Disease‐associated patterns of disomic chromosomes in hyperhaploid neoplasms

Abstract

The chromosome number of human tumors varies widely, from near-haploidy to more than decaploidy. Overt hyperhaploid (24-34 chromosomes) tumors constitute a small minority (0.2-0.3% of cytogenetically investigated lesions), but occur in many different disease entities. In these karyotypes, most chromosomes are present in one copy; one or a few chromosomes are disomic. Published reports on 141 strictly hyperhaploid tumors, supplemented with nine previously unpublished cases, were used for evaluating the pattern of disomic chromosomes. Only one tumor type, acute lymphoblastic leukemia (ALL), was sufficiently common (n = 75) to allow proper evaluation; other neoplasms were lumped together in as reasonably logical groups as possible, including 10 myeloid leukemias (ML), nine plasma cell neoplasms (PCN), 13 chondrosarcomas (CS), 11 soft tissue tumors (STT), nine adeno- or squamous cell carcinomas (ASC), and eight tumors of the nervous system (TNS); the remaining 15 tumors could not be grouped. It was evident that the pattern of disomies is nonrandom. Moreover, unique signatures for each tumor group were detected. Among ALL, most disomies were independent of age and gender, except for disomy 10, which was overrepresented in females. Chromosome 21 was invariably disomic, whereas chromosome 17 was always monosomic. The most frequent disomies were two gonosomes in ML, chromosomes 7, 9, 11, 3, 18, and 19 in PCN, 7, 5, 20, 19, and 21 in CS, 20 in STT, 7 in ASC, and 1, 7, and 9 in TNS. Chromosome 1 was often partially disomic, due to unbalanced structural rearrangements, with segment 1q21-31 in common. Doubling of the hyperhaploid clone was found in at least one-third of the cases, apart from in ML where only one of 10 cases showed chromosome doubling. The present findings indicate that retention of disomy for some chromosomes is pathogenetically important and that the chromosome(s) maintained in two copies is related to cell type or histological context.

Hyperhaploidy is a novel high-risk cytogenetic subgroup in multiple myeloma

“…Our findings here, and those of others suggest that an unknown number of patients with hypotriploid or near triploid clones likely passed through a hyperhaploid stage without detection, and that the double chromosome number in a near triploid clone can become the dominating clone and mask the presence of a hyperhaploid origin. 5,11,36 In this study both routine cytogenetics and iFISH strategies were uninformative in identifying certain clones. Metaphase cytogenetics is known to be uninformative because of the low proliferation of the plasma cells, while iFISH can be uninformative because of improper probe selection or inappropriate cut-off values.…”

“…Accordingly, these clones appear to arise independently of hyperdiploid clones by a catastrophic loss of chromosomes from a diploid cell, as has been found in other hyperhaploid malignancies. 5,11 …”

“…5 We and others have previously reported a small number of hyperhaploid karyotypes in MM; 5-10 however, hyperhaploidy is most consistently identified and recognized as a category for numerical aberrations in childhood acute lymphoblastic leukemia (ALL). 11 In childhood ALL the hyperhaploid clones occur in two subgroups, a near-haploid group (25-29 chromosomes) and low hypodiploidy subgroup (30-39 chromosomes).…”

Comprehensive genetic analysis of a paediatric pleomorphic myxoid liposarcoma reveals near‐haploidization and loss of the RB1 gene

“…Cell culturing, harvesting and G‐banding were performed according to established methods . FISH analyses of interphase nuclei with regard to rearrangement of the FUS , EWSR1 and DDIT3 genes were carried out with commercial break‐apart probes (Vysis, Downers Grove, IL, USA).…”

Near-haploid and low-hypodiploid acute lymphoblastic leukemia: two distinct subtypes with consistently poor prognosis

“…It is possible that the hypodiploidy is a passenger event, but the fact that severe hypodiploidy is seen across a wide spectrum of neoplasms and involves different chromosomes in different diagnoses indicates that it does affect tumorigenesis. 26 A common assumption has been that the widespread LOH resulting from hypodiploidy leads to the unmasking of recessive alleles. 5,23,27,28 A candidate could be TP53, since the loss of chromosome 17, and thereby 1 TP53 allele, together with a mutation in the remaining copy in low-hypodiploid ALL, could result in complete absence of a functioning protein.…”