Scattered genomic amplification in dedifferentiated liposarcoma

Abstract

Background: Atypical lipomatous tumor (ALT), well differentiated liposarcoma (WDLS) and dedifferentiated liposarcoma (DDLS) are cytogenetically characterized by near-diploid karyotypes with no or few other aberrations than supernumerary ring or giant marker chromosomes, although DDLS tend to have somewhat more complex rearrangements. In contrast, pleomorphic liposarcomas (PLS) have highly aberrant and heterogeneous karyotypes. The ring and giant marker chromosomes contain discontinuous amplicons, in particular including multiple copies of the target genes CDK4, HMGA2 and MDM2 from 12q, but often also sequences from other chromosomes.Results: The present study presents a DDLS with an atypical hypertriploid karyotype without any ring or giant marker chromosomes. SNP array analyses revealed amplification of almost the entire 5p and discontinuous amplicons of 12q including the classical target genes, in particular CDK4. In addition, amplicons from 1q, 3q, 7p, 9p, 11q and 20q, covering from 2 to 14 Mb, were present. FISH analyses showed that sequences from 5p and 12q were scattered, separately or together, over more than 10 chromosomes of varying size. At RNA sequencing, significantly elevated expression, compared to myxoid liposarcomas, was seen for TRIO and AMACR in 5p and of CDK4, HMGA2 and MDM2 in 12q. Conclusions: The observed pattern of scattered amplification does not show the characteristics of chromothripsis, but is novel and differs from the well known cytogenetic manifestations of amplification, i.e., double minutes, homogeneously staining regions and ring chromosomes. Possible explanations for this unusual distribution of amplified sequences might be the mechanism of alternative lengthening of telomeres that is frequently active in DDLS and events associated with telomere crisis.

A Pan-Cancer Study of Somatic TERT Promoter Mutations and Amplification in 30,773 Tumors Profiled by Clinical Genomic Sequencing

“…34e36 In contrast, tumor types where TERT amplification was the prevalent alteration included well-differentiated/dedifferentiated liposarcoma (14.1%) and adrenocortical carcinoma (13.6%) (Figure 2F). 37,38 Of note, high rates of TERT alterations were documented in the primary tumors themselves for aggressive variants of thyroid cancer, such as poorly differentiated (n Z 73; 52%), anaplastic (n Z 55; 69%), and tall cell variant of papillary thyroid cancer (n Z 43; 74%), as is depicted in Figure 3. In contrast, these alterations were predominantly documented in metastatic/recurrent tumors for classic well-differentiated papillary thyroid cancer (n Z 58; 52%) and Hurthle cell carcinoma (n Z 26; 54%).…”

Genotyping of circulating cell‐free DNA enables noninvasive tumor detection in myxoid liposarcomas

“…Ring chromosomes, allowing for gene amplification, constitute the characteristic cytogenetic feature of some STS including well‐differentiated and de‐differentiated liposarcoma (WDLS/DDLS). They contain multiple copies of the target genes CDK4, HMGA2 and MDM2 from 12q . We developed a ddPCR assay to detect MDM2 copy number variations (CNV) at low frequency.…”

“…They contain multiple copies of the target genes CDK4, HMGA2 and MDM2 from 12q. 19 We developed a ddPCR assay to detect MDM2 copy number variations (CNV) at low frequency. One primer pair amplifies a 70 bp region in MDM2, which is detected by a FAM labeled probe.…”

Double minute chromosomes harboring MDM2 amplification in a pediatric atypical lipomatous tumor

“…Only a few exceptions have been reported. For instance, in an adult case of DDLPS showing neither rings and large markers nor dmin, 12q amplification was scattered and inserted into several chromosomes . The presence of dmin, in addition to the classical ring or marker chromosomes, has been reported only in a few cases .…”