PARP1 expression in soft tissue sarcomas is a poor‐prognosis factor and a new potential therapeutic target

Abstract

Soft tissue sarcomas (STSs) are aggressive tumors with few efficient systemic therapies. Poly(ADP‐ribose) polymerase‐1 (PARP1) inhibitors represent an emerging therapeutic option in tumors with genomic instability. The genomics of STSs is complex in more than half of cases, suggesting a high level of inherent DNA damage and genomic instability. Thus, STSs could be efficiently targeted with PARP inhibitors. Promising preclinical results have been reported, but few data are available regarding PARP1 expression in clinical samples. We examined PARP1 mRNA expression in 1464 clinical samples of STS, including 1432 primary tumors and 32 relapses, and searched for correlations with clinicopathological features, including metastasis‐free survival (MFS). Expression was heterogeneous across the samples, not different between primary and secondary tumors, and was correlated to PARP1 DNA copy number. In the 1432 primary tumors, the ‘PARP1‐high’ samples were associated with younger patients, more frequent locations at the extremities, superficial trunk and head and neck, more leiomyosarcomas and other STSs and less liposarcomas and myxofibrosarcomas, more grade 3, more high‐risk CINSARC tumors, and more ‘chromosomically instable’ tumors. They were associated with shorter MFS, independently of other significant prognostic features, including the CINSARC signature. We found a strong involvement of genes overexpressed in the ‘PARP1‐high’ samples in cell cycle, DNA replication, and DNA repair. PARP1 expression refines the prediction of MFS in STSs, and similar expression exists in secondary and primary tumors, supporting the development of PARP1 inhibitors.

Novel Therapeutic Insights in Dedifferentiated Liposarcoma: A Role for FGFR and MDM2 Dual Targeting

“…In order to validate these results in an independent series of patients, we examined FGFR1 and FGFR4 mRNA expression in our pooled data set of 58 WDLPS and 218 DDLPS samples and 11 normal fat samples [ 33 ]. Their clinicopathological characteristics are summarized in Table S3 .…”

“…It included WDLPS/DDLPS cases from 276 patients and 11 normal fat samples. It corresponds to a sample subset included in a pooled series of 1432 primary soft tissue sarcomas that we had previously gathered from 16 public data sets [ 33 ]. All samples had been profiled using DNA microarrays or RNA Sequencing.…”

Transgelin interacts with PARP1 and affects Rho signaling pathway in human colon cancer cells

“…PARP1 has been found over-expressed in some malignant tumors and promoting tumor metastasis in soft tissue sarcoma [41] and non-small cell lung cancer [42]. Moreover, the nuclear localization of PARP1 can affect the chemo-sensitivity of hepatocellular carcinoma to oxaliplatin [43].…”

Transgelin interacts with PARP1 in human colon cancer cells

“…PARP1 has been reported to play an important role in the early development and progression of CRC [42,43]. It has also been found to promote tumor metastasis in soft tissue sarcoma [44] and non-small cell lung cancer [45]. Moreover, Dorsam et al [46] have shown that PARP1 reduced the N-nitroso compounds (NOC)-induced tumorigenesis, regulated intestinal in ammation through innate immune response and promoted colorectal tumor growth.…”