Cytogenetics of bone tumors

Osteochondroma

Osteochondroma is the most common benign bone tumor, often found in patients under the age of 20 years. The majority of osteochondroma cases (85%) have presented as sporadic, solitary, nonhereditary lesions. The rest have occurred as multiple lesions in the context of hereditary multiple osteochondromas (HMOs), which were inherited in an autosomal dominant manner and as part of the contiguous gene syndrome, such as Langer–Giedion and Potocki–Shaffer syndromes (also known as proximal 11p deletion syndrome) [ , ]. Linkage analysis has pinpointed three different chromosomal locations: 8q24.1 ( EXT1 ), 11p11-p12 ( EXT2 ), and 19p ( EXT3 ) ( Fig. 37.1 [ ]). The first two gene loci, EXT1 on 8q24.1 and EXT2 on 11p11-p12, have subsequently been cloned. The third gene, EXT3 on 19p, has not been cloned yet. Almost 90% of patients with HMOs have had EXT1 or EXT2 mutations [ , ]. Approximately 0.5%–2% of patients with osteochondromas had malignant transformation in adulthood, but these rarely metastasized [ , ].

Cytogenetic investigation of limited samples obtained from sporadic osteochondroma cases showed that the consistent findings were the loss or rearrangement of 8q, especially at the breakpoint 8q24.1. One sporadic tumor also had a deletion of the 11p11-p12 region. One hereditary tumor was also found to have a cytogenetic change at the 8q24.1 region [ , , ]. Feely and colleagues [ ] reported that 10 out of 37 (27%) osteochondroma samples (including both sporadic and hereditary lesions) had a loss or structural change of 8q24.1. The same samples were further investigated by FISH analysis using the DNA probe specific for the 8q24.1 region and showed 27 out of 34 (79%) had a loss of one hybridization signal in the 8q24.1 region. Sawyer and colleagues [ ] reported cytogenetic data on eight osteochondroma tumors and demonstrated not only that chromosome 8q24.1 was involved, but that five out of seven abnormal tumor samples also had rearrangements of chromosome 1, which clustered in the 1p13-p22 region, including inversions, insertions, or translocations. Recently, Hameetman and coworkers [ ] studied eight nonhereditary osteochondromas using array-CGH assay and found all eight oestochondromas had a large deletion of 8q; seven of them had an additional small deletion of the other allele of 8q that contained the EXT1 gene. This finding proved that the EXT1 is a classical tumor suppressor gene in the nonhereditary osteochondromas.

Chondroma

Based on the location of the lesions, chondromas are classified as (1) enchondroma (within the medullary cavity), (2) periosteal chondroma (on the surface of the bone), and (3) soft tissue chondroma (in the soft tissue). Cytogenetic analysis of the tumors has been attempted and so far, no consistent, specific structural or numerical chromosomal changes have been identified. However, Dahlén and coworkers [ ] reported their cytogenetic findings in 14 chondroma samples (8 soft tissue chondromas and 6 skeletal chondromas). Seven of the 14 cases showed chromosomal rearrangements of the 12q13-q15 region. The HMGA2 gene was mapped to the 12q15 region and HMGA2 gene expression was detected in chondromas with or without cytogenetically visible 12q rearrangements. In addition to 12q, a gain of chromosome 5 and loss of chromosomes 6, 13, 19, and 22 were also detected [ , ]. Most recent cytogenetic analyses of 14 chondromas showed heterogeneous changes involving chromosomes other than 12q [ ].

Chondroblastoma

Even though no consistent structural or numerical changes in the chondroblastomas were found in limited sporadic case studies [ ], structural abnormalities of chromosome 5 seemed to occur frequently [ ]. Recently, a specific driver mutation (p.Lys36Met) in the H3F3B gene has been reported in 95% of chondroma cases studied [ ].

Chondromyxoid fibroma

Chondromyxoid fibroma is a rare benign bone tumor most commonly arising in the metaphysis of long bones in young adults [ ]. Cytogenetic analysis from approximately 37 cases showed involvement of 6p25, 6q13, 6q23, and 6q25 regions on chromosome 6 [ ]. Of note, a recurrent pericentric inversion, inv(6)(p25q13), has been described in multiple studies [ , ]. Using whole-genome mate-pair sequencing and RNA sequencing, Nord et al. demonstrated the GRM1 gene at 6q24.3 region was upregulated through promoter swapping and gene fusion in 18 of 20 chondromyxoid fibroma cases [ ].