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Previous reports on possible genomic imprinting of the neuroblastoma tumour suppressor gene on chromosome 1p36 have been conflicting. Here we report on the parental origin of 1p36 alleles lost in 47 neuroblastomas and on a detailed Southern blot analysis of the extent of the 1p deletions in 38 cases. The results are remarkably different for tumours with and without N-myc amplification. In the N-myc single copy tumours we show that the lost 1p36 alleles are of preferential maternal origin (16 of 17 cases) and that the commonly deleted region maps to 1p36.2-3. In contrast, all N-myc amplified neuroblastomas have larger 1p deletions, extending from the telomere to at least 1p35-36.1. These deletions are of random parental origin (18 of 30 maternal LOH). This strongly suggests that different suppressor genes on 1p are inactivated in these two types of neuroblastoma. Deletion of a more proximal suppressor gene is associated with N-myc amplification, while a distal, probably imprinted, suppressor can be deleted in N-myc single copy cases.

Neuroblastomas frequently have deletions of chromosome 1p and amplification of the N-myc oncogene. We analysed 53 neuroblastomas for the N-myc copy number, loss of heterozygosity (LOH) of chromosome 1p36 and the parental origin of the lost alleles. Allelic loss of 1p36 was found in 15 tumours. All N-myc amplified tumours belonged to this subset. In 13/15 tumours with LOH of 1p36 the lost allele was of maternal origin. This non-random distribution implies that the two alleles of the putative neuroblastoma suppressor gene on chromosome 1p36 are functionally different, depending on their parental origin. This is the first evidence as far as we know for genomic imprinting on chromosome 1p.

Acute lymphoblastic leukemia (ALL) in infants under 1 year is strongly associated with translocations involving 11q23 (MLL gene), CD10-negative B-lineage (proB) immunophenotype, and poor outcome. The present study analyses the relationship between age, MLL rearrangements, proB-lineage, and in vitro drug resistance determined using the MTT assay. Compared to 425 children aged over 1 year with common/preB (c/preB) ALL, the 44 infants were highly resistant to steroids (for prednisolone (PRED) more than 580-fold, P ¼ 0.001) and L-asparaginase (L-ASP) (12-fold, P ¼ 0.001), but more sensitive to cytarabine (AraC) (1.9-fold, P ¼ 0.001) and 2-chlorodeoxyadenosine (2-CdA) (1.7-fold, Po0.001). No differences were found for vincristine, anthracyclines, thiopurines, epipodophyllotoxines, or 4-hydroperoxy (HOO)-ifosfamide. ProB ALL of all ages had a profile similar to infant ALL when compared with the group of c/ preB ALL: relatively more resistant to L-ASP and PRED (and in addition thiopurines), and more sensitive to AraC and 2-CdA. Age was not related to cellular drug resistance within the proB ALL group (o1 year, n ¼ 32, vs X1 year, n ¼ 19), nor within the MLL-rearranged ALL (o1 year, n ¼ 34, vs X1 year, n ¼ 8). The translocation t(4;11)(q21;q23)-positive ALL cases were more resistant to PRED (47.4-fold, P ¼ 0.033) and 4-HOO-ifosfamide (4.4-fold, P ¼ 0.006) than those with other 11q23 abnormalities. The expression of P-glycoprotein, multidrug-resistance protein, and lung-resistance protein (LRP) was not higher in infants compared to older c/preB ALL patients, but LRP was higher in proB ALL and MLL-rearranged ALL of all ages. In conclusion, infants with ALL appear to have a distinct in vitro resistance profile with the proB immunophenotype being of importance. The role of MLL cannot be excluded, with the t(4;11) being of special significance, while age appears to play a smaller role.

In this paper we describe the analysis of genetic changes in chromosome 11 in Wilms' tumours. Using a range of probes for regions 11p15, 11p13 and 11q we have screened DNA from 14 Wilms' tumours together with control DNA obtained from the patients' lymphocytes and their parents. We have been able to demonstrate loss of heterozygosity in 5 of the 14 different Wilms' tumours. In three of these five tumours, loss of heterozygosity did not involve markers for 11p13, 11p15.4 or the proximal region of 11p15.5, but only some markers assigned to the most distal part of 11p15.5. In two of these tumours we could demonstrate unequal mitotic recombination in 11p with breakpoints in the hypervariable regions 5' of the insulin gene and/or 3' of the HRASI proto-oncogene. In one tumour, from a Beckwith-Wiedemann patient, all markers for the region 11q13-pter became hemizygous; the region 11q13-qter remained heterozygous. These results demonstrate that loss of heterozygosity in Wilms' tumours may not necessarily involve the proposed Wilms' tumours locus at 11p13 but may be limited to 11p15.5. This suggests that not only the 11p13 region, but also the 11p15.5 region is involved in Wilms' tumour development. The possible role of both regions in the development of Wilms' tumour is discussed.

We compared the efficacy of intensified chemotherapy followed by myeloablative therapy and autologous stem cell rescue with intensified chemotherapy alone in patients newly diagnosed with multiple myeloma. There were 261 eligible patients younger than 66 years with stage II/III multiple myeloma who were randomized after remission induction therapy with vincristine, adriamycin, dexamethasone (

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