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1.  A low frequency variant at 8q24.21 is strongly associated with risk of oligodendroglial tumors and IDH1 or IDH2 mutated astrocytomas 
Nature genetics  2012;44(10):1122-1125.
SNPs mapped to 8q24.21 have been shown to be associated with glioma development. By means of tag SNP genotyping/imputation, pooled next-generation sequencing (NGS) using long-range PCR, and subsequent validation SNP genotyping we identified seven low-frequency SNPs that were consistently and highly associated with glioma risk (p=10−25 to 10−14). The most associated SNP, rs55705857, remained highly significant after individual adjustment for the other top six and two previously published SNPs. After stratifying by histologic and tumor genetic subtype, the most significant associations were with oligodendroglial tumors and IDH1 or IDH2 mutated gliomas, (ORrs55705857 = 5.1, p=1.1x10−31 and ORrs55705857 = 4.8, p=6.6 x10−22, respectively). Strong associations were observed for IDH1 or IDH2 mutated astrocytomas (grades II–IV) (OR rs55705857=5.16–6.66; p=4.7x10−12 to 2.2x10−8), but not IDH1 or IDH2 wild-type astrocytomas (smallest p=0.26). The conserved sequence block that includes rs55705857 is consistently modeled as a microRNA.
PMCID: PMC3600846  PMID: 22922872
Oligodendroglioma; Glioblastoma; IDH1 and IDH2 mutation; single nucleotide polymorphism
2.  Distinct germline polymorphisms underlie glioma morphologic heterogeneity 
Cancer genetics  2011;204(1):13-18.
Two recent genome-wide association studies reported that single nucleotide polymorphisms (SNPs) in (or near) TERT (5p15), CCDC26 (8q24), CDKN2A/B (9p21), PHLDB1 (11q23), and RTEL1 (20q13) are associated with infiltrating glioma. From these reports it was not clear if the SNP associations predispose to glioma in general or whether they are specific to certain glioma grades or morphologic subtypes. To identify hypothesized associations between susceptibility loci and tumor subtype, we genotyped two case/control groups composed of the spectrum of infiltrating glioma subtypes, and stratified the analyses by type. We report that specific germline polymorphisms are associated with different glioma subtypes. CCDC26 (8q24) region polymorphisms are strongly associated with oligodendroglial tumor risk (rs4295627, OR=2.05, p=8.3*10−11), but not glioblastoma risk. The opposite is true of RTEL (20q13) region polymorphisms which are significantly associated with glioblastoma (rs2297440, OR = 0.56, p= 4.6*10−10) but not oligodendroglial tumor. The SNPs in or near CCDC26 (8q24) are associated with oligodendroglial tumors regardless of combined 1p and 19q deletion status; however, the association is greatest for those with combined deletion (rs4295627, OR=2.77, p=2.6*10-9). These observations generate hypotheses concerning the possible mechanisms by which specific SNPs (or alterations in linkage disequilibrium with such SNPs) are associated with glioma development.
PMCID: PMC3062955  PMID: 21356187
Glioma; Genetic Association; 1p/19q deletion
3.  Sleeping Beauty-mediated somatic mutagenesis implicates CSF1 in the formation of high grade astrocytomas 
Cancer research  2010;70(9):3557-3565.
The Sleeping Beauty (SB) transposon system has been used as an insertional mutagenesis tool to identify novel cancer genes. To identify glioma-associated genes, we evaluated tumor formation in brain tissue from 117 transgenic mice that had undergone constitutive SB-mediated transposition. Upon analysis, 21 samples (18%) contained neoplastic tissue with features of high grade astrocytomas. These tumors expressed glial markers and were histologically similar to human glioma. Genomic DNA from SB-induced astrocytoma tissue was extracted and transposon insertion sites were identified. Insertions in the growth factor gene Csf1 were found in 13 of the 21 tumors (62%), clustered in introns 5 and 8. Using RT-PCR, we documented increased Csf1 RNAs in tumor versus adjacent normal tissue, with identification of transposon-terminated Csf1 mRNAs in astrocytomas with SB insertions in intron 8. Analysis of human glioblastomas revealed increased levels of Csf1 RNA and protein. Together, these results indicate that SB-insertional mutagenesis can identify high-grade astrocytoma-associated genes, and they imply an important role for CSF1 in the development of these tumors.
PMCID: PMC2862088  PMID: 20388773
Astrocytoma; Sleeping Beauty; Mutagenesis; Colony stimulating factor-1
4.  Preferential Expression of the Secreted and Membrane forms of Tumor Endothelial Marker 7 transcripts in Osteosarcoma 
Anticancer research  2009;29(11):4317-4322.
High expression of tumor endothelial marker 7 (TEM7) is correlated with osteogenic sarcoma (OS) metastasis and poor survival of patients. The TEM7 gene produces four alternatively spliced transcripts with distinct functional domains; the expression pattern of these transcripts in OS is unknown.
Materials and Methods
mRNA expression was assessed in 5 OS cell lines, 7 normal bone, and 9 OS tumor specimens by reverse transcriptase polymerase chain reaction.
All OS cell lines, 6/9 tumors but none of the bone specimens expressed mRNA of TEM7 secreted forms 1 and 2. A total of 3/5 OS cell lines, 8/9 of tumors and 4/7 of bone specimens expressed mRNA of the TEM7 intracellular form. One out of 5 cell lines, 2/7 tumors and none of the bone specimens expressed mRNA of the TEM7 membrane form. The secreted forms had 20-fold higher expression in metastatic (LM7) compared to non-metatstatic (SAOS-2) cells.
The mRNA of secreted and the membrane forms of TEM7 are preferentially expressed in OS.
PMCID: PMC2800050  PMID: 20032373
TEM7; alternative splicing; osteosarcoma; PCR; metastasis
6.  High expression of Tumor Endothelial Marker 7 is associated with metastasis and poor survival of patients with osteogenic sarcoma 
Gene  2007;399(2):137-143.
Our objective is to identify genes regulating metastasis of osteogenic sarcoma (OGS) since metastasis is the primary cause of mortality among patients with OGS. To identify such genes, we first created a database of differentially expressed genes between six low-grade and six high-grade OGS tumors, and between a normal immortalized osteoblast cell line (FOB) and four commercially available OGS-derived cell lines. We specifically searched for surface-proteins over-expressed in high-grade OGS, since we hypothesize that tumor-cell specific surface markers are key to metastasis. A gene encoding Tumor Endothelial Marker7 (TEM7) was selected as a candidate for further study. TEM7 expression pattern was assessed by RT-PCR, Western blotting and immunostaining. TEM7 mRNA was abundantly expressed in SAOS cells (derived from high-grade OGS), but not in FOB or MG63 cells (derived from low-grade OGS). Virtually no expression of TEM7 protein was observed in FOB cells but abundant expression was noted in SAOS and TE85 cells. Employing immunostaining of 92 human OGS specimens (50 high grade and 42 low-grade) collected before chemotherapy show 97% (37 of 38) of high-grade OGS specimens with metastasis have high TEM7 staining. Further, we found that elevated expression of TEM7 correlated with poor survival (p<0.04) of affected patients. Inhibiting TEM7 function by siRNA inhibited invasion and migration of OGS cells with metastatic potential. Our results suggest TEM7 expression level closely parallels histology-based prognostication of OGS metastasis and, therefore, it is a therapeutic target. This is the first demonstration of a link between TEM7 and cancer metastasis.
PMCID: PMC2066185  PMID: 17560052
TEM7; Osteogenic sarcoma; Metastasis; siRNA; Tumor marker

Results 1-6 (6)