RESUMEN

The incidence of pediatric adrenal cortical carcinoma (ACC) in southern Brazil is 10-15 times higher than that of pediatric ACC worldwide. Because childhood ACC is associated with Li-Fraumeni syndrome, we examined the cancer history and p53 status of 36 Brazilian patients and their families. Remarkably, 35 of 36 patients had an identical germ-line point mutation of p53 encoding an R337H amino acid substitution. Differences within intragenic polymorphic markers demonstrated that at least some mutant alleles arose independently, thus eliminating a founder effect. In tumor cells, the wild-type allele was deleted, and mutant p53 protein accumulated within the nuclei. Although these features are consistent with Li-Fraumeni syndrome-associated adrenal tumors, there was no history of increased cancer incidence among family members. Therefore, this inherited R337H p53 mutation represents a low-penetrance p53 allele that contributes in a tissue-specific manner to the development of pediatric ACC.

Asunto(s)

Neoplasias de la Corteza Suprarrenal/genética , Genes p53 , Mutación de Línea Germinal , Mutación Puntual , Secuencia de Bases , Núcleo Celular/metabolismo , Niño , Cartilla de ADN , Femenino , Humanos , Pérdida de Heterocigocidad , Masculino , Linaje , Proteína p53 Supresora de Tumor/metabolismo

RESUMEN

Adrenocortical tumors (ACT) in children under 15 years of age exhibit some clinical and biological features distinct from ACT in adults. Cell proliferation, hypertrophy and cell death in adrenal cortex during the last months of gestation and the immediate postnatal period seem to be critical for the origin of ACT in children. Studies with large numbers of patients with childhood ACT have indicated a median age at diagnosis of about 4 years. In our institution, the median age was 3 years and 5 months, while the median age for first signs and symptoms was 2 years and 5 months (N = 72). Using the comparative genomic hybridization technique, we have reported a high frequency of 9q34 amplification in adenomas and carcinomas. This finding has been confirmed more recently by investigators in England. The lower socioeconomic status, the distinctive ethnic groups and all the regional differences in Southern Brazil in relation to patients in England indicate that these differences are not important to determine 9q34 amplification. Candidate amplified genes mapped to this locus are currently being investigated and Southern blot results obtained so far have discarded amplification of the abl oncogene. Amplification of 9q34 has not been found to be related to tumor size, staging, or malignant histopathological features, nor does it seem to be responsible for the higher incidence of ACT observed in Southern Brazil, but could be related to an ACT from embryonic origin.

Asunto(s)

Humanos , Masculino , Preescolar , Adenoma/genética , Neoplasias de la Corteza Suprarrenal/genética , Carcinoma/genética , Cromosomas Humanos Par 9/genética , Amplificación de Genes , Adenoma/epidemiología , Adenoma/etnología , Neoplasias de la Corteza Suprarrenal/epidemiología , Neoplasias de la Corteza Suprarrenal/etnología , Carcinoma/epidemiología , Carcinoma/etnología , Contaminación Ambiental/efectos adversos , Incidencia , Mutación , Clase Social

RESUMEN

Childhood adrenocortical tumors (ACT) are rare. In the USA, only about 25 new cases occur each year. In Southern Brazil, however, approximately 10 times that many cases are diagnosed each year. Most cases occur in the contiguous states of Sao Paulo and Paraná. The cause of this higher rate has not been identified. Familial genetic predisposition to cancer (p53 mutations) and selected genetic syndromes (Beckwith-Wiedemann syndrome) have been associated with childhood ACT in general but not with the Brazilian counterpart. Most of the affected children are young girls with classic endocrine syndromes (virilizing and/or Cushing). Levels of urinary 17-ketosteroids and plasma dehydroepiandrosterone sulfate (DHEA-S), which are abnormal in approximately 90 percent of the cases, provide the pivotal clue to a diagnosis of ACT. Typical imaging findings of pediatric ACT consist of a large, well-defined suprarenal tumor containing calcifications with a thin capsule and central necrosis or hemorrhage. The pathologic classification of pediatric ACT is troublesome. Even an experienced pathologist can find it difficult to differentiate carcinoma from adenoma. Surgery is the single most important procedure in the successful treatment of ACT. The role of chemotherapy in the management of childhood ACT has not been established although occasional tumors are responsive to mitotane or cisplatin-containing regimens. Because of the heterogeneity and rarity of the disease, prognostic factors have been difficult to establish in pediatric ACT. Patients with incomplete tumor resection or with metastatic disease at diagnosis have a dismal prognosis. In patients with localized and completely resected tumors, the size of the tumor has predictive value. Patients with large tumors have a much higher relapse rate than those with small tumors.

Asunto(s)

Humanos , Masculino , Femenino , Recién Nacido , Lactante , Preescolar , Niño , Adolescente , Adulto , Adenoma/fisiopatología , Neoplasias de la Corteza Suprarrenal/fisiopatología , Carcinoma/fisiopatología , Adenoma/diagnóstico , Adenoma/terapia , Neoplasias de la Corteza Suprarrenal/diagnóstico , Neoplasias de la Corteza Suprarrenal/terapia , Carcinoma/diagnóstico , Carcinoma/terapia , Pronóstico

RESUMEN

Adrenocortical tumors (ACT) in children under 15 years of age exhibit some clinical and biological features distinct from ACT in adults. Cell proliferation, hypertrophy and cell death in adrenal cortex during the last months of gestation and the immediate postnatal period seem to be critical for the origin of ACT in children. Studies with large numbers of patients with childhood ACT have indicated a median age at diagnosis of about 4 years. In our institution, the median age was 3 years and 5 months, while the median age for first signs and symptoms was 2 years and 5 months (N = 72). Using the comparative genomic hybridization technique, we have reported a high frequency of 9q34 amplification in adenomas and carcinomas. This finding has been confirmed more recently by investigators in England. The lower socioeconomic status, the distinctive ethnic groups and all the regional differences in Southern Brazil in relation to patients in England indicate that these differences are not important to determine 9q34 amplification. Candidate amplified genes mapped to this locus are currently being investigated and Southern blot results obtained so far have discarded amplification of the abl oncogene. Amplification of 9q34 has not been found to be related to tumor size, staging, or malignant histopathological features, nor does it seem to be responsible for the higher incidence of ACT observed in Southern Brazil, but could be related to an ACT from embryonic origin.

Asunto(s)

Adenoma/genética , Neoplasias de la Corteza Suprarrenal/genética , Carcinoma/genética , Cromosomas Humanos Par 9/genética , Amplificación de Genes , Adenoma/epidemiología , Adenoma/etnología , Neoplasias de la Corteza Suprarrenal/epidemiología , Neoplasias de la Corteza Suprarrenal/etnología , Carcinoma/epidemiología , Carcinoma/etnología , Preescolar , Contaminación Ambiental/efectos adversos , Humanos , Incidencia , Masculino , Mutación , Clase Social

RESUMEN

Childhood adrenocortical tumors (ACT) are rare. In the USA, only about 25 new cases occur each year. In Southern Brazil, however, approximately 10 times that many cases are diagnosed each year. Most cases occur in the contiguous states of São Paulo and Paraná. The cause of this higher rate has not been identified. Familial genetic predisposition to cancer (p53 mutations) and selected genetic syndromes (Beckwith-Wiedemann syndrome) have been associated with childhood ACT in general but not with the Brazilian counterpart. Most of the affected children are young girls with classic endocrine syndromes (virilizing and/or Cushing). Levels of urinary 17-ketosteroids and plasma dehydroepiandrosterone sulfate (DHEA-S), which are abnormal in approximately 90% of the cases, provide the pivotal clue to a diagnosis of ACT. Typical imaging findings of pediatric ACT consist of a large, well-defined suprarenal tumor containing calcifications with a thin capsule and central necrosis or hemorrhage. The pathologic classification of pediatric ACT is troublesome. Even an experienced pathologist can find it difficult to differentiate carcinoma from adenoma. Surgery is the single most important procedure in the successful treatment of ACT. The role of chemotherapy in the management of childhood ACT has not been established although occasional tumors are responsive to mitotane or cisplatin-containing regimens. Because of the heterogeneity and rarity of the disease, prognostic factors have been difficult to establish in pediatric ACT. Patients with incomplete tumor resection or with metastatic disease at diagnosis have a dismal prognosis. In patients with localized and completely resected tumors, the size of the tumor has predictive value. Patients with large tumors have a much higher relapse rate than those with small tumors.

Asunto(s)

Adenoma , Neoplasias de la Corteza Suprarrenal , Carcinoma , Adenoma/diagnóstico , Adenoma/epidemiología , Adenoma/genética , Adenoma/terapia , Adolescente , Neoplasias de la Corteza Suprarrenal/diagnóstico , Neoplasias de la Corteza Suprarrenal/epidemiología , Neoplasias de la Corteza Suprarrenal/genética , Neoplasias de la Corteza Suprarrenal/terapia , Adulto , Carcinoma/diagnóstico , Carcinoma/epidemiología , Carcinoma/terapia , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Pronóstico

RESUMEN

Although several genes have been investigated in adrenal tumorigenesis, the genetic background of adrenocortical tumors (ACT) remains poorly characterized. In southern Brazil, the annual incidence of ACT is unusually high, ranging from 3.4-4.2/million children, compared with a worldwide incidence of 0.3/million children younger than 15 yr. Environmental factors have been implicated because the distribution of these tumors follows a regional, rather than a familial, pattern. However, decreased penetrance of a particular gene defect cannot be excluded. Because linkage or other traditional genetic analyses would not be appropriate to investigate the defect(s) associated with ACT in this population, we used comparative genomic hybridization (CGH) to screen for DNA sequence copy number changes in 9 nonfamilial ACT (6 carcinomas and 3 adenomas) from unrelated patients from this region. Six female (aged 10 months to 6 3/4 yr) and 3 male (1 1/12 to 3 1/4 yr) patients were studied. Three carcinomas were at stage I, 1 was at stage II, and another was at stage III. Two carcinomas had evidence of invasion of the vena cava, and 3 were more than 3 cm in size. All patients underwent surgical excision of their tumors; chemotherapy was administered to cancer patients. Currently, all patients are alive and in remission, with the exception of 1 patient with stage III cancer. High mol wt DNA was extracted from tumor tissue obtained at surgery and frozen at -70 C. This DNA was labeled and used for CGH according to standard procedures. Digital image analysis was performed to detect chromosomal gains or losses. CGH evaluation revealed extensive genetic aberrations in both adenomas and carcinomas; there were no significant differences relative to age, gender, size, or stage of the tumor (P > 0.1). Chromosomes and chromosomal regions 1q, 5p, 5q, 6p, 6q, 8p, 8q, 9q, 10p, 11q, 12q, 13q, 14q, 15q, 16, 18q, 19, and 20q demonstrated gains, whereas 2q, 3, 4, 9p, 11, 13q, 18, 20p, and Xq showed losses. The most striking finding was consistent copy number gain of chromosomal region 9q34 in 8 of the 9 tumors. We conclude that both benign and malignant ACT from southern Brazil show multiple genetic aberrations, including a consistent gain of chromosomal region 9q34. This genomic area may harbor genetic defects that predispose to ACT formation and are shared by the patients who were investigated in this study or are accumulated epigenetically under the influence of a common factor, such as an environmental mutagen.

Asunto(s)

Neoplasias de la Corteza Suprarrenal/genética , Brasil , Preescolar , Aberraciones Cromosómicas/genética , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 4/genética , Cromosomas Humanos Par 9/genética , Femenino , Dosificación de Gen , Humanos , Lactante , Masculino , Hibridación de Ácido Nucleico

Asunto(s)

Neoplasias de la Corteza Suprarrenal/diagnóstico , 17-Cetosteroides/orina , Adolescente , Neoplasias de la Corteza Suprarrenal/etiología , Neoplasias de la Corteza Suprarrenal/terapia , Factores de Edad , Niño , Preescolar , Síndrome de Cushing/diagnóstico , Deshidroepiandrosterona/sangre , Deshidroepiandrosterona/orina , Contaminantes Ambientales/efectos adversos , Femenino , Humanos , Hipertensión/diagnóstico , Lactante , Recién Nacido , Masculino , Pronóstico , Estudios Retrospectivos , Factores Sexuales , Resultado del Tratamiento , Virilismo/diagnóstico