Loss of Heterozygosity, but Not Microsatellite Instability, Is Present in Sporadic Dedifferentiated Liposarcoma: A Study of 46 Genetically Confirmed Cases
Jessica L Davis, Andrew E Horvai. UCSF, San Francisco, CA
Background: Defective DNA repair mechanisms often lead to complex karyotypes, promote tumorigenesis and are detectible by microsatellite instability (MSI). That such defects play roles in sarcoma is suggested by the incidence of sarcomas, especially liposarcomas, in patients with germline mutations in mismatch repair genes (Lynch syndrome). Past studies have shown that MSI is rare in sporadic, well-differentiated liposarcomas, but also that the nonlipogenic components of dedifferentiated liposarcomas are genetically more complex than the matched lipogenic components. Thus, DNA repair defects may play a role unique to the dedifferentiated subtype of liposarcoma. This study evaluates the presence of MSI in a large group of well-characterized dedifferentiated liposarcomas.
Design: We studied 46 cases of dedifferentiated liposarcoma, confirmed by histology and 12q13-15 amplification. All cases were sporadic with no documented history of Lynch syndrome. Seven tumors showed low-grade histology. Twenty-five tumors were retroperitoneal with the remainder in the extremities and trunk. The non-lipogenic component and normal tissue from each case were microdissected and the presence of mismatch repair defects was detected using fluorescence based PCR for five mononucleotide microsatellite markers (BAT25, BAT26, NR21, NR24, MONO27) as well as two pentanucleotide repeat markers (PentaC and PentaD). If present, loss of heterozygosity (LoH) at the same markers was also recorded.
Results: Forty-five of 46 (98%) cases of dedifferentiated liposarcoma were microsatellite stable. One case (2%) of high grade dedifferentiated liposarcoma primary to the trunk, showed MSI at a single locus (NR24), and also had LoH at PentaD. Overall, LoH was observed in 10/49 (20%) cases. LoH was only identified at either PentaC (3/49, 6%), PentaD (4/49, 8%) or both (3/49, 6%). The dedifferentiated liposarcomas with LoH showed predominantly (9/10, 90%) high grade pleomorphic histology but the presence of LoH did not correlate statistically with either grade or tumor location (p=0.8 and p=0.4, respectively).
Conclusions: Given the absence of MSI, mismatch repair defects likely do not contribute to sporadic dedifferentiated liposarcoma tumorigenesis. The previously observed association between Lynch syndrome and liposarcoma may represent unique mechanisms in Lynch patients. However, the results do support that LoH at multiple loci are present in a subset of dedifferentiated liposarcomas and may contribute to tumorigenesis or progression.
Category: Bone & Soft Tissue
Monday, March 19, 2012 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 9, Monday Morning