Osteosarcoma (OS) has a high degree of chromosomal instability and total copy number (CN) changes. We examined 58 human OS samples including 40 primary tumors, 11 explants, and 7 cell lines using single nucleotide polymorphism (SNP) arrays, and revealed that 70% of the samples had one or more recurrent CN-neutral loss of heterozygosity (CNN‑LOH) also known as uniparental disomy (UPD). Importantly, 17% of the samples showed prominent homozygous deletion of 3q13.31, suggesting its role in tumorigenesis. We identified and characterized two novel lncRNAs, LOC285194 and BC040587, within this genomic locus, strongly suggesting their tumor suppressor activity. Frequent deletions and UPD suggest that OS often has mutant or non-expressed tumor suppressor genes including two lncRNAs.

Abstract Purpose of study: We sought to identify genomic modifiers of gynecologic cancer penetrance in BRCA1 185delAG mutation carriers. In a pilot study using the Illumina 610K Quad chip to perform a whole genome analysis of 592,532 single nucleotide polymorphisms (SNP), we found significant SNP genotype differences in the PARK2 gene between BRCA1 185delAG mutation carriers who developed gynecologic cancer (cases) compared to those who did not (controls). These SNPS created a haplotype structure that was present at four-times higher frequency in cases than controls (37% vs. 9%, p=0.0009). We hypothesized that PARK2, which has been shown to be mutated in other cancers and to have a tumor suppressive function, plays a role in the biology of BRCA1-associated gynecologic cancer development. Experimental Procedures: To validate a PARK2 risk haplotype in an independent dataset, we isolated germline DNA from 85 BRCA1 185delAG mutation carriers and used TaqMan SNP Genotyping to genotype seven SNPs in PARK2. To determine whether a correlation exits between the PARK2 risk haplotype and PARK2 expression levels in tissue, we quantified PARK2 expression in normal ovaries and ovarian cancer tissue using quantitative real-time PCR (qPCR). To determine the rate of PARK2 mutations in 17 BRCA1-associated ovarian cancers, we used a touchdown PCR protocol to amplify and sequence each PARK2 exon. To identify exon deletions and duplications in the PARK2 gene, we utilized the multiplex ligation-dependent probe amplification (MLPA) technique. Summary of Data: In an independent dataset of 85 BRCA1 185delAG mutation carriers, we found the PARK2 risk haplotype to be present in 35 (17%) of cases. The risk haplotype was present in a higher proportion of cancer cases than benign controls (6/12 or 50% vs. 29/73 or 8%), but this was not significant (p=0.54). We did not find a difference in PARK2 ovarian tissue expression levels in patients with and without the PARK2 risk haplotype. We sequenced the PARK2 gene and performed MPLA analysis from tumor DNA of 17 ovarian cancers from BRCA1 185delAG mutation carriers, but did not identify any deleterious PARK2 mutations or exon deletions and duplications. Conclusions: We did not validate a PARK2 risk haplotype as a modifier of gynecologic cancer penetrance in BRCA1 185delAG mutation carriers. We did not find evidence for PARK2 inactivation in BRCA1-associated gynecologic tumors. Citation Format: Christine Walsh, Hoorig Nassanian, Hasmik Agadjanian, Carl Miller, Sandra Orsulic, Beth Karlan. No association between PARK2 and BRCA1-associated gynecologic cancers [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1348.

Super-resolution fluorescence microscopy is anticipated to be a powerful tool in observing biological structures and processes smaller than the diffraction limit of light microscopy (~200nm). Yet, many super-resolution techniques (STORM/PALM, STED) employ photo-switchable fluorescent probes (i.e., dyes and fluorescent proteins) that are limited in brightness and stability, reducing potential image resolution. Here, we describe photo-switchable quantum dots (QDs) with enhanced brightness and stability, and excellent optical properties, including narrow emission spectra and broad excitation spectra, compared to fluorescent dyes. These QDs are composed of one green QD, one gold nanoparticle (AuNP), and complimentary single stranded DNA (ssDNA) modified with photo-sensitive azobenzene groups bound to each of the particles. Because of the azobenzene photosensitive property, the ssDNA strands hybridize when excited with visible light, yielding a QD-AuNP conjugate in which QD fluorescence is quenched through Förster resonance energy transfer (FRET); and dehybridize under visible light, yielding separate QDs and AuNPs that are free to diffuse from each other. Because FRET is strongly distance dependent (i.e., α 1/r6, in this case, a few nanometers), QD fluorescence is restored. Moreover, the photo-switchable QD-AuNP conjugate scheme has the potential to be integrated with a DNA nano-machine platform, adding the potential for photo-manipulated functionality. As a preliminary proof of concept, we tethered different nanocomponents, including QD micelle assemblies and AuNPs, to DNA origami structures (hinge and platform shapes) using ssDNA hybridization.

Epithelial ovarian cancers (EOC) represent the gynecologic malignancy with the highest mortality rate. The Cancer Genome Atlas demonstrated a high degree of genetic heterogeneity among the papillary serous (PS) tumors, the most lethal of the EOC subtypes. Aside from almost universal mutation in TP53, there was a low prevalence of recurrent mutations in other genes, presenting a challenge to the development of targeted therapeutics against this aggressive tumor type. We are developing a mouse model of EOC by introducing defined genetic alterations to mouse ovarian surface epithelial (MOSE) cells. We had a particular interest in developing a cyclin E amplified tumor model, as CCNE1 amplification is found in 20% of human EOC tumors, making this one of the most prevalent PS EOC subtypes. We infected MOSE cells from p53-/- mice with different combinations of oncogenes encoded in retroviral vectors including CCNE1, myc and H-RAS. MOSE cells were infected with one or two oncogenes, passaged and injected into the peritoneal cavity of nude mice. Myc-HRAS caused the rapid development of hemorrhagic ascites and intraperitoneal carcinomatosis in 5 of 5 mice by day 18. HRAS alone and HRAS-CCNE1 both caused intraperitoneal and omental tumors to develop with clear ascites by day 35 in 5 of 5 mice. Myc caused bloating due to the development of frank hemoperitoneum in all 5 mice between days 101 and 150. Only 4 of the 5 mice had small volume intraperitoneal tumors. Myc-CCNE1 similarly caused bloating due to ascites in 2 mice and hemoperitoneum in 2 mice. Three of these four mice had small volume intraperitoneal tumors. One mouse has not developed any phenotype by 150 days. CCNE1 alone has not caused tumor formation in any of 5 mice by day 150. Histology of the Myc-HRAS, HRAS, HRAS-CCNE1, and Myc tumors were all consistent with high-grade undifferentiated carcinoma. Tumor cells generated in the Myc-HRAS, HRAS and HRAS-CCNE1 experiments were capable of causing intraperitoneal tumor development in immunocompetent C57BL/6 mice by day 17, 29 and 54 respectively. Taken together, our data demonstrate a reproducible mouse model for the development of high-grade epithelial ovarian carcinomas with defined genetic alterations that are capable of study in both immunodeficient and immunocompetent mice. Tumor phenotypes varied based on the combination of activated oncogenes. Citation Format: Hasmik Agadjanian, Dong-Joo Cheon, Elena Diaz, Anna Laury, Carl Miller, Beth Karlan, Sandra Orsulic, Christine Walsh. A mouse model of epithelial ovarian cancer with defined oncogenic drivers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 329. doi:10.1158/1538-7445.AM2013-329

BACKGROUND: The nucleotide excision repair (NER) pathway is the principal DNA repair pathway for removing bulky platinum DNA adducts. Suboptimal DNA repair may lead to improved response to platinum agents. The objective of this study was to determine whether single-nucleotide polymorphisms (SNPs) in NER pathway genes could be markers of platinum response in ovarian cancer. METHODS: The authors identified patients with advanced- stage, papillary serous ovarian cancer who underwent primary cytoreductive surgery followed by platinum- based chemotherapy. DNA was isolated from peripheral blood specimens. Twenty- two SNPs within NER genes (xeroderma pigmentosum [XP] complementation group A [XPA], XPB/excision repair cross- complementing rodent repair deficiency, complementation group 3 [ERCC3], XPC, XPD/ERCC2, XPF/ERCC4, XPG/ERCC5, Cockayne syndrome group B protein [CSB]/ERCC8, ERCC1) were genotyped using polymerase chain reaction analysis. RESULTS: In total, 139 patients with stage III and IV papillary serous ovarian cancer were genotyped. The XPC (reference SNP 3731108 [rs3731108]) adenosine- guanine (AG)/AA genotype versus the GG genotype was associated with prolonged a progression- free survival (PFS) of 21.3 months versus 13.4 months (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.42- 0.95; P.03). The XPC (rs1124303) guanosine- thymidine (GT)/GG genotype versus the TT genotype was associated with a prolonged PFS of 22.8 months versus 14.9 months (HR, 0.47; 95% CI, 0.24- 0.94; P.03). The XPC poly(AT) (PAT) (-/+)/(-/+) genotype versus the (+/+) genotype was associated with a prolonged PFS of 17 months versus 11.6 months (HR, 0.56; 95% CI, 0.36- 0.89; P.01). The XPF/ERCC4 (rs12926685) cytidine- thymidine (CT)/CC genotype versus the TT genotype was associated with a prolonged PFS of 16.7 months versus 12.4 months (HR, 0.63; 95% CI, 0.41- 0.95; P.03). On multivariate analysis adjusting for breast cancer (BRCA) gene and cytoreductive surgery status, the XPC SNPs remained significantly associated with prolonged PFS. CONCLUSIONS: The current results indicated that XPC is a key component of the NER pathway that participates in DNA damage repair. SNPs in the XPC gene may represent novel markers of ovarian cancer response to platinum- based chemotherapy. Cancer 2012; 118: 689- 97. (C) 2011 American Cancer Society.

Abstract Introduction: Cyclin E deregulation appears to be an important event in the pathogenesis of a subset of epithelial ovarian cancers associated with poor outcome. One mechanism of cyclin E deregulation is through enhanced p27 degradation, which eliminates a powerful negative regulator of cyclin E. The proteasome inhibitor bortezomib has been shown to inhibit the growth of both ovarian and colorectal tumor cell lines through upregulation of p27 and induction of apoptosis, giving it a potential therapeutic role in the subset of ovarian cancers that overexpress cyclin E. Studies demonstrate that as many as five low molecular weight (LMW) isoforms of cyclin E exist, while only the 50-kDa cyclin E form is typically expressed in normal tissues. These LMW isoforms are tumor-specific and cause increased cell proliferation, elevated kinase activity and increased clonogenicity. LMW cyclin E isoforms are generated via proteolysis of the normal 50-kDa cyclin E form by elastase, which itself can be selectively inhibited by indole-3-carbinol (I3C), a natural component of Brassica vegetables. I3C exhibits potent anticarcinogenic properties and has recently been shown to shift the stable accumulation of cyclin E from the LMW to 50-kDa cyclin E form. By taking advantage of the specific inhibitory properties of I3C and bortezomib in the processing and potential expression of cyclin E, respectively, we hypothesize that ovarian cancers overexpressing cyclin E may demonstrate an enhanced response to targeted combination therapy with I3C and bortezomib. Methods: A panel of ovarian cancer cell lines was screened for cyclin E and p27 protein levels through western blotting. Representative cell lines with high and low cyclin E expression were treated with I3C and bortezomib and evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation assay and western blotting analysis. Results: OVCAR3 was found to express high levels of cyclin E and moderate levels of p27. In contrast, OVCAR5 was found to express low levels of cyclin E and high levels of p27. Treatment of OVCAR3 cells with I3C stabilized the expression of the normal 50-kDa cyclin E form in a dose-dependent manner. The combination of I3C and bortezomib treatment in OVCAR3 and OVCAR5 cells caused a significantly greater degree of cytotoxicity compared to either drug alone. While the effect was seen in both cell lines, inhibition of cell proliferation was more enhanced in the cyclin E overexpressing cell line OVCAR3. Conclusions: Indole-3-carbinol is a natural dietary substance that sensitizes ovarian cancer cells to the proteasome inhibitor bortezomib through stabilization and inhibition of cyclin E activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3880.

In an attempt to fully characterize the complex chromosomal changes of osteosarcoma (OS), 58 human OS samples including 40 primary OS tumors, 11 OS explants, and 7 OS cell lines were subjected to Affymetrix 50K and 250K single nucleotide polymorphism (SNP) array analysis. Allele-specific copy number (CN) analysis using anonymous references (AsCNAR) algorithm revealed many allele-specific events previously undetectable by conventional analysis. Common regions of high CN amplifications were identified in 1q21.1-q24.1 (14% of the samples), 6p21.1-p12.1 (14%), 8q23.3-qter (16%), 14q11.2-q12 (17%), and 17p12-p11.2 (16%). Interestingly, many amplicons showed allele-specific amplification frequently accompanying deletion of the other allele. The most prominent allele-specific amplifications were found in 8q23.3-qter. 59 % of the samples showed various levels of CN gains in this region. All human OS cell lines (U2OS, G292, MG63, HT161, HOS, and SAOS2) except SJSA (86 % of the cell lines) showed high CN amplification in the region. Although amplification of chromosome 8 q-arm (8q) targeting MYC oncogene is frequently found in many cancers, Many amplicons identified in the region were MYC-independent. Fluoresence In-Situ Hybridization (FISH) using BAC clones verified the presence of MYC-independent amplicons as well as frequent fusion and translocation of the amplicons into other chromosomes. To check the possibility of new cancer-related genes other than MYC gene in 8q, we checked the mRNA expression levels of all known genes in the amplicons of 7 human OS cell lines by quantitative reverse transcription PCR (qRT-PCR). Gene expression levels were normalized to the expression level in normal human osteoblast cell line hFOB1.19. Many genes in the region showed increased mRNA expression level: TRPS1 (median value of 34-fold increased expression), RAD21 (5-fold), THRAP6 (6-fold), CCN3 (24-fold), ENPP2 (10-fold), DEPDC6 (7-fold), SNTB1 (8-fold), FBXO32 (5-fold), ADCY8 (5-fold), CCN4 (12-fold), and PTK2 (4-fold) showed more than 10-fold increase in two or more cell lines. Common regions of homozygous deletions were also identified: 3q13.31 (16% of the samples), 7q35-q36.3 (9%), 9p21.3 (7%), and Xp21 (7%) were frequently deleted. Interestingly, many deletions targeted membrane associated guanylate kinase (MAGUK) family genes such as MAGI2, DLG2, and DLGAP2. In conclusion, our results suggest that there are several possible cancer-related genes in 8q regions as well as in homozygously deleted regions in OS. These findings will help developing new diagnostic markers and therapeutic targets. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1413.

BackgroundAcute myeloid leukemia is a clonal hematopoietic malignant disease; about 45-50% of cases do not have detectable chromosomal abnormalities. Here, we identified hidden genomic alterations and novel disease-related regions in normal karyotype acute myeloid leukemia/myelodysplastic syndrome samples.Design and MethodsThirty-eight normal karyotype acute myeloid leukemia/myelodysplastic syndrome samples were analyzed with high-density single-nucleotide polymorphism microarray using a new algorithm: allele-specific copy-number analysis using anonymous references (AsCNAR). Expression of mRNA in these samples was determined by mRNA microarray analysis.ResultsEighteen samples (49%) showed either one or more genomic abnormalities including duplication, deletion and copy-number neutral loss of heterozygosity. Importantly, 12 patients (32%) had copy-number neutral loss of heterozygosity, causing duplication of JAK2 (1 case) or AML1/RUNX1 (1 case); and each had loss of either mutant FLT3 (2 cases) the normal allele. Nine patients (24%) had small copy-number changes (< 10 Mb) including deletions of NF1, ETV6/TEL, CDKN2A and CDKN2B. Interestingly, mRNA microarray analysis showed a relationship between chromosomal changes and mRNA expression levels: loss or gain of chromosomes led, respectively, to either a decrease or increase of mRNA expression of genes in the region.ConclusionsThis study suggests that at least one half of cases of normal karyotype acute myeloid leukemia/myelodysplastic syndrome have readily identifiable genomic abnormalities, as found by our analysis; the high frequency of copy-number neutral loss of heterozygosity is especially notable.

Asparagine synthetase (ASNS) is an enzyme expressed ubiquitously in mammalian cells. Here, we discovered two 14-bp tandem repeat (2R, wild-type) sequences in the first intron of the gene. The 14-bp sequence is similar to the three GC-boxes (GC-I, -II, and -III) found in the promoter region of the ASNS gene, as well as, the binding site of transcription factor Sp-1. Approximately 75% of acute lymphoblastic leukemia (ALL) samples had the 2R sequence in both allele; however, 20% and 3% ALL samples had three (3R) and four (4R) 14-bp tandem repeats in one allele, respectively; the other allele had 2R. The tandem repeat sequence was not specific to the leukemia cells but represents a novel germline polymorphism. Interestingly, the 14-bp sequence functioned as a transcriptional enhancer element as shown by reporter analysis and formed a protein–DNA complex in vitro. Our data for the first time show that the ASNS gene has tandem repeated sequences as a polymorphism, and it can function as a transcriptional element; increased number of tandem repeat producing increased activity. Clinical significance in ALL requires further studies.

ROR1 is a receptor tyrosine kinase-like orphan receptor that is abundantly expressed in B-cell leukemias. ROR1 and a related protein, ROR2, have frizzled domains and can sequester Wnts to mediate signaling in a non-canonical Wnt pathway. No specific ligand has yet been assigned to ROR1. Analysis of SNP array data from ovarian cancers frequently finds trisomy affecting the area including ROR1 on chromosome 1p31. Copy number peaks greater than 4 copies overlapped in one ovarian cancer cell line and four ovarian cancer patient samples. The peaks defined a minimum region of just under 1 megabase, amplifying two known genes: ROR1 and UBE2U. Expression analysis by real-time PCR showed that ROR1, but not UBE2U, is abundantly expressed in several ovarian cancer cell lines. Western blots confirmed the conclusion that the increased copy number was driving over-expression. The Catalogue of Somatic Mutations in Cancer (COSMIC) report 6 missense mutations affecting ROR1, two of which were found in ovarian cancer patient samples. The sequencing screen by COSMIC suggests that mutations of the ROR1 gene are clustered in two hotspots. The putative hotspots are being examined for mutations by sequencing amplified fragments in twelve cell lines. Results thus far have found no mutations. Continuing studies will address whether the ROR1 gene acts as an oncogene in ovarian cancer by examining its role in proliferation and differentiation in vitro and in mouse models. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1352.

Barrett's esophagus (BE) is a metaplastic condition caused by chronic gastroesophageal reflux which represents an early step in the development of esophageal adenocarcinoma (EAC). Single‐nucleotide polymorphism microarray (SNP‐chip) analysis is a novel, precise, high‐throughput approach to examine genomic alterations in neoplasia. Using 250K SNP‐chips, we examined the neoplastic progression of BE to EAC, studying 11 matched sample sets: 6 sets of normal esophagus (NE), BE and EAC, 4 of NE and BE and 1 of NE and EAC. Six (60%) of 10 total BE samples and 4 (57%) of 7 total EAC samples exhibited 1 or more genomic abnormalities comprising deletions, duplications, amplifications and copy‐number‐neutral loss of heterozygosity (CNN‐LOH). Several shared abnormalities were identified, including chromosome 9p CNN‐LOH [2 BE samples (20%)], deletion of CDKN2A [4 BE samples (40%)] and amplification of 17q12‐21.2 involving the ERBB2, RARA and TOP2A genes [3.1 Mb, 2 EAC (29%)]. Interestingly, 1 BE sample contained a homozygous deletion spanning 9p22.3–p22.2 (1.2 Mb): this region harbors only 1 known gene, basonuclin 2 (BNC2). Real‐time PCR analysis confirmed the deletion of this gene and decreased the expression of BNC2 mRNA in the BE sample. Furthermore, transfection and stable expression of BNC2 caused growth arrest of OE33 EAC cells, suggesting that BNC2 functions as a tumor suppressor gene in the esophagus and that deletion of this gene occurs during the development of EAC. Thus, this SNP‐chip analysis has identified several early cytogenetic events and novel candidate cancer‐related genes that are potentially involved in the evolution of BE to EAC. © 2009 UICC

INTRODUCTION:The purpose of this study was to analyze 2003 Mississippi Behavioral Risk Factor Surveillance System (BRFSS) data to describe the health of Mississippians with arthritis or chronic joint pain. For this study, we made statistical estimates of the extent of arthritis burden among the respondents and delineated measurable differences in sociodemographic factors, health status, and the prevalence of associated risk factors. Our findings compare health-related quality of life, physical activity, and key demographic characteristics and obesity rates, controlling for differences among the subgroups by age, sex, educational attainment, income, and race/ethnicity.METHODS:Respondents to Mississippi's 2003 BRFSS were assigned to 1 of 5 distinct and mutually exclusive subgroups: 1) those with intermittent joint symptoms (IJS), 2) those with chronic joint symptoms (CJS), 3) those with doctor-diagnosed arthritis without CJS (DDA-CJS), 4) those with doctor-diagnosed arthritis with chronic joint symptoms (DDA+CJS), and 5) those with no joint symptoms (NJS). To determine the prevalence of arthritis and the continuum of disease progression, we compared the health-related quality of life, physical activity, and obesity of the respondents.RESULTS:Respondents with DDA+CJS were older than those with NJS (mean age, 57.1 years vs 38.7 years); they were more likely to be female (60.5% vs 51.7%), to have a high school diploma or less education (59.3% vs 45.4%), to be in fair to poor health (odds ratio [OR], 10.0), to be physically inactive (OR, 2.7), and to be overweight or obese (OR, 2.5).CONCLUSION:Health status, physical disability, and weight control may be substantially improved through heightened levels of physical activity. However, in spite of the potential for marked improvement, adult Mississippians, especially those clients with DDA+CJS, remain reluctant to commit to exercise regimens. Findings from this study suggest a need to encourage Mississippians with DDA+CJS to engage in some regular physical activity, which could reduce the damaging effects of disease and improve their health. Increasing the health care resources earmarked for arthritis self-help and physical activity programs is one potential avenue to address the problem.

The FBXW7 (also known as AGO, hCDC4, FBW7 and SEL-10) gene encodes a subunit of an ubiquitin protein ligase which regulates levels of cyclin E, NOTCH and other proteins. Engineered FBXW7 null cells display cell cycle and chromosome stability defects. Mutations of FBXW7 have been found in human colorectal, ovarian, endometrial tumors and T-cell acute lymphocytic leukemias. Prompted by these findings we have examined acute myeloid leukemia, non-Hodgkin's lymphoma, T-cell acute lymphocytic leukemia, B-cell acute lymphocytic leukemia and adult T-cell leukemia DNA for mutations of the FBXW7 gene. Mutations were detected by PCR-SSCP of all coding exons of the three isoforms of FBXW7, shifted bands were direct sequenced. As expected, mutations were found in T-cell acute lymphocytic leukemias. However mutations of FBXW7 were also found in four of 118 B-cell acute lymphocytic leukemias and one of 24 adult T-cell leukemia samples. The nucleotide changes consisted of an insertion, resulting in a frameshift mutation, and missense mutations of highly conserved residues. All mutations affected the FBXW7 target interacting domain. These observations suggest that disruption of FBXW7 has a role in several forms of lymphocytic leukemias and not exclusively T-cell acute lymphocytic leukemia.

Acute promyelocytic leukemia (APL) is a hematopoietic malignant disease characterized by the chromosomal translocation t(15;17), resulting in the formation of the PML-RARA gene. Here, 47 t(15;17) APL samples were analyzed with high-density single-nucleotide polymorphism microarray (50-K and 250-K SNP-chips) using the new algorithm AsCNAR (allele-specific copy-number analysis using anonymous references). Copy-number-neutral loss of heterozygosity (CNN-LOH) was identified at chromosomes 10q (3 cases), 11p (3 cases), and 19q (1 case). Twenty-eight samples (60%) did not have an obvious alteration (normal-copy-number [NC] group). Nineteen samples (40%) showed either one or more genomic abnormalities: 8 samples (17%) had trisomy 8 either with or without an additional duplication, deletion, or CNN-LOH (+8 group); and 11 samples (23%) had genomic abnormalities without trisomy 8 (other abnormalities group). These chromosomal abnormalities were acquired somatic mutations. Interestingly, FLT3-ITD mutations (11/47 cases) occurred only in the group with no genomic alteration (NC group). Taken together, these results suggest that the pathway of development of APL differs in each group: FLT3-ITD, trisomy 8, and other genomic changes. Here, we showed for the first time hidden abnormalities and novel disease-related genomic changes in t(15;17) APL.

Objectives: To identify sociodemographic and health-related determinants of Breast and Cervical Cancer Screening behaviors and evaluate progress toward Healthy People 2010 cancer-related objectives.Design: The Behavioral Risk Factor Surveillance System 2005 data served as the numerical predicate for identifying or validating sociodemographic and health-related quality of life predictors, or both, and for determining any relative progress.Setting/Participants: Eleven U.S. states (n = 27,625 women).Main Outcome Measures: Determinants of Breast and Cervical Cancer Screening and assessment of progress toward Healthy People 2010 objectives 3-11 and 3-13.Results: Nine significant predictors of annual Breast and Cervical Cancer Screening (reported as odds ratios) were identified through regression analysis: adequate health care coverage, nonsmoking, age between 40 and 64 years, age greater than or equal to 65 years, no activity limitations, Black, non-Hispanic race, income greater than or equal to $35K, current exercise performance, and no risk for high blood cholesterol. Also, Healthy People 2010 objective 3-11 was not met; however, objective 3-13 was exceeded by 2.0%.Conclusions: The national health initiatives appear to benefit select American women (overall declining mortality rates from breast and cervical cancer); however, there seems to be a negative economy of scale with respect to age-as age increases, Breast and Cervical Cancer Screening declines and morbidity/mortality increases. Given this disparity, as of 2005, related Healthy People 2010 objectives remain unrealized.

High-resolution single nucleotide polymorphism genomic microarray (SNP-chip) is a useful tool to define gene dosage levels over the whole genome, allowing precise detection of deletions and duplications/amplifications of chromosomes in cancer cells. We found that this new technology can also identify breakpoints of chromosomes involved in unbalanced translocations, leading to identification of fusion genes. Using this technique, we found that the PAX5 gene was rearranged to a variety of partner genes including ETV6, FOXP1, AUTS2, and C20orf112 in pediatric acute lymphoblastic leukemia (ALL). The 3' end of the PAX5 gene was replaced by the partner gene. The PAX5 fusion products bound to PAX5 recognition sequences as strongly as wild-type PAX5 and suppressed its transcriptional activity in a dominant-negative fashion. In human B cell leukemia cells, binding of wild-type PAX5 to a regulatory region of BLK, one of the direct downstream target genes of PAX5, was diminished by expression of the PAX5-fusion protein, leading to repression of BLK. Expression of PAX5-fusion genes in murine bone marrow cells blocked development of mature B cells. PAX5-fusion proteins may contribute to leukemogenesis by blocking differentiation of hematopoietic cells into mature B cells. SNP-chip is a powerful tool to identify fusion genes in human cancers.