Abstract
Background: Drug development in sarcoma has been hampered by the rarity and heterogeneity of the disease and lack of predictive biomarkers to therapies. We assessed protein expression and gene alterations in a large number of bone and soft tissue sarcomas in order to categorize the molecular alterations, identify predictive biomarkers and discover new therapeutic targets. Methods: Data from sarcoma specimens profiled for protein expression, gene amplification/translocation and DNA sequencing was reviewed. Results: 2539 sarcoma specimens of 22 subtypes were included. TOPO2A was the most overexpressed protein at 52.8%. There was overexpression or loss of other sarcoma relevant proteins such as SPARC, PTEN and MGMT. Approximately 50% of the sarcomas expressed PD-L1 by IHC and presented with PD-1+ TILs, notably the LMS, chondrosarcomas, liposarcomas and UPS. Gene amplification/rearrangement of ALK, cMYC, HER2, PIK3CA, TOPO2A and cMET was relatively uncommon. EGFR gene amplification occurred at a rate of 16.9%. DNA sequencing of 47 genes identified mutations in 47% of the samples. The most commonly mutated genes were TP53 (26.3%) and BRCA2 (17.6%). Overexpression of TOPO2A was associated with TP53 mutation (P = 0.0001). Conclusion: This data provides the landscape of alterations in sarcoma. Future clinical trials are needed to validate these targets.
Keywords: sarcoma, biomarkers, targeted therapies, DNA sequencing, protein expression
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4494935/
Multi-platform profiling of over 2000 sarcomas: Identification of biomarkers and novel therapeutic targets
Re: Multi-platform profiling of over 2000 sarcomas: Identification of biomarkers and novel therapeutic targets
Protein biomarkers
TOPO2A overexpression, an anthracycline associated response biomarker, was noted in 52.8% of the sarcomas and in greater than 60% of MPNST, angiosarcoma, LMS, rhabdomyosarcoma and UPS. High expression of TOPO2A has been previously reported at a rate of 50% in STS, when median percentage was chosen as the cutoff to discriminate between high and low expressing tumors, rather than criteria previously described in breast cancer [10, 11]. Overexpression of serum protein acidic and rich in cysteine (SPARC), a biomarker for albumin bound paclitaxel, was seen in 35.9% of the cases, especially in over 60% of epithelioid hemangioendothelioma (EHE) and chondrosarcoma (notably conventional chondrosarcoma), as well as 48.7% of angiosarcomas. A previous study of SPARC expression by IHC, noted a rate of high SPARC staining in 56% of specimens, but given the small sample size (n = 27), specific histology correlations could not be made [12]. Low MGMT expression, a temozolomide associated biomarker, was noted in a variety of sarcomas including alveolar soft part sarcoma (21 ASPS), desmoid, EHE, perivascular epithelioid cell tumor (PEComa), endometrial stromal sarcoma (ESS), giant cell tumor, liposarcoma, LMS, malignant peripheral nerve sheath tumor (MPNST), osteosarcoma and UPS. There was low expression of MGMT in 65.3% of the sarcomas overall. Previous studies have only considered nuclear staining positive, and have reported a much lower rate of MGMT loss in LMS and other STS subtypes, therefore validation of a particular method is required to determine the predictive value in STS [13]. PTEN loss was seen in 38.6% of the sarcomas, most commonly in epithelioid sarcoma, chordoma, alveolar rhabdomyosarcoma and osteosarcoma. PTEN loss was only noted in 32.2% of non-uterine LMS and 37.6% of uterine LMS. Previous work on complex genomic sarcomas such as LMS, UPS and MPNST have reported rates of PTEN loss in 29%–44% of the sarcomas, [14, 15] but data on the expression of PTEN in rarer sarcomas is lacking. cKIT overexpression was noted in 28.5% of angiosarcoma, 19% of desmoplastic small round cell tumor (DSRCT) and 37.3% of Ewing's sarcoma. There were 2 cases of sclerosing rhabdomyosarcoma, both of which overexpressed cKIT. This is a rare sarcoma whose treatment paradigm is not yet clearly defined. PDGFRA was overexpressed in 22.1% of the sarcomas, including, 38.5% of angiosarcoma, 33.3% of liposarcoma, 33.3% of fibrosarcoma, 31.8% of Ewing's sarcoma, 30.8% of chondrosarcoma, 27.8% of osteosarcoma, 27.8% of UPS and 18.3% of non-uterine LMS. High PDGFRA expression has been described previously in many of these tumors [16–18]. In a series by Rodrigo and colleagues HER2 protein expression by IHC was negative in all sarcoma samples [10]. HER2 overexpression was noted in only one case in this series, an ESS, confirming that this is not an important pathway in sarcoma (Figure (Figure1a1a and and1b1b and
TOPO2A overexpression, an anthracycline associated response biomarker, was noted in 52.8% of the sarcomas and in greater than 60% of MPNST, angiosarcoma, LMS, rhabdomyosarcoma and UPS. High expression of TOPO2A has been previously reported at a rate of 50% in STS, when median percentage was chosen as the cutoff to discriminate between high and low expressing tumors, rather than criteria previously described in breast cancer [10, 11]. Overexpression of serum protein acidic and rich in cysteine (SPARC), a biomarker for albumin bound paclitaxel, was seen in 35.9% of the cases, especially in over 60% of epithelioid hemangioendothelioma (EHE) and chondrosarcoma (notably conventional chondrosarcoma), as well as 48.7% of angiosarcomas. A previous study of SPARC expression by IHC, noted a rate of high SPARC staining in 56% of specimens, but given the small sample size (n = 27), specific histology correlations could not be made [12]. Low MGMT expression, a temozolomide associated biomarker, was noted in a variety of sarcomas including alveolar soft part sarcoma (21 ASPS), desmoid, EHE, perivascular epithelioid cell tumor (PEComa), endometrial stromal sarcoma (ESS), giant cell tumor, liposarcoma, LMS, malignant peripheral nerve sheath tumor (MPNST), osteosarcoma and UPS. There was low expression of MGMT in 65.3% of the sarcomas overall. Previous studies have only considered nuclear staining positive, and have reported a much lower rate of MGMT loss in LMS and other STS subtypes, therefore validation of a particular method is required to determine the predictive value in STS [13]. PTEN loss was seen in 38.6% of the sarcomas, most commonly in epithelioid sarcoma, chordoma, alveolar rhabdomyosarcoma and osteosarcoma. PTEN loss was only noted in 32.2% of non-uterine LMS and 37.6% of uterine LMS. Previous work on complex genomic sarcomas such as LMS, UPS and MPNST have reported rates of PTEN loss in 29%–44% of the sarcomas, [14, 15] but data on the expression of PTEN in rarer sarcomas is lacking. cKIT overexpression was noted in 28.5% of angiosarcoma, 19% of desmoplastic small round cell tumor (DSRCT) and 37.3% of Ewing's sarcoma. There were 2 cases of sclerosing rhabdomyosarcoma, both of which overexpressed cKIT. This is a rare sarcoma whose treatment paradigm is not yet clearly defined. PDGFRA was overexpressed in 22.1% of the sarcomas, including, 38.5% of angiosarcoma, 33.3% of liposarcoma, 33.3% of fibrosarcoma, 31.8% of Ewing's sarcoma, 30.8% of chondrosarcoma, 27.8% of osteosarcoma, 27.8% of UPS and 18.3% of non-uterine LMS. High PDGFRA expression has been described previously in many of these tumors [16–18]. In a series by Rodrigo and colleagues HER2 protein expression by IHC was negative in all sarcoma samples [10]. HER2 overexpression was noted in only one case in this series, an ESS, confirming that this is not an important pathway in sarcoma (Figure (Figure1a1a and and1b1b and
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