committee consists of the following individuals: Julie A. Ross (Chair), David Malkin (Vice-chair),  John Perentesis, Xiao-ou Shu, Gail Tomlinson, Greta Bunin, Jonathan Buckley,  Andrew Olshan, Kim Nagel, Brad Pollock (Cancer Control Liaison) and Kate MacGregor (public member). John Potter and Martha Linet serve as Epi committee consultants. In addition, we are forming an Epi Interest Group in which young, as well as established, investigators are encouraged to apply (see overleaf).

The mission of the C.O.G. Epi Program is to promote and facilitate research investigating the causes of childhood cancer. Recognizing accomplishments, as well as recent challenges, below is an outline of the work that will be undertaken by the C.O.G. Epi Committee over the several years: 

• Establishment of a North American pediatric cancer registry. In order to enhance research and facilitate case accrual to non-therapeutic and prevention research studies,  the C.O.G. Epi Committee, in collaboration with investigators at the National Cancer Institute, and State, Provincial, and regional cancer registries, is working to establish the Children’s Cancer Research Network (CCRN), which will form the basis of a national pediatric cancer registry. The establishment of the CCRN will facilitate the systematic registration of pediatric and adolescent patients diagnosed with cancer in the United States and Canada, and provide an unparalleled resource to conduct etiologic (as well as late effects and cancer control research) on childhood cancer for investigators both within and outside of C.O.G..

• Design of new studies and workshops to address and improve methodological approaches. Epidemiologic studies suggest an important role for specific parental and child exposures in the etiology of childhood cancers. However, studies of childhood cancer often rely solely on questionnaire data obtained from interviews conducted with the parents of children with and without cancer; there is a paucity of data regarding the reliability of recall of past exposures. The C.O.G. Epi Committee also recognizes the need to identify additional sources for exposure assessment including existing records, direct and indirect measurements, and biological assays. Finally, there has been difficulty in recruiting appropriate control groups for case-control comparisons. The Epi Committee will propose studies and workshops to evaluate these issues and offer potential solutions. 

• Expanded investigations of gene-environment interactions, familial cancer syndromes, and viruses in childhood cancer etiology. It is estimated that less than 5% of all childhood cancers are due to major genetic mutations or syndromes. Additional studies are warranted including: a) the integration of host genetic susceptibility markers into future case-control studies of childhood cancer, b) design of studies to further understand the prevalence of known familial cancer syndromes, as well as to identify novel, previously unrecognized, or poorly defined familial associations, and c) further exploration of the potential role of viruses (including SV40, BKV, and JCV).

• Dissemination of information to physicians, scientists, nurses, parents, and lay people. While it is important to publish new findings, the Epi Committee recognizes the need to provide appropriate context to epidemiology studies and their results. In particular, the C.O.G. Epi Committee is concerned that the distortion of reporting of articles diminish the credibility of epidemiologic studies among C.O.G. staff, as well as confuse parents, patients, and lay people. The C.O.G. Epi committee will take an active role in education, and develop materials for the dissemination of information to physicians, scientists, nurses, parents, patients, and lay people.

The C.O.G. Epidemiology Committee is inviting applications for membership to the Epi Interest Group. The Epi Steering Committee is also moving forward with an agenda that will include the formation of Task Forces/Subcommittees including: 

1. Gene-environment interactions: including the planning of future case-control studies to explore gene-environment interactions in childhood cancer etiology.
2. Family cancer/viral etiology: including etiologic studies that identify novel familial cancer syndromes, as well as the potential role of viruses.
3. Methodological Studies: including planning studies to improve methodological approaches in study design such as alternatives to random digit dialing control selection, alternatives and adjuncts to questionnaires to assess exposures including direct and indirect measures, and studies that utilize biological samples. 
4. Education: including identification of ways in which to communicate and disseminate information regarding epidemiology studies to physicians, nurses, parents, children, and lay individuals. 

These task forces would also involve opportunities for young investigators.

We would ask that all interested individuals send a statement of their interest (including indicating a task force(s) that they may be interested in joining) and their CV as soon as possible (by email ross@epi.umn.edu). The Epi Steering committee expects to make a final decision regarding applications by early fall. 

Is ALL caused by a virus?

Evidence for a contribution of infection to the etiology of childhood leukemia comes largely from epidemiological studies.  There is a ten-fold variation in incidence in different countries and variation in incidence rates is also seen between individual countries.  Rates are highest in regions with higher socioeconomic status and an increased risk of 15-25% has been reported in households and communities with higher standards of living.  This increased risk has been interpreted as suggesting that delayed exposure to one or more infectious agents may be involved in the etiology of childhood leukemia and, in particular, the precursor ALL occurring in young children. An alternative but not mutually exclusive hypothesis is that childhood leukemia occurs as a rare response to a common transforming virus.  Kinlen et al. reported that influxes of new populations into previously isolated communities are associated with an increased incidence of childhood leukemia [Lancet 1990; 336:577-88].  In aneffort to identify viruses that might contribute to the etiology of common ALL, MacKenzie et al [Leukemia 2001; 15:415-21] have screened 20 leukemic samples for the presence of 4 lymphotropic herpes viruses.  The investigators used as controls 28 peripheral blood samples from children with other causes of cancer.  The authors observed detection rates of virus that were similar in the leukemia and control panels.  In addition, 18 leukemic samples were surveyed for putative new herpes viruses using degenerate primers (primers that detect commonly conserved areas of herpes viruses) and did not identify any novel herpes virus genome. 

COMMENT:  The struggle to confirm the epidemiological observations regarding infectious exposure and etiology of acute lymphoblastic leukemia continues. Epidemio-logical data regarding population mixing continues to appear in the literature [see C3 vol. 12, no. 2, March 2001]. The identification of the interaction between environment, genetic background and infectious exposure may be complex and require new paradigms for full understanding. 

Give me a break

Nijmegen break syndrome (NBS) is a rare autosomal disorder associated with immune deficiency, microcephaly, short stature, chromosome fragility and increased susceptibility to lymphoid malignancy.  Veron et al. [Cancer Research 2001; 61:3570-2] have analyzed all 16 exons of the NBS-1 gene from 47 children with first relapse of ALL for mutations.  In 7 of them (14.9%), 4 novel amino acid substitutions were identified.  The germline origin of the mutation was confirmed in 3 patients, while a mutation was shown to be somatic (present in the leukemia cells only) in the remaining cases.  No additional mutations were found on the second allele in any of the 7 patients.  This suggests that NBS does not act like a typical tumor suppressor gene.  The observed NBS-1 gene mutations in ALL patients suggest possible involvement in the pathogenesis of the disease. 

COMMENT: NBS is a rare genetic disorder which clinically resembles ataxia telangiectasia (AT).  It has long been believed that individual heterozygotes for an AT gene mutation (generally parents of affected cases) have an increased risk of malignancy, particularly breast cancer.  These data suggest that heterozygotes for NBS may also have an increased risk of malignancy.  These data contrast to the paper by Stumm et al. [Cancer Genetics and Cytogenetics 2001; 126:60-2]. This study used a different technique to look for deletions of the NBS-1 gene in B-cell lymphomas.  The malignancy was typical of NBS.  None were found, however.  The Veron paper suggests that point mutations may be more typical of the mutations in NBS associated with malignancy, in contrast to the mutations associated with the syndrome, which are typically truncating mutations.  The authors of the ALL study are expanding their investigation to larger groups of patients, which will enable them to study more closely the impact of these mutations on clinical features and outcome of the leukemia. 

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