Jay S Wunder

Washington University in St. Louis, San Luis, Missouri, United States

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Publications (256)1265.05 Total impact

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    ABSTRACT: The etiologic contribution of germline genetic variation to sporadic osteosarcoma is not well understood. Osteosarcoma is a sentinel cancer of Li-Fraumeni syndrome (LFS), in which approximately 70% of families meeting the classic criteria have germline TP53 mutations. We sequenced TP53 exons in 765 osteosarcoma cases. Data were analyzed with χ(2) tests, logistic regression, and Cox proportional hazards regression models. We observed a high frequency of young osteosarcoma cases (age <30 years) carrying a known LFS- or likely LFS-associated mutation (3.8%) or rare exonic variant (5.7%) with an overall frequency of 9.5%, compared with none in case patients age 30 years and older (P < .001). This high TP53 mutation prevalence in young osteosarcoma cases is statistically significantly greater than the previously reported prevalence of 3% (P = .0024). We identified a novel association between a TP53 rare variant and metastasis at diagnosis of osteosarcoma (rs1800372, odds ratio = 4.27, 95% confidence interval = 1.2 to 15.5, P = .026). Genetic susceptibility to young onset osteosarcoma is distinct from older adult onset osteosarcoma, with a high frequency of LFS-associated and rare exonic TP53 variants. Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.
    CancerSpectrum Knowledge Environment 07/2015; 107(7). DOI:10.1093/jnci/djv101 · 15.16 Impact Factor
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    ABSTRACT: Surgical resection with curative intent for giant cell tumor of bone (GCTB) may be associated with severe morbidity. This interim analysis evaluated reduction in surgical invasiveness after denosumab treatment in patients with resectable GCTB. Patients with primary or recurrent GCTB, for whom the initially planned surgery was associated with functional compromise or morbidity, received denosumab 120 mg subcutaneously every 4 weeks (additional doses on days 8 and 15 of the first cycle). Planned and actual GCTB-related surgical procedures before and after denosumab treatment were reported. Patients were followed for surgical outcome, adverse events, and recurrence following resection. Overall, 222 patients were evaluable for surgical downstaging (54 % were women; median age 34 years). Lesions (67 % primary and 33 % recurrent) were located in the axial (15 %) and appendicular skeleton (85 %). At the data cutoff date, most patients had not yet undergone surgery (n = 106; 48 %) or had a less morbid procedure (n = 84; 38 %) than originally planned. Median (interquartile range) time on denosumab was 19.5 (12.4-28.6) months for the 106 patients who had not undergone surgery and were continuing on monthly denosumab. Native joint preservation was 96 % (n = 24/25) for patients with planned joint/prosthesis replacement and 86 % (n = 30/35) for patients with planned joint resection/fusion. Of the 116 patients who had surgery (median postsurgical follow-up 13.0 [8.5-17.9] months), local recurrence occurred in 17 (15 %) patients. For patients with resectable GCTB, neoadjuvant denosumab therapy resulted in beneficial surgical downstaging, including either no surgery or a less morbid surgical procedure.
    Annals of Surgical Oncology 06/2015; DOI:10.1245/s10434-015-4634-9 · 3.94 Impact Factor
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    ABSTRACT: The aim of this study was to determine the relationship of the time interval between completion of preoperative radiation therapy (RT) and surgical resection on wound complications (WCs) in extremity soft tissue sarcoma (STS). Overall, 798 extremity STS patients were managed with preoperative RT and surgery from 1989 to 2013. WCs were defined as requiring secondary operations/invasive procedures for wound care, use of vacuum-assisted closure, prolonged dressing changes, or infection within 120 days of surgery. Mean tumor size was 8.8 cm. A total of 743 (93 %) tumors were primary presentations, 565 (71 %) patients had lower extremity tumors, and 238 patients (30 %) had a prior unplanned excision. Of 242 patients (30 %) who developed a WC, 206 (37 %) had lower extremity tumors and 36 (15 %) had upper extremity tumors. Mean time from RT completion to surgery was 41.3 (range 4-470) days; 42.0 (range 4-470) days for upper extremity cases, and 41.1 (range 4-109) days for lower extremity cases. Similarly, mean time interval for patients who developed a WC was 40.9 (range 4-100) days, and 41.5 (range 4-470) days for those who did not develop a WC (p = 0.69). Thirty-nine cases (5 %) had surgery within 3 weeks of RT; 15 (38 %) patients developed WCs versus 227 (30 %) patients who had their tumors excised after 3 weeks (p = 0.28). One hundred and twenty-nine (16 %) patients had surgery within 4 weeks, and 39 (30 %) patients developed WCs versus 203 (30 %) patients who had their tumors excised after 4 weeks (p = 1.0). A trend towards a higher rate of WCs was seen for those patients who had surgery after 6 weeks (28 % prior vs. 34 % after; p = 0.08). There was no difference in WCs with intensity-modulated RT (IMRT) versus non-IMRT cases (p = 0.6). The time interval between preoperative RT and surgical excision in extremity STS had minimal influence on the development of WCs. Four- or 5-week intervals showed equivalent complication rates between the two groups, suggesting an optimal interval to reduce potential WCs.
    Annals of Surgical Oncology 05/2015; DOI:10.1245/s10434-015-4631-z · 3.94 Impact Factor
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    ABSTRACT: A common and aggressive subtype of soft-tissue sarcoma, undifferentiated pleomorphic sarcoma (UPS) was examined to determine the role of micro-RNAs (miRNAs) in modulating distant metastasis. Following histopathologic review, 110 fresh frozen clinically annotated UPS samples were divided into two independent cohorts for Training (42 patients), and Validation (68 patients) analyses. Global miRNA profiling on the Training Set and functional analysis in vitro suggested that miRNA-138 and its downstream RHO-ROCK cell adhesion pathway was a convergent target of miRNAs associated with the development of metastasis. A six-miRNA signature set prognostic of distant metastasis-free survival (DMFS) was developed from Training Set miRNA expression values. Using the six-miRNA signature, patients were successfully categorized into high- and low-risk groups for DMFS in an independent Validation Set, with a hazard ratio (HR) of 2.25 (p = 0.048). After adjusting for other known prognostic variables such as age, gender, tumor grade, size, depth, and treatment with radiotherapy, the six-miRNA signature retained prognostic value with a HR of 3.46 (p < 0.001). A prognostic miRNA biomarker for clinical validation was thus identified along with a functional pathway that modulates UPS metastatic phenotype.
    Oncotarget 04/2015; · 6.63 Impact Factor
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    ABSTRACT: Pigmented villonodular synovitis (PVNS) is a rare proliferative process of the synovium which most commonly affects the knee and occurs in either a localised (LPVNS) or a diffuse form (DPVNS). The effect of different methods of surgical synovectomy and adjuvant radiotherapy on the rate of recurrence is unclear. We conducted a systematic review and identified 35 observational studies in English which reported the use of surgical synovectomy to treat PVNS of the knee. A meta-analysis included 630 patients, 137 (21.8%) of whom had a recurrence after synovectomy. For patients with DPVNS, low-quality evidence found that the rate of recurrence was reduced by both open synovectomy (odds ration (OR) = 0.47; 95% CI 0.25 to 0.90; p = 0.024) and combined open and arthroscopic synovectomy (OR = 0.19, 95% CI = 0.06 to 0.58; p = 0.003) compared with arthroscopic surgery. Very low-quality evidence found that the rate of recurrence of DPVNS was reduced by peri-operative radiotherapy (OR = 0.31, 95% CI 0.14 to 0.70; p = 0.01). Very low-quality evidence suggested that the rate of recurrence of LPVNS was not related to the surgical approach. This meta-analysis suggests that open synovectomy or synovectomy combined with peri-operative radiotherapy for DPVNS is associated with a reduced rate of recurrence. Large long-term prospective multicentre observational studies, with a focus on both rate of recurrence and function, are required to confirm these findings. Cite this article: Bone Joint J 2015;97-B:550-7. ©2015 The British Editorial Society of Bone & Joint Surgery.
    The Bone & Joint Journal 04/2015; 97-B(4):550-7. DOI:10.1302/0301-620X.97B4.34907 · 2.80 Impact Factor
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    ABSTRACT: Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 03/2015; 96(3):487-97. DOI:10.1016/j.ajhg.2015.01.011 · 10.99 Impact Factor
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    ABSTRACT: Enchondromas are benign cartilage tumors and precursors to malignant chondrosarcomas. Somatic mutations in the isocitrate dehydrogenase genes (IDH1 and IDH2) are present in the majority of these tumor types. How these mutations cause enchondromas is unclear. Here, we identified the spectrum of IDH mutations in human enchondromas and chondrosarcomas and studied their effects in mice. A broad range of mutations was identified, including the previously unreported IDH1-R132Q mutation. These mutations harbored enzymatic activity to catalyze α-ketoglutarate to d-2-hydroxyglutarate (d-2HG). Mice expressing Idh1-R132Q in one allele in cells expressing type 2 collagen showed a disordered growth plate, with persistence of type X-expressing chondrocytes. Chondrocyte cell cultures from these animals or controls showed that there was an increase in proliferation and expression of genes characteristic of hypertrophic chondrocytes with expression of Idh1-R132Q or 2HG treatment. Col2a1-Cre;Idh1-R132Q mutant knock-in mice (mutant allele expressed in chondrocytes) did not survive after the neonatal stage. Col2a1-Cre/ERT2;Idh1-R132 mutant conditional knock-in mice, in which Cre was induced by tamoxifen after weaning, developed multiple enchondroma-like lesions. Taken together, these data show that mutant IDH or d-2HG causes persistence of chondrocytes, giving rise to rests of growth-plate cells that persist in the bone as enchondromas.
    Proceedings of the National Academy of Sciences 02/2015; 112(9):201424400. DOI:10.1073/pnas.1424400112 · 9.81 Impact Factor
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    ABSTRACT: This Sawbones and cadaver study was performed to assess the accuracy and reproducibility of pelvic bone cuts made with use of a novel navigation system with a navigated osteotome and oscillating saw. Using a novel navigation system and a three-dimensional planning tool, we navigated pelvic bone cuts that were representative of typical cuts made in pelvic tumor resections. The system includes a prototype mobile C-arm for intraoperative cone-beam computed tomography, real-time optical tracking (Polaris), and three-dimensional visualization software. Three-dimensional virtual radiographs were utilized in addition to triplanar (axial, sagittal, and coronal) navigation. In part one of the study, we navigated twenty-four sacral bone cuts in Sawbones models and validated our results in sixteen similar cuts in cadavers. In part two, we developed three Sawbones models of pelvic tumors based on actual patient scenarios and compared three navigated resections with three non-navigated resections for each tumor model. Part three assessed the accuracy of the system with multiple users. There were ninety navigated cuts in Sawbones that were compared with fifty-four non-navigated cuts. In the navigated Sawbones cuts, the mean entry and exit cuts were 1.4 ± 1 mm and 1.9 ± 1.2 mm from the planned cuts, respectively. In comparison, the entry and exit cuts in Sawbones that were not navigated were 2.8 ± 4.9 mm and 3.5 ± 4.6 mm away from the planned osteotomy site. The navigated cuts were significantly more accurate (p ≤ 0.01). In the cadaver study, navigated entry and exit cuts were 1.5 ± 0.9 mm and 2.1 ± 1.5 mm from the planned cuts. The variation among three different users was 1 mm on both the entry and exit cuts. Navigation to guide pelvic bone cuts is accurate and feasible. Three-dimensional radiographs should be used for improved accuracy. Navigated cuts were significantly more accurate than non-navigated cuts were. A margin of 5 mm between the target tumor volume and the planned cut plane would result in a negative margin resection in more than 95% of the cuts. The accuracy of pelvic bone tumor resections and pelvic osteotomies can be improved with navigation to within 5 mm of the planned cut. Copyright © 2015 by The Journal of Bone and Joint Surgery, Incorporated.
    The Journal of Bone and Joint Surgery 01/2015; 97(1):40-46. DOI:10.2106/JBJS.N.00276 · 4.31 Impact Factor
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    ABSTRACT: Pigmented villonodular synovitis (PVNS) is a rare proliferative process of the synovium which most commonly affects the knee and occurs in either a localised (LPVNS) or a diffuse form (DPVNS). The effect of different methods of surgical synovectomy and adjuvant radiotherapy on the rate of recurrence is unclear. We conducted a systematic review and identified 35 observational studies in English which reported the use of surgical synovectomy to treat PVNS of the knee. A meta-analysis included 630 patients, 137 (21.8%) of whom had a recurrence after synovectomy. For patients with DPVNS, low-quality evidence found that the rate of recurrence was reduced by both open synovectomy (odds ration (OR) = 0.47; 95% CI 0.25 to 0.90; p = 0.024) and combined open and arthroscopic synovectomy (OR = 0.19, 95% CI = 0.06 to 0.58; p = 0.003) compared with arthroscopic surgery. Very low-quality evidence found that the rate of recurrence of DPVNS was reduced by peri-operative radiotherapy (OR = 0.31, 95% CI 0.14 to 0.70; p = 0.01). Very low-quality evidence suggested that the rate of recurrence of LPVNS was not related to the surgical approach. This meta-analysis suggests that open synovectomy or synovectomy combined with peri-operative radiotherapy for DPVNS is associated with a reduced rate of recurrence. Large long-term prospective multicentre observational studies, with a focus on both rate of recurrence and function, are required to confirm these findings. Cite this article: Bone Joint J 2015;97-B:550–7.
    The Bone & Joint Journal 01/2015; 97-B:550-557. DOI:10.1302/0301-620X.97B4 · 2.80 Impact Factor
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    ABSTRACT: Background Complex anatomy of the forearm may impact on local control and survivals of soft tissue sarcoma. Little is known about characteristics and oncologic outcomes following surgical treatment. Methods Demographic and tumor data of 117 patients with forearm soft tissue sarcoma were collected and analyzed. Following limb salvage, survivals, and prognostic factors were studied. ResultsSeventy-three patients were males (62%) and 53 (45%) were referred after unplanned excision. Pleomorphic undifferentiated sarcoma was most frequent (45%). The average tumor size was 5.1cm and grade III histology was mostly identified (53%). With radiotherapy, local recurrence occurs in 8 patients (7%) and 30 patients (24%) developed metastasis. Overall survival, disease free survival, local recurrence free survival, and metastasis free survival were 83%, 74%, 93%, and 74%, respectively. Better survival was found for grade I (80% vs. 60%) and small size (<5cm) (72% vs. 47%). Large size tumor, extra-compartmental site, extramuscular, and virgin tumor were positive predictors of metastasis. Conclusion Soft tissue sarcomas of the forearm are often referred after unplanned excision. Limb salvage was achieved for most and local recurrence remained low in context of radiotherapy. Metastatic progression remained frequent. Low grade and small size were predictors of survival. J. Surg. Oncol. 2014 110:676-681. (c) 2014 Wiley Periodicals, Inc.
    Journal of Surgical Oncology 11/2014; 110(6). DOI:10.1002/jso.23686 · 2.84 Impact Factor
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    ABSTRACT: Although telomeres are maintained in most cancers by telomerase activation, a subset of tumors utilize alternative lengthening of telomeres (ALT) to sustain self-renewal capacity. In order to study the prevalence and significance of ALT in childhood brain tumors we screened 517 pediatric brain tumors using the novel C-circle assay. We examined the association of ALT with alterations in genes found to segregate with specific histological phenotypes and with clinical outcome. ALT was detected almost exclusively in malignant tumors (p = 0.001). ALT was highly enriched in primitive neuroectodermal tumors (12 %), choroid plexus carcinomas (23 %) and high-grade gliomas (22 %). Furthermore, in contrast to adult gliomas, pediatric low grade gliomas which progressed to high-grade tumors did not exhibit the ALT phenotype. Somatic but not germline TP53 mutations were highly associated with ALT (p = 1.01 × 10−8). Of the other alterations examined, only ATRX point mutations and reduced expression were associated with the ALT phenotype (p = 0.0005). Interestingly, ALT attenuated the poor outcome conferred by TP53 mutations in specific pediatric brain tumors. Due to very poor prognosis, one year overall survival was quantified in malignant gliomas, while in children with choroid plexus carcinoma, five year overall survival was investigated. For children with TP53 mutant malignant gliomas, one year overall survival was 63 ± 12 and 23 ± 10 % for ALT positive and negative tumors, respectively (p = 0.03), while for children with TP53 mutant choroid plexus carcinomas, 5 years overall survival was 67 ± 19 and 27 ± 13 % for ALT positive and negative tumors, respectively (p = 0.07). These observations suggest that the presence of ALT is limited to a specific group of childhood brain cancers which harbor somatic TP53 mutations and may influence the outcome of these patients. Analysis of ALT may contribute to risk stratification and targeted therapies to improve outcome for these children.
    Acta Neuropathologica 10/2014; DOI:10.1007/s00401-014-1348-1 · 9.78 Impact Factor
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    ABSTRACT: There are few reports detailing recurrence rates or functional outcomes after combined arthroscopic and open synovectomy to treat diffuse pigmented villonodular synovitis (DPVNS) of the knee.
    Knee Surgery Sports Traumatology Arthroscopy 10/2014; DOI:10.1007/s00167-014-3375-9 · 2.84 Impact Factor
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    ABSTRACT: BACKGROUND: The objectives of this study were to evaluate the risk of local recurrence and survival after soft tissue sarcoma (STS) resection with positive margins and to evaluate the safety of sparing adjacent critical structures. METHODS: One hundred sixty-nine patients with localized STS who had positive resection margins were identified from a prospective database. Patients who had positive margins were stratified into 3 groups, each representing a specific clinical scenario: critical structure positive margin (eg major nerve, vessel, or bone), tumor bed resection positive margin, and unexpected positive margin. The rates of local recurrence-free survival (LRFS) and cause-specific survival (CSS) were calculated and compared with relevant control patients who had negative margins after STS resection. RESULTS: After planned close dissection to preserve critical structures, the 5-year LRFS and CSS rates both depended on the quality of the surgical margins (97% and 80.3%, respectively, for those with negative margins vs 85.4% and 59.4%, respectively, for those with positive margins; P = .015 and P = .05, respectively). Negative margins achieved through resection of critical structures because of tumor invasion or encasement only slightly improved the 5-year rates of LRFS (91.2%) and CSS (63.6%; P = .8 and P = .9, respectively). The lowest 5-year LRFS and CSS rates were 63.4% and 59.2%, respectively, after an unexpected positive margin during primary surgery. CONCLUSIONS: After patients undergo resection of STS with positive margins, oncologic outcomes can be predicted based on the clinical context. Sparing adjacent critical structures in this setting is safe and contributes to improved functional outcomes. (C) 2014 American Cancer Society.
    Cancer 09/2014; 120(18). DOI:10.1002/cncr.28793 · 4.90 Impact Factor
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    ABSTRACT: Creating spontaneous yet genetically tractable human tumors from normal cells presents a fundamental challenge. Here we combined retroviral and transposon insertional mutagenesis to enable cancer gene discovery starting with human primary cells. We used lentiviruses to seed gain- and loss-of-function gene disruption elements, which were further deployed by Sleeping Beauty transposons throughout the genome of human bone explant mesenchymal cells. De novo tumors generated rapidly in this context were high-grade myxofibrosarcomas. Tumor insertion sites were enriched in recurrent somatic copy-number aberration regions from multiple cancer types and could be used to pinpoint new driver genes that sustain somatic alterations in patients. We identified HDLBP, which encodes the RNA-binding protein vigilin, as a candidate tumor suppressor deleted at 2q37.3 in greater than one out of ten tumors across multiple tissues of origin. Hybrid viral-transposon systems may accelerate the functional annotation of cancer genomes by enabling insertional mutagenesis screens in higher eukaryotes that are not amenable to germline transgenesis.
    Nature Genetics 08/2014; 46(9). DOI:10.1038/ng.3065 · 29.65 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWAS) have mapped risk alleles for at least ten distinct cancers to a small region of 63,000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (ASSET) across six distinct cancers in 34,248 cases and 45,036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single nucleotide polymorphisms (SNPs): five in the TERT gene (region 1: rs7726159, P=2.10x10-39; region 3: rs2853677, P=3.30x10-36 and PConditional=2.36x10-8; region 4: rs2736098, P=3.87x10-12 and PConditional=5.19x10-6, region 5: rs13172201, P=0.041 and PConditional=2.04x10-6; and region 6: rs10069690, P=7.49x10-15 and PConditional=5.35x10-7) and one in the neighboring CLPTM1L gene (region 2: rs451360; P=1.90x10-18 and PConditional=7.06x10-16). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele specific effects on DNA methylation were seen for a subset of risk loci indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
    Human Molecular Genetics 07/2014; DOI:10.1093/hmg/ddu363 · 6.68 Impact Factor
  • Journal of Medical Imaging and Radiation Sciences 06/2014; 45(2):183-184. DOI:10.1016/j.jmir.2014.03.076
  • Operative Techniques in Orthopaedics 06/2014; 24(2):79-84. DOI:10.1053/j.oto.2014.02.010
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    ABSTRACT: Despite the importance of Hedgehog signaling in bone development, the relationship between Hedgehog pathway expression and osteosarcoma clinical characteristics and outcome has not been investigated. In this study of 43 high-grade human osteosarcoma samples, we detected high expression levels of the Hedgehog ligand gene, IHH, and target genes, PTCH1 and GLI1, in most samples. Further analysis in tumors of patients with localized disease at diagnosis identified coexpression of IHH and PTCH1 exclusively in large tumors. Higher levels of IHH were observed more frequently in males and patients with higher levels of GLI1 were more responsive to chemotherapy. Subgroup analysis by tumor size and IHH expression indicated that the well-known association between survival and tumor size was further refined when IHH levels were taken into consideration.
    Sarcoma 03/2014; 2014:261804. DOI:10.1155/2014/261804
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    ABSTRACT: Hedgehog (Hh) pathway inhibition in cancer has been evaluated in both the ligand-independent and ligand-dependent settings, where Hh signaling occurs either directly within the cancer cells, or within the non-malignant cells of the tumor microenvironment. Chondrosarcoma is a malignant tumor of cartilage in which there is ligand-dependent activation of Hh signaling. IPI-926 is a potent, orally delivered small molecule that inhibits Hh pathway signaling by binding to Smoothened (SMO). Here, the impact of Hh pathway inhibition on primary chondrosarcoma xenografts was assessed. Mice bearing primary human chondrosarcoma xenografts were treated with IPI 926. The expression levels of known Hh pathway genes, in both the tumor and stroma, and endpoint tumor volumes were measured. Gene expression profiling of tumors from IPI-926-treated mice was conducted to identify potential novel Hh target genes. Hh target genes were studied to determine their contribution to the chondrosarcoma neoplastic phenotype. IPI-926 administration results in down-modulation of the Hh pathway in primary chondrosarcoma xenografts, as demonstrated by evaluation of the Hh target genes GLI1 and PTCH1, as well as inhibition of tumor growth. Chondrosarcomas exhibited autocrine and paracrine Hh signaling and both were affected by IPI-926. Decreased tumor growth is accompanied by histopathological changes, including calcification and loss of tumor cells. Gene profiling studies identified genes differentially expressed in chondrosarcomas following IPI-926 treatment, one of which, ADAMTSL1, regulates chondrosarcoma cell proliferation. These studies provide further insight into the role of the Hh pathway in chondrosarcoma and provide a scientific rationale for targeting the Hh pathway in chondrosarcoma.
    Molecular Cancer Therapeutics 03/2014; 13(5). DOI:10.1158/1535-7163.MCT-13-0731 · 6.11 Impact Factor

Publication Stats

6k Citations
1,265.05 Total Impact Points

Institutions

  • 2015
    • Washington University in St. Louis
      • Division of Urologic Surgery
      San Luis, Missouri, United States
  • 1999–2015
    • Mount Sinai Hospital, Toronto
      • • Department of Medical Imaging
      • • Department of Pathology and Laboratory Medicine
      Toronto, Ontario, Canada
  • 1991–2014
    • University of Toronto
      • • Department of Surgery
      • • Department of Medical Imaging
      Toronto, Ontario, Canada
  • 2005–2013
    • Sinai Hospital
      Mount Sinai, New York, United States
  • 1993–2013
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
  • 2012
    • St. Michael's Hospital
      Toronto, Ontario, Canada
    • National Cancer Institute (USA)
      • Division of Cancer Epidemiology and Genetics
      Bethesda, MD, United States
    • McMaster University
      • Department of Surgery
      Hamilton, Ontario, Canada
  • 2010–2012
    • SickKids
      • Division of Orthopaedic Surgery
      Toronto, Ontario, Canada
  • 1996–2012
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 2008–2009
    • Beijing University of Technology
      Peping, Beijing, China
  • 1999–2007
    • Mount Sinai Hospital
      New York City, New York, United States
  • 2002
    • Université de Montréal
      Montréal, Quebec, Canada
  • 1998
    • Memorial Sloan-Kettering Cancer Center
      • Department of Surgery
      New York City, NY, United States
    • The University of Western Ontario
      • Division of Orthopaedic Surgery
      London, Ontario, Canada