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Multi-platform profiling of over 2000 sarcomas: identification of biomarkers and novel therapeutic targets.

Movva S, Wen W, Chen W, Millis SZ, Gatalica Z, Reddy S, von Mehren M, Van Tine BA - Oncotarget (2015)

Bottom Line: 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).

View Article: PubMed Central - PubMed

Affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.

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.

No MeSH data available.


Related in: MedlinePlus

DNA sequencing in sarcomaA. Most frequent mutation (%) B. Mutation type C. Mutations in STS D. Mutations in bone sarcoma. ASPS = alveolar soft part sarcoma, DSRCT = desmoplastic small round cell tumor, ESS = endometrial stromal sarcoma, SFT = solitary fibrous tumor, LMS = leiomyosarcoma, UPS = undifferentiated pleomorphic sarcoma, MPNST = malignant peripheral nerve sheath tumor, PEComa = perivascular epithelioid cell tumor.
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Figure 2: DNA sequencing in sarcomaA. Most frequent mutation (%) B. Mutation type C. Mutations in STS D. Mutations in bone sarcoma. ASPS = alveolar soft part sarcoma, DSRCT = desmoplastic small round cell tumor, ESS = endometrial stromal sarcoma, SFT = solitary fibrous tumor, LMS = leiomyosarcoma, UPS = undifferentiated pleomorphic sarcoma, MPNST = malignant peripheral nerve sheath tumor, PEComa = perivascular epithelioid cell tumor.

Mentions: 591 samples were profiled by NGS and 1250 by Sanger sequencing. 47% of the samples had an identifiable mutation in 35 of the 47 genes analyzed. The most commonly mutated genes overall were TP53 (26.3%) and BRCA2 (17.6%). Histologies carrying mutations at a frequency of ≥ 5% included: angiosarcoma (APC, BRAF, GNA11, HRAS KDR, KRAS, NRAS), chondrosarcoma [IDH1 (conventional and unknown/other), PTEN (myxoid), cMET (conventional and mesenchymal)], desmoid (APC, CTNNB1, STK11), ESS (AKT1, cMET, FGFR2, GNAS, KRAS, RET, SMO), Ewing's sarcoma (APC, ATM, HNF1A, PTEN), fibrosarcoma (KRAS), giant cell tumor (KRAS), myxoid liposarcoma (AKT1, ATM, cMET, JAK3, PIK3CA, PTEN), dedifferentiated liposarcoma (HNF1), well-differentiated liposarcoma (cMET), LMS (BRCA2, RB1), MPNST (BRAF V600E), osteosarcoma (cKIT, FLT3), rhabdomyosarcoma [FLT3 (pleomorphic), PIK3CA (uknown/other), PTEN (unknown/other), PTPN11 (alveolar), SMARCB1 (unknown/other)], solitary fibrous tumor (cKIT, PDGFRA, PIK3CA, STK11), synovial sarcoma (ABL1, ATM, BRAF, cKIT, KDR, MLH1) and UPS (KDR, PIK3CA). BRCA2 mutations were seen in 17% of LMS, both uterine and non-uterine. PTEN and RB1 mutations were noted exclusively in non-uterine LMS and not in those of uterine origin. NRAS mutations were detected in 20% of non-breast angiosarcomas, and were not found in those of breast origin. The PIK3CA mutations noted in liposarcoma (5 cases) were found in 4 myxoid liposarcomas and in 1 high grade pleomporphic liposarcoma. No EGFR mutations were detected in our series (Figure 2a–d and Supplementary Table 3). One case of MPNST carried a G12V KRAS mutation. We detected BRAF, PTEN, p53 and NRAS mutations in angiosarcoma specimens, not previously described in the literature [4].


Multi-platform profiling of over 2000 sarcomas: identification of biomarkers and novel therapeutic targets.

Movva S, Wen W, Chen W, Millis SZ, Gatalica Z, Reddy S, von Mehren M, Van Tine BA - Oncotarget (2015)

DNA sequencing in sarcomaA. Most frequent mutation (%) B. Mutation type C. Mutations in STS D. Mutations in bone sarcoma. ASPS = alveolar soft part sarcoma, DSRCT = desmoplastic small round cell tumor, ESS = endometrial stromal sarcoma, SFT = solitary fibrous tumor, LMS = leiomyosarcoma, UPS = undifferentiated pleomorphic sarcoma, MPNST = malignant peripheral nerve sheath tumor, PEComa = perivascular epithelioid cell tumor.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494935&req=5

Figure 2: DNA sequencing in sarcomaA. Most frequent mutation (%) B. Mutation type C. Mutations in STS D. Mutations in bone sarcoma. ASPS = alveolar soft part sarcoma, DSRCT = desmoplastic small round cell tumor, ESS = endometrial stromal sarcoma, SFT = solitary fibrous tumor, LMS = leiomyosarcoma, UPS = undifferentiated pleomorphic sarcoma, MPNST = malignant peripheral nerve sheath tumor, PEComa = perivascular epithelioid cell tumor.
Mentions: 591 samples were profiled by NGS and 1250 by Sanger sequencing. 47% of the samples had an identifiable mutation in 35 of the 47 genes analyzed. The most commonly mutated genes overall were TP53 (26.3%) and BRCA2 (17.6%). Histologies carrying mutations at a frequency of ≥ 5% included: angiosarcoma (APC, BRAF, GNA11, HRAS KDR, KRAS, NRAS), chondrosarcoma [IDH1 (conventional and unknown/other), PTEN (myxoid), cMET (conventional and mesenchymal)], desmoid (APC, CTNNB1, STK11), ESS (AKT1, cMET, FGFR2, GNAS, KRAS, RET, SMO), Ewing's sarcoma (APC, ATM, HNF1A, PTEN), fibrosarcoma (KRAS), giant cell tumor (KRAS), myxoid liposarcoma (AKT1, ATM, cMET, JAK3, PIK3CA, PTEN), dedifferentiated liposarcoma (HNF1), well-differentiated liposarcoma (cMET), LMS (BRCA2, RB1), MPNST (BRAF V600E), osteosarcoma (cKIT, FLT3), rhabdomyosarcoma [FLT3 (pleomorphic), PIK3CA (uknown/other), PTEN (unknown/other), PTPN11 (alveolar), SMARCB1 (unknown/other)], solitary fibrous tumor (cKIT, PDGFRA, PIK3CA, STK11), synovial sarcoma (ABL1, ATM, BRAF, cKIT, KDR, MLH1) and UPS (KDR, PIK3CA). BRCA2 mutations were seen in 17% of LMS, both uterine and non-uterine. PTEN and RB1 mutations were noted exclusively in non-uterine LMS and not in those of uterine origin. NRAS mutations were detected in 20% of non-breast angiosarcomas, and were not found in those of breast origin. The PIK3CA mutations noted in liposarcoma (5 cases) were found in 4 myxoid liposarcomas and in 1 high grade pleomporphic liposarcoma. No EGFR mutations were detected in our series (Figure 2a–d and Supplementary Table 3). One case of MPNST carried a G12V KRAS mutation. We detected BRAF, PTEN, p53 and NRAS mutations in angiosarcoma specimens, not previously described in the literature [4].

Bottom Line: 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).

View Article: PubMed Central - PubMed

Affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.

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.

No MeSH data available.


Related in: MedlinePlus