Neuroblastoma in two siblings supports the role of 1p36 deletion in tumor development.

Familial neuroblastoma occurs rarely. We studied a family with three children; one of them has a disseminated (stage 4) and another has a localized (stage 2) neuroblastoma. We observed subtelomeric locus D1Z2 (1p36) deletion in both tumors by using double-color fluorescence in situ hybridization. The MYNC gene was found in single copy in both tumors. Loss of heterozygosity (LOH) and restriction fragment length polymorphism analyses were performed by using DNA from frozen tumor cells and from microdissected tumor areas excised from paraffin-embedded sections. We detected somatic LOH at locus D1S468 (1p36) in a tumor-cell population with a trisomy 1 of the stage-2 patient. Neuroblastoma cells of the stage-4 patient were diploid and showed allelic loss at the following loci: D1S172, D1S80, D1S94, D1S243, D1S468, D1S214, D1S241, and D1S164. Haplotype study showed that the siblings inherited the same paternal 1p36-->pter chromosome region by homologous recombination and that, in the two tumors, arm 1p of different chromosomes of maternal origin was damaged. Our results suggest that the siblings inherited the predisposition to neuroblastoma associated with paternal 1p36 region and that tumors developed as a consequence of somatic loss of the maternal 1p36 allele.

Cytogenetic and molecular study of 32 Down syndrome families: potential leukaemia predisposing role of the most proximal segment of chromosome 21q.

Down syndrome (DS) children have a 10-20-fold increased risk of developing ALL or AML compared to non-DS children. An increased disomic homozygosity of the polymorphic DNA markers in the pericentromeric region of chromosome 21q (21q11) has repeatedly been found in DS patients with ANLL-M7 and DS-specific transient abnormal myelopoiesis (TAM), compared to the majority of DS subjects without leukaemia. Analysis of cytogenetic heteromorphisms and 26 polymorphic DNA markers from chromosome 21q showed an increased number of pericentromeric crossovers between the non-disjoined chromosomes in DS-ANLL cases (3/11), compared to DS-ALL (0/9) and DS-nonleukaemic cases (0/12). These findings are compatible with the model of disomic homozygosity of the predisposing allele of a putative pericentromeric gene, as an explanation for the high prevalence of ANLL in DS.

Restriction fragment length polymorphism analysis reveals different allele frequency and a linkage disequilibrium at locus D1S94 in neuroblastoma patients.

Deletion of chromosome 1p and MYCN amplification have been reported as frequent abnormalities in human neuroblastoma. We studied loss of heterozygosity (LOH) in 50 (48 informative) Italian neuroblastoma patients by restriction fragment length polymorphisms (RFLPs) analysis using anonymous and hypervariable region (HVR) sequences. Twelve cases (25%) showed LOH at one or more loci. Locus D1S94 was the most frequently involved in LOH events (8/12) of deleted cases (66.6%). MYCN amplification was observed in 20% of patients which showed a significantly lower event-free survival probability (EFSp) (P = 0.004). We also studied the allelic distribution in the constitutional DNA of neuroblastoma patients (n = 44) and a matched group of healthy Italian subjects (n = 79) for loci D1S112 and D1S94. A significantly (P = 0.01) different allele frequency was detected for the two groups at locus D1S94, but not at D1S112. Moreover, the neuroblastoma population did not confirm the Hardy-Weinberg expectations at the former locus. This observation suggests the existence of an allelotype associated with neuroblastoma susceptibility.

Peculiar allelotype associated with susceptibility to neuroblastoma.

Human neuroblastoma (NB) is characterized genetically by deletions of the short arm of chromosome I and by MYCN amplification. Loss of heterozygosity (LOH) has been found frequently for region 1p36. We have studied restriction fragment length polymorphisms (RFLPs) by using anonymous and hypervariable region (HVR) sequences to demonstrate LOH for 1p loci in 50 Italian neuroblastoma patients. Twelve cases (25%) showed LOH at one or more loci. Locus D1S94 was the most frequently involved (8/12 cases with deletion; 67%). MYCN amplification was observed in 20% of the patients. We also studied the allelic distribution in the constitutional DNA of neuroblastoma patients and of healthy Italian subjects for loci D1S112 and D1S94. A significantly (P = 0.01) different allele frequency was detected in the two groups at locus D1S94, but not at D1S112. Furthermore, the NB population was not in Hardy-Weinberg equilibrium at the former locus. This new observation suggests the existence of an allelotype associated with the susceptibility to neuroblastoma.

Genetic epidemiology of colorectal cancer.

Starting from a survey of the studies on familial aggregation of colorectal cancer, we introduce the aims of genetic epidemiology. One of its main goals is to assess population frequency of cancer susceptibility genes and to determine the age-specific risks for carriers with respect to non-carriers. In section two, segregation analysis investigations are reviewed, and inferences on the relevance of genetic components of susceptibility to colorectal cancer are drawn. In section three, the HNPCC paradigm is discussed in the light of the Knudson model of tumorigenesis and recent advances of molecular research. In the last section we show an example of genotype/environment interaction in the etiology of a particular cancer and present a conceptual framework for studies on cancer genetic epidemiology in terms of attributable and relative risk.

Pentasomy 21 in leukemia complicating Diamond-Blackfan anemia.

We present the cytogenetic pattern of a leukemic infant with Diamond-Blackfan anemia (DBA). The karyotype was characterized by clonal evolution involving consecutive gains of chromosome 21 up to pentasomy. No chromosomal changes were present in normal lymphocytes. Such a karyotype evolution has been described in some cases of acute leukemia associated with Down Syndrome, but rarely in non-Down cases.

Molecular epidemiology of cancer in immune deficiency.

Molecular epidemiology may help fill the gap between epidemiological and biological models for cancerogenesis, allowing useful comparisons between series of cases carrying different biological characteristics. The defective regulation of immune responses is probably the common basis of cancer origin in genetically determined immune deficiency (GDID). Lymphomas are the most common neoplasms, showing an extremely high incidence in early age, frequent unusual location (extra-nodal) and histology, and rapid progression and spread with little response to therapy. A high incidence of lymphoma is also found in acquired (AIDS) or iatrogenic (transplant recipients) immune defective patients. The emergence of a malignant clone may be linked to unregulated polyclonal B- or T-cell proliferation and to disturbances in chromosomal rearrangements and in clonal selection, which are unique features of the immune cells regulation. It is useful to compare patterns of malignancies observed in GDIDs and in chromosomal breakage syndromes (CBS). In ataxia-teleangectasia (AT), selective errors at sites of special recombination involved in immune cell rearrangements may account for both immune deficiency and frequent types of malignant transformation. Different cytogenetic alterations and different types of malignancies are more common in Bloom syndrome, and in other GDIDs unrelated to chromosomal fragility, possibly due to different regulatory impairments. Viral infection (EBV, HPV, CMV) is likely to be a factor in any of the above steps. Therefore, individual exposure to viral (or other environmental) agents may be related to frequent location (skin, ano-genital areas, digestive tracts) of nonlymphatic cancers both in some GDIDs and in acquired or iatrogenic immune deficiencies. Cells that are homozygous for GDID are not malignant themselves, but are more likely to undergo new mutations to malignancy, due both to disregulation of the immune system and to environmental agents.

Effect of x-rays on chromosome 21 nondisjunction.

In a series of 156 females and 149 males with a Down syndrome (DS) child, a case-control study was performed to evaluate the effect of abdominal-pelvic exposure to diagnostic x-rays prior to conception on nondisjunction (ND). Cytogenetic analysis using QFQ banding allowed unequivocal identification of ND parents as cases. Partners of ND parents were treated as control group. Odds ratio for the association of x-rays exposure and ND occurrence (stratified for sex and age) was 1.85 (borderline to significance: with a 95% confidence interval 1-3.44). Such an association appeared highly significant in older fathers and borderline to significant in younger mothers, when age groups were analyzed separately. By comparing mean parental ages at birth of the propositus, the prevalence of exposure to x-rays appeared moderately associated with aging in control parents of both sexes. Furthermore, the mean age of unexposed ND parents of paternally derived SD cases was the same as the referent population's, suggesting that age is not a risk factor for ND in the male, except for being associated with increasing exposure risk. Conversely, risk attributable to x-rays exposure in the female appears to be progressively diluted with increasing age, by strongly age-dependent high risk, presumably due to biologic factors that are not affected by environmental exposure.

Origin of extra chromosome 21 in 343 families: cytogenetic and molecular approaches.

As the knowledge of parental origin and meiotic stage of nondisjunction is the prerequisite to evaluation of the possible etiological factors in trisomy 21, we have examined 343 families with at least one Down syndrome child. Of these, 322 were primary trisomies, including 24 mosaics, and 21 were structural rearrangements. This study was carried out by analysing chromosome 21 cytogenetic heteromorphisms and molecular RFLPs. In our study first maternal meiotic nondisjunction (75.3%) is the most common mechanism leading to primary trisomies. In the 24 mosaic cases, the most frequent error occurred at the first meiotic division (83%). The origin of structural rearrangements was maternal in 15 of 21 cases. Trisomy 21q21q was due to an isochromosome, and not to a translocation.

Crossing over and chromosome 21 nondisjunction: a study of 60 families.

To test the hypothesis that meiotic nondisjunction may be caused by reduced chiasma frequency, hence recombination, we investigated 60 families with a trisomic child affected with Down syndrome (DS). We analyzed cytogenetic heteromorphisms (CH) and a number of restriction fragment length polymorphisms spanning regions 11.1 through 22.3 of 21q in both parents, in the DS child and, when available (21 families), in a normal sib. The parental origin and meiotic stage of nondisjunction were determined by combining the results of both CH and RFLP analysis. Crossover events were detected as switches in the parental haplotype expected in both DS and normal sibs. Available recombination frequency data were used to calculate the expected number of crossover events in nondisjoined and in normally segregating chromosomes, given the allele combination present in each family. The observed number of crossover events in normal meioses and in second-division nondisjunctions were consistent with the calculated figures. However, a significant reduction in the observed number of crossover events was found in nondisjoined chromosomes derived from errors in the first meiotic division and, in particular, in the proximal portion of 21q.

[AIDS in Africa]. / AIDS in Africa.

While AIDS (Acquired Immunodeficiency Syndrome) certainly represents a worldwide health problem, the attention of many researchers and epidemiologists, besides the WHO itself, has recently focused on Africa for the following reasons: 1) The etiologic agent of AIDS, the Human Immunodeficiency Virus (HIV) (previously named HTLV-III or LAV) is likely to have originated in Africa. Solid evidence has been accumulated that antibodies against HIV were present in African sera collected in the early 1960s. In the same period widespread infection by viruses strictly related to HIV has been documented in primates living in tropical Africa. A second type of HIV (now named HIV-2 and previously known as HTLV-IV or LAV-2) which is responsible for a milder AIDS-related disease, has been subsequently identified in West African inhabitants with its own simian correlate. Although epidemiological evidence for the presence of AIDS in Africa in these early periods is scanty, sporadic cases have retrospectively been identified. 2) Up to 1986, AIDS epidemiology in Africa has been hampered by inconsistency of demographic data, inadequacy of public health services and difficulty of obtaining the necessary laboratory evidence. The few data available (Zaire, Rwanda), suggests an annual incidence in 1983 of 170-800 per million, comparable to higher U.S. and European rates. There is no evidence, however, that African epidemy precedes that of the U.S., for which there is no explanation at present. On the other hand, recent data indicate an alarming acceleration of the African epidemy, that spreads well beyond the risk groups which have been recognized in Western countries. 3) Prevalent infection routes in Africa are not entirely overlapping with Western countries'. Rather than homosexual intercourse (U.S.) and syringe sharing by drug abusers (Italy), most African cases seem to be transmitted by heterosexual promiscuous contacts and, to a lesser extent, by blood derivates and recycled syringes. Insects and tribal rituals have been also suspected as vehicles of infection in Africa; widespread prostitution and inadequate health facilities certainly are. As a consequence, transplacental infection appear much more common than in the West. 4) Clinical aspects of AIDS progression in Africa appear linked to the different spectrum of opportunistic agents present on the continent and to the general hygienic and social conditions prevailing among its people. Rather than generalized lymphoadenopathies and Pneumocystes Carini pneumonia, diarrhoea and extreme weight loss ("Slim disease") represent the most common clinical pattern.

PIP: In regard to AIDS, attention has focused on Africa for the following reasons: 1) Solid evidence indicates that antibodies against HIV were present in African sera collected in the early 1960s. 2) Up to 1986, AIDS epidemiology was hampered by inconsistent demographic data, inadequate public health services, and scanty laboratory evidence. 3) Prevalent infection routes in Africa are not entirely overlapping with Western countries. 4) Clinical aspects of AIDS progression in Africa appear linked to the different opportunistic agents and to the prevailing hygienic and social conditions. In 1983, in Rwanda and Zaire, the annual incidence of HIV infection ranged from 17 to 800/million and 170/ million, respectively. In the first five months of 1985, the range of annual incidence in Africa was 50-1000/million. In Zaire, the male-female infection ratio was 1:1.2 and the average age of infected people was 33.6 years. Seropositivity ranged from 1% to 15%. The distribution of African AIDS is characterized by heterosexual transmission, transmission via contaminated syringes, blood transfusion, and maternal-fetal transmission. Lack of condom use among prostitutes and multiple partners are the main routes of heterosexual transmission. Other routes are high risk sexual practices as well as traditional and tribal rituals (clitoridectomy/female genital mutilation). Perinatal infection results from maternal-fetal transmission but also from blood transfusion and the use of unsterilized syringes. In 1986, in Zaire, among 2384 hospital workers, significantly more seropositivity occurred in a group who had had injections in the previous three years. A 1986 study also hinted at the possible role of insects in HIV infection. The major symptoms of AIDS in an African context, in addition to the usual depletion of CD4 lymphocytes, include diarrhea and weight loss, candida, cryptococcus, cytomegalovirus, cryptosporidium, and herpes simplex. Only 14% of AIDS patients in Africa have pneumonia carinii as compared with 63% of AIDS patients in Europe. The concomitant infection with both HIV and tuberculosis is particularly high in Africa.

Parental age and the origin of trisomy 21. A study of 302 families.

Several studies have attempted to define the role of parental age in determining the prevalence of 47, +21 according to the origin of nondisjunction. This report analyzes the original data of 197 informative families from Italy and reviews the available literature (96 families from Denmark and 201 from other countries). Mothers whose gametes showed nondisjunction are treated as cases, and those with normal meiosis as controls within each study. To utilize the data fully, maternal age at birth of a 47, +21 individual is treated as a continuous variable in a nonparametric comparison. The combined evidence indicates that nondisjunction in the female is associated with a significant age difference between cases and controls which is mostly due to errors in the second meiotic division. It may be inferred that in the general population, aging enhances nondisjunction at both first and second division in the female, while aging in the male is presumably associated mostly (or only) with first division errors. Implications and alternative models are discussed.

Congenital leukemia: persistent spontaneous regression in a patient with an acquired abnormal karyotype.

Congenital leukemia is a rare disease accounting for about 1% of all leukemias in childhood. While cases associated with Down's syndrome not infrequently show a spontaneous regression, such an event is very rare in non-Down cases and exceptional in those (among the latter) which present clonal cytogenetic alterations in the neoplastic cells. We present the case of a patient with congenital leukemia and an abnormal karyotype (limited to the neoplastic clone), in which an apparently spontaneous and prolonged remission occurred after a relapse.