Evidence of an epigenetic origin for high-risk 1q21 copy number aberrations in multiple myeloma.

Multiple myeloma is a B-cell malignancy stratified in part by cytogenetic abnormalities, including the high-risk copy number aberrations (CNAs) of +1q21 and 17p(-). To investigate the relationship between 1q21 CNAs and DNA hypomethylation of the 1q12 pericentromeric heterochromatin, we treated in vitro peripheral blood cultures of 5 patients with balanced constitutional rearrangements of 1q12 and 5 controls with the hypomethylating agent 5-azacytidine. Using G-banding, fluorescence in situ hybridization, and spectral karyotyping, we identified structural aberrations and copy number gains of 1q21 in the treated cells similar to those found in patients with cytogenetically defined high-risk disease. Aberrations included 1q12 triradials, amplifications of regions juxtaposed to 1q12, and jumping translocations 1q12. Strikingly, all 5 patients with constitutional 1q12 rearrangements showed amplifications on the derivative chromosomes distal to the inverted or translocated 1q12 region, including MYCN in 1 case. At the same time, no amplification of the 1q21 region was found when the 1q12 region was inverted or absent. These findings provide evidence that the hypomethylation of the 1q12 region can potentially amplify any genomic region juxtaposed to it and mimic CNAs found in the bone marrow of patients with high-risk disease.

Jumping translocations of 1q12 in multiple myeloma: a novel mechanism for deletion of 17p in cytogenetically defined high-risk disease.

Multiple myeloma (MM) is a B-cell malignancy driven in part by increasing copy number alterations (CNAs) during disease progression. Prognostically significant CNAs accumulate during clonal evolution and include gains of 1q21 and deletions of 17p, among others. Unfortunately, the mechanisms underlying the accumulation of CNAs and resulting subclonal heterogeneity in high-risk MM are poorly understood. To investigate the impact of jumping translocations of 1q12 (JT1q12) on receptor chromosomes (RCs) and subsequent clonal evolution, we analyzed specimens from 86 patients selected for unbalanced 1q12 aberrations by G-banding. Utilizing spectral karyotyping and locus-specific fluorescence in situ hybridization, we identified 10 patients with unexpected focal amplifications of an RC that subsequently translocated as part of a sequential JT1q12 to one or more additional RCs. Four patients exhibited amplification and translocation of 8q24 (MYC), 3 showed amplification of 16q11, and 1 each displayed amplification of 18q21.3 (BCL2), 18q23, or 4p16 (FGFR3). Unexpectedly, in 6 of 14 patients with the combination of the t(4;14) and deletion of 17p, we identified the loss of 17p as resulting from a JT1q12. Here, we provide evidence that the JT1q12 is a mechanism for the simultaneous gain of 1q21 and deletion of 17p in cytogenetically defined high-risk disease.

De novo proximal duplication of 1(q12q22) in a female infant with multiple congenital anomalies.

Reports of small proximal 1q duplications are rare. We report a 1 month-old female who was referred to clinic because she was believed to have features suggestive of Turner syndrome. The patient's dysmorphic features included a prominent nose, low-set and crumpled ears, slightly high palate, short neck, high-pitched cry, mild micrognathia, hypoplastic labia majora, and somewhat deep palmar creases. Traditional G-band chromosome studies of the patient were interpreted as 46,XX,dup(1)(q12q21). To further evaluate the extent of the chromosome 1 duplication, Spectral Karyotyping and a series of six fluorescence in situ hybridization (FISH) probes were utilized. The FISH probes refined the extent of the duplication to involve the region 1(q12q22) indicating the duplicated segment was larger than interpreted by the G-banding studies. This first case of non-mosaic proximal duplication of 1q to be characterized by multiple locus specific FISH probes should allow a more refined delineation of the phenotypic findings and clinical significance associated with this rare chromosomal duplication.

Evidence for telomeric fusions as a mechanism for recurring structural aberrations of chromosome 11 in giant cell tumor of bone.

Giant cell tumor of bone (GCTB) is a benign but often aggressive tumor with a tendency toward local recurrence. Telomeric associations (tas) or telomeric fusions are common cytogenetic findings that have been implicated in the initiation of chromosome instability and tumorigenesis. We performed cytogenetic studies on 5 cases of GCTB to further characterize chromosome aberrations in these tumors. Four of the 5 cases showed abnormal karyotypes with clonal telomeric fusions involving chromosome 11. In 3 cases, the telomeric fusions of 11pter were apparently the precursor lesions to the progression of sub-clones with structural chromosome aberrations of 11p. Two tumors demonstrated a similar pattern of progression resulting in whole arm losses of 11p, including sub-clones with both whole-arm unbalanced translocations and whole-arm deletions. A third tumor with clonal tas of 11pter showed 2 additional subclones, one with ring chromosome 11 and the other with an extra copy of 1q. To our knowledge, the 2 cases with del(11)(p11) represent the first report of a recurring structural chromosome aberration in GCTB. These findings support the concept that telomeric instability is responsible for a large degree of intratumor heterogeneity and serves as a precursor lesion to subsequent clonal structural aberrations of chromosome 11 in GCTB.

Recurring breakpoints of 1p13 approximately p22 in osteochondroma.

Cytogenetic studies of osteochondromas are scarce but have previously shown recurring clonal aberrations involving chromosome 8. We have studied a series of eight tumors and have found recurring aberrations not only involving chromosome 8, but also chromosome 1 in five of the seven abnormal tumors. Surprisingly, three of the chromosome 1 aberrations involved pericentric inversions. Four tumors showed aberrations involving the region 1p13 approximately p22 by mechanisms including inversion, insertion, and translocation. These findings indicate that aberrations of chromosome 1p, in a region spanning 1p13 approximately p22, may be nonrandomly involved in the cytogenetic progression of osteochondroma.