S. Singer

Evaluation of a clinically applicable post-surgical classification system for primary retroperitoneal soft-tissue sarcoma.

Background: The present AJCC/TNM staging system is of limited value for prediction of prognosis for patients with retroperitoneal sarcoma. The objective of the present study was to develop a postsurgical classification system that would enable comparison of outcomes for patients with primary retroperitoneal soft-tissue sarcoma.Methods: Four classes were defined: I, low-grade/complete resection/no metastasis; II, high-grade/complete resection/no metastasis; III, any-grade/incomplete resection/no metastasis; and IV, any-grade/any resection/distant metastasis. The prognostic value of this classification system was analyzed in a population-based multicenter group(MCG) of patients with primary retroperitoneal soft-tissue sarcoma (n = 124) and in a cohort of patients treated in a single tertiary referral center (SCG; n = 107).Results: Overall 5-year survival rates were 55% in the SCG and 43% in the MCG (P = 0.02). Class III (incomplete resection) was more frequent in the MCG than in the SCG (33% vs. 16%; P = 0.02). In the SCG, stage-specific 5-year survival rates were 89%, 40%, 26%, and 17% for classes I, II, III, and IV, respectively (P < 0.001), in comparison with 68%, 46%, 24%, and 0% in the MCG (P < 0.001). In a comparison of class-specific survival between the groups, only class I patients in the SCG had significantly better survival than class I patients in the MCG (P = 0.048).Conclusions: Classification based on grade, completeness of resection, and distant metastasis offers a reproducible prognostic tool that can be used to evaluate treatment strategies for primary retroperitoneal soft-tissue sarcoma. The probability of complete resection was significantly higher in the SCG than in the MCG. In patients with low-grade, completely resected sarcoma, there is a significant survival benefit with treatment in a high-volume tertiary center of excellence.

Abstract 4972: High-throughput functional profiling of dedifferentiated liposarcoma cell lines

We previously profiled several adult soft-tissue sarcoma subtypes using sequencing, copy number analysis, and gene expression arrays. This high-throughput genetic profiling revealed dozens of candidate genes deserving of further functional validation. To prioritize genes, we performed a pooled shRNA screen to identify essential genes in liposarcoma. Dedifferentiated liposarcoma (DDLS) served as a model for this approach as multiple robust cell lines are available. Five DDLS cell lines (DDLS8817, LPS141, FU-DDLS-1, RDD8107, and LP6) were infected with a pool of 54,020 lentiviral shRNAs targeting ∼11,000 genes (median 5 shRNAs per gene) and passaged for 16 doublings. DNA was extracted and hairpin sequences were PCR amplified and hybridized to a custom microarray that interrogates all shRNAs in the pool. shRNAs were ranked according to their differential abundance between early and late passages. Genes corresponding to the most significantly depleted shRNAs are presumed to affect cell proliferation and are candidate oncogenes. We compared the pattern of hairpin depletion in the DDLS cell lines to a panel of over 60 cell lines representing other common cancers screened with the same pooled shRNA library. The 5 DDLS cell lines clustered into 3 distinct groups. Only one gene appeared to be essential in all 3 groups: WWTR1 (TAZ1), a master-regulator of adipocyte differentiation. Twenty-eight genes appeared essential in at least two DDLS groups including MDM2 and ZBTB2, both reported to negatively regulate the tumor suppressor gene TP53. Low-throughput in vitro experiments have confirmed that WWTR1 knockdown using two shRNA clones inhibits LPS141 proliferation by 78 and 75% after 4 days as compared to scramble (p=0.004 and 0.06 respectively). Our complementary genome-scaled functional screen has confirmed a known oncogene in DDLS and revealed additional candidate genes that appear to have a role in proliferation. Further integration of existing datasets may nominate additional genes essential for liposarcoma pathogenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4972. doi:10.1158/1538-7445.AM2011-4972