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|Background||Eligibility to Participate in the IPACTR|
|Inherited Constitutional Genetic Changes in Pediatric ACT||Confidentiality|
|Aims and Objectives of the IPACTR||References|
Adrenocortical tumors (ACT) are very rare in children and teenagers.1 Of all new cases of cancer diagnosed each year in the United States and Europe in patients less than 20 years old, only about 0.2% are ACT.2,3 The international incidence of ACT is not well defined but appears to differ geographically, with a high incidence observed in southern Brazil.4-8
Because ACT is rare, little is known about its natural history. Some cases of ACT are associated with inherited gene mutations, while others are not.9 Studies at St. Jude10-12 and elsewhere have found that most children with ACT, particularly those less than 4 years of age, have inherited mutations in the P53 gene. Inherited P53 mutations are less frequent in older children and adolescents with ACT and are very rare in adults with ACT.
Some families that carry P53 mutations do not have an abnormal incidence of cancer.13-15 Other families, which carry other types of P53 mutations, can have a pervasive history of cancer (Li-Fraumeni syndrome).16
Some of the features that predict the success of treatment are known.17-19 The most important of these features, identified in a large series of patients,20 was complete surgical removal of the tumor. Incomplete tumor removal was associated with a dismal outcome. Among children whose tumors had been completely removed, tumor size was the strongest predictor of cure; the cure rate for children with large tumors (≥200 cm3) was about half that for children with smaller tumors.
The Children’s Oncology Group (COG) is now conducting a study in which children with ACT are treated uniformly, and the English pediatric rare tumor consortium has provided therapy guidelines. These efforts should help to clarify optimal treatment approaches21 and to examine the effects of different inherited P53 mutations and genetic changes found within the tumors.22-24
The International Pediatric Adrenocortical Tumor Registry (IPACTR) is a tumor registry that collects information about this rare tumor from all over the world. The registry data can be analyzed to gain an overview of the disease and its treatment, outcome, and risk factors and to design future studies to gain more information. It may also help pediatric cancer physicians to agree on the best current treatment approach. The combined data from COG and IPACTR studies are also expected to provide meaningful insight into the biology of ACT. Finally, because most pediatric ACTs secrete hormones, the IPACTR data will help to discover the long-term effects of these hormones on children's growth and development.
In addition to obtaining information, we plan to store frozen tumor samples for molecular studies. These tumor samples will be obtained, stored, and managed according to established procedures and country-specific guidelines. The samples will be coded and only the referring physicians, IPACTR researchers, and study coordinators will know the names of the patients.
Because pediatric ACT is strongly associated with inherited mutations in the P53 gene, children with ACT and one of their parents are likely to carry a P53 mutation. Most such carriers are at increased risk of various types of cancer, depending on the specific type of P53 mutation. A blood test (P53 sequencing) can reveal whether an individual carries a P53 mutation. People who are tested for P53 mutation should meet with a health care provider trained in genetic counseling (a genetic counselor) who can explain the implications of the test.
Because carriers of P53 mutations are at increased risk of diverse types of cancer, it is likely that some of the patients’ relatives will develop cancer; it would be helpful to add this information to IPACTR. These relatives may be contacted and asked whether they would agree to contribute to IPACTR research by providing a blood sample and/or tumor sample. Patients with ACT may also have developed other types of cancer, or may do so after being registered in IPACTR. IPACTR investigators would like to obtain samples of these tumors to determine whether they harbor a P53 mutation.
The primary goal of the IPACTR study is to collect demographic and medical information—including a detailed family history of cancer—about children and adolescents with ACT in order to learn more about these tumors, their treatment, and the outcome of therapy, worldwide. We also wish to store ACT samples (tumor banking) for molecular studies to clarify the role of the P53 gene and other genetic pathways in these tumors.
Participating patients must be age 21 years or younger at the time of diagnosis of ACT. Patients’ parents and relatives who develop cancer can be registered at any age. It is not necessary to come to St. Jude Children’s Research Hospital to participate. All arrangements will be made by telephone and mail.
Study numbers will be used instead of patient names or medical record numbers, with the exception of St. Jude patients. No participant names will be recorded on the data collection forms. The list containing the study number and the medical record number will be maintained in a locked file and will be destroyed after all data have been analyzed.
 Bernstein L, Gurney JG. Carcinomas and other malignant epithelial neoplasms. In: Ries LAG, Smith MA, Gurney JG, et al, eds. Cancer and survival among children and adolescents: United States SEER program 1975-1995. Bethesda, MD: 1999:139-147.
 Gatta G, Capocaccia R, Stiller C, et al. Childhood cancer survival trends in Europe: a EUROCARE Working Group study. J Clin Oncol. 2005;23:3742-3751.
 Lack EE, Mulvihill JJ, Travis WD, Kozakewich HP. Adrenal cortical neoplasms in the pediatric and adolescent age group. Clinicopathologic study of 30 cases with emphasis on epidemiological and prognostic factors. Pathol Annu. 1992;27 Pt 1:1-53.
 Stiller CA. International variations in the incidence of childhood carcinomas. Cancer Epidemiol Biomarkers Prev. 1994;3:305-310.
 Birch JM, Marsden HB, Swindell R. Incidence of malignant disease in childhood: a 24-year review of the Manchester Children's Tumour Registry data. Br J Cancer. 1980;42:215-223.
 Mosso ML, Colombo R, Giordano L, et al. Childhood cancer registry of the Province of Torino, Italy. Survival, incidence, and mortality over 20 years. Cancer. 1992;69:1300-1306.
 Marigo C, Muller H, Davies JN. Survey of cancer in children admitted to a Brazilian charity hospital. J Natl Cancer Inst. 1969;43:1231-1240.
 Drut R, Hernandez A, Pollono D. Incidence of childhood cancer in La Plata, Argentina, 1977-1987. Int J Cancer. 1990;45:1045-1047.
 Ribeiro RC, Figueiredo B. Childhood adrenocortical tumours. Eur J Cancer. 2004;40:1117-1126.
 Varley JM, McGown G, Thorncroft M, et al. Are there low-penetrance TP53 Alleles? Evidence from childhood adrenocortical tumors. Am J Hum Genet. 1999;65:995-1006.
 Ribeiro RC, Sandrini F, Figueiredo B, et al. An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci U S A. 2001;98:9330-9335.
 DiGiammarino EL, Lee AS, Cadwell C et al. A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. Nat Struct Biol. 2002;9:12-16.
 Figueiredo BC, Sandrini R, Zambetti GP, et al. Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation. J Med Genet. 2006;43:91-96.
 West AN, Ribeiro RC, Jenkins J, et al. Identification of a novel germ line variant hotspot mutant p53-R175L in pediatric adrenal cortical carcinoma. Cancer Res. 2006;66:5056-5062.
 Ribeiro RC, Rodriguez-Galindo C, Figueiredo BC, et al. Germline TP53 R337H mutation is not sufficient to establish Li-Fraumeni or Li-Fraumeni-like syndrome. Cancer Lett. 2006;247:353-355;.
 Malkin D, Li FP, Strong LC, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990;250:1233-1238.
 Bugg MF, Ribeiro RC, Roberson PK, et al. Correlation of pathologic features with clinical outcome in pediatric adrenocortical neoplasia. A study of a Brazilian population. Brazilian Group for Treatment of Childhood Adrenocortical Tumors. Am J Clin Pathol. 1994;101:625-629.
 Ribeiro RC, Michalkiewicz EL. Adrenocortical Tumors in Children. In: Raghavan D, Brecher M, Johnson D, Meropol N, Moots P TJ, eds. Textbook of Uncommon Cancer. West Sussex, England: John Wiley & Sons, Ltd.; 1999:611-620.
 Ribeiro RC, Sandrini Neto RS, Schell MJ, et al. Adrenocortical carcinoma in children: a study of 40 cases. J Clin Oncol. 1990;8:67-74.
 Michalkiewicz E, Sandrini R, Figueiredo B, et al. Clinical and outcome characteristics of children with adrenocortical tumors: a report from the International Pediatric Adrenocortical Tumor Registry. J Clin Oncol. 2004;22:838-845.
 A Multi-Disciplinary Consensus Statement of Best Practice from a Working Group Convened Under the Auspices of the BSPED and UKCCSG (rare tumour working groups). Adrenocortical Tumours (ACT). In: Spoudeas HA, ed. Paediatric Endocrine Tumors. West Sussex, United Kingdom: Novo Nordisk Ltd.; 2005:47-63.
 Longui CA, Lemos-Marini SHV, Figueiredo B, et al. Inhibin a-subunit (INHA) gene and locus changes in paediatric adrenocortical tumours from TP53 R337H mutation heterozygote carriers. J Med Genet. 2004;41:354-359.
 Figueiredo BC, Cavalli LR, Pianovski MA, et al. Amplification of the steroidogenic factor 1 gene in childhood adrenocortical tumors. J Clin Endocrinol Metab. 2005;90:615-619.
 Figueiredo BC, Stratakis CA, Sandrini R, et al. Comparative genomic hybridization analysis of adrenocortical tumors of childhood. J Clin Endocrinol Metab. 1999;84:1116-1121.