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Kristin L White,
Robert A Vierkant,
Zachary Fogarty,
Bridget Charbonneau,
Matthew S Block,
Paul D P Pharoah,
Georgia Chenevix-Trench,
Mary Anne Rossing,
Daniel W Cramer,
Leigh Pearce, [......],
Sharon E Johnatty,
Anna Defazio,
Honglin Song,
Jonathan Tyrer,
Thomas A Sellers,
Catherine M Phelan,
Kimberly R Kalli,
Julie M Cunningham,
Brooke L Fridley,
Ellen L Goode
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ABSTRACT: BACKGROUND: Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNPs) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes. METHODS: Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000 observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates. RESULTS: We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined. CONCLUSIONS: These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. Impact: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed.
Cancer Epidemiology Biomarkers & Prevention 03/2013; · 4.12 Impact Factor
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ABSTRACT: PURPOSE: Ovarian cancer has the highest mortality rate of all the gynecologic malignancies and is responsible for ~140,000 deaths annually worldwide. Copy number amplification is frequently associated with activation of oncogenic drivers in this tumor type, but their cytogenetic complexity and heterogeneity has made it difficult to determine which gene(s) within an amplicon represent the genuine oncogenic driver. We sought to identify amplicon targets by conducting a comprehensive functional analysis of genes located in regions of amplification in high-grade serous and endometrioid ovarian tumors. EXPERIMENTAL DESIGN: High-throughput siRNA screening was used to systematically assess all genes within regions commonly amplified in high grade serous and endometrioid cancer. We describe the results from a boutique siRNA screen of 272 genes in a panel of 18 ovarian cell lines. Hits identified by the functional viability screen were further interrogated in primary tumor cohorts to determine the clinical outcomes associated with amplification and gene over expression. RESULTS: We identified a number of genes as critical for cellular viability when amplified, including URI1, PAK4, GAB2 and DYRK1B. Integration of primary tumor gene expression and outcome data provided further evidence for the therapeutic utility of such genes, particularly URI1 and GAB2, which were significantly associated with survival in two independent tumor cohorts. CONCLUSIONS: By taking this integrative approach to target discovery we have streamlined the translation of high-resolution genomic data into pre-clinical in vitro studies, resulting in the identification of a number of genes that may be specifically targeted for the treatment of ovarian tumors.
Clinical Cancer Research 01/2013; · 7.74 Impact Factor
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ABSTRACT: Mutations in RAD51D have been associated with an increased risk of hereditary ovarian cancer and although they have been observed in the context of breast and ovarian cancer families, the association with breast cancer is unclear. The aim of this current study was to validate the reported association of RAD51D with ovarian cancer and assess for an association with breast cancer. We screened for RAD51D mutations in BRCA1/2 mutation-negative index cases from 1,060 familial breast and/or ovarian cancer families (including 741 affected by breast cancer only) and in 245 unselected ovarian cancer cases. Exons containing novel non-synonymous variants were screened in 466 controls. Two overtly deleterious RAD51D mutations were identified among the unselected ovarian cancers cases (0.82%) but none were detected among the 1,060 families. Our data provide additional evidence that RAD51D mutations are enriched among ovarian cancer patients, but are extremely rare among familial breast cancer patients.
PLoS ONE 01/2013; 8(1):e54772. · 4.09 Impact Factor
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ABSTRACT: Mucinous carcinomas represent a distinct morphological subtype which can arise from several organ sites including the ovary, and their genetic characteristics are largely under-described. Exome sequencing of 12 primary mucinous ovarian tumours identified RNF43 as the most frequently somatically mutated novel gene, secondary to KRAS and mutated at an equal frequency with TP53 and BRAF. Further screening of RNF43 in a larger cohort of ovarian tumours identified additional mutations, with a total frequency of 2 of 22 (9%) in mucinous ovarian borderline tumours and 6 of 29 (21%) in mucinous ovarian carcinomas. Seven mutations were predicted to truncate the protein and one missense mutation was predicted to be deleterious by in silico analysis. Six tumours had allelic imbalance at the RNF43 locus with loss of the wildtype allele. The mutation spectrum strongly suggests that RNF43 is an important tumour suppressor gene in mucinous ovarian tumours, similar to its reported role in mucinous pancreatic pre-cancerous cysts. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology 10/2012; · 6.32 Impact Factor
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Florentine S Hilbers,
Juul T Wijnen,
Nicoline Hoogerbrugge,
Jan C Oosterwijk,
Margriet J Collee,
Paolo Peterlongo,
Paolo Radice,
Siranoush Manoukian,
Irene Feroce,
Fabio Capra, [......],
Kenneth Offit,
Sohela Shah, Ian G Campbell,
Ella R Thompson,
Paul A James,
Alison H Trainer,
Javier Gracia,
Javier Benitez,
Christi J van Asperen,
Peter Devilee
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ABSTRACT: Recently, rare germline variants in XRCC2 were detected in non-BRCA1/2 familial breast cancer cases, and a significant association with breast cancer was reported. However, the breast cancer risk associated with these variants needs further evaluation.
The coding regions and exon-intron boundaries of XRCC2 were scanned for mutations in an international cohort of 3548 non-BRCA1/2 familial breast cancer cases and 1435 healthy controls using various mutation scanning methods. Predictions on functional relevance of detected missense variants were obtained from three different prediction algorithms.
The only protein-truncating variant detected was found in a control. Rare non-protein-truncating variants were detected in 20 familial cases (0.6%) and nine healthy controls (0.6%). Although the number of variants predicted to be damaging or neutral differed between prediction algorithms, in all instances these categories were evenly represented among cases and controls.
Our data do not confirm an association between XRCC2 variants and breast cancer risk, although a relative risk smaller than two could not be excluded. Variants in XRCC2 are unlikely to explain a substantial proportion of familial breast cancer.
Journal of Medical Genetics 10/2012; 49(10):618-20. · 6.36 Impact Factor
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Ella R Thompson,
Maria A Doyle,
Georgina L Ryland,
Simone M Rowley,
David Y H Choong,
Richard W Tothill,
Heather Thorne,
Daniel R Barnes,
Jason Li,
Jason Ellul,
Gayle K Philip,
Yoland C Antill,
Paul A James,
Alison H Trainer,
Gillian Mitchell, Ian G Campbell
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ABSTRACT: Despite intensive efforts using linkage and candidate gene approaches, the genetic etiology for the majority of families with a multi-generational breast cancer predisposition is unknown. In this study, we used whole-exome sequencing of thirty-three individuals from 15 breast cancer families to identify potential predisposing genes. Our analysis identified families with heterozygous, deleterious mutations in the DNA repair genes FANCC and BLM, which are responsible for the autosomal recessive disorders Fanconi Anemia and Bloom syndrome. In total, screening of all exons in these genes in 438 breast cancer families identified three with truncating mutations in FANCC and two with truncating mutations in BLM. Additional screening of FANCC mutation hotspot exons identified one pathogenic mutation among an additional 957 breast cancer families. Importantly, none of the deleterious mutations were identified among 464 healthy controls and are not reported in the 1,000 Genomes data. Given the rarity of Fanconi Anemia and Bloom syndrome disorders among Caucasian populations, the finding of multiple deleterious mutations in these critical DNA repair genes among high-risk breast cancer families is intriguing and suggestive of a predisposing role. Our data demonstrate the utility of intra-family exome-sequencing approaches to uncover cancer predisposition genes, but highlight the major challenge of definitively validating candidates where the incidence of sporadic disease is high, germline mutations are not fully penetrant, and individual predisposition genes may only account for a tiny proportion of breast cancer families.
PLoS Genetics 09/2012; 8(9):e1002894. · 8.69 Impact Factor
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ABSTRACT: Introduction: Mucinous tumors are the second most common form of epithelial ovarian tumor, yet the cell of origin for this histologic subtype remains undetermined. Although these tumors are thought to arise through a stepwise progression from benign cystadenoma to borderline tumor to invasive carcinoma, few studies have attempted to comprehensively characterize the genetic changes specific to this subtype or its precursors. Methods: To explore the spectrum of genomic alterations common to mucinous tumors we carried out high-resolution genome-wide copy number analysis, mutation screening by Sanger sequencing and immunohistochemistry on a series of primary ovarian mucinous cystadenomas (n = 20) and borderline tumors (n = 22). RESULTS: Integration of copy number data, targeted mutation screening of RAS/RAF pathway members and immunohistochemistry reveals that p16 loss and RAS/RAF pathway alterations are highly recurrent events that occur early during mucinous tumor development. The frequency of concurrence of these events was observed in 40% of benign cystadenomas and 68% of borderline tumors. CONCLUSIONS: This study is the largest and highest resolution analysis of mucinous benign and borderline tumors carried out to date and provides strong support for these lesions being precursors of primary ovarian mucinous adenocarcinoma. The high level of uniformity in the molecular events underlying the pathogenesis of mucinous ovarian tumors provides an opportunity for treatments targeting specific mutations and pathways. Clin Cancer Res; 18(19); 5267-77. ©2012 AACR.
Clinical Cancer Research 08/2012; 18(19):5267-5277. · 7.74 Impact Factor
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ABSTRACT: KLLN is a p53 target gene with DNA binding function and represents a highly plausible candidate breast cancer predisposition gene. We screened for predisposing variants in 860 high-risk breast cancer families using high resolution melt analysis. A germline c.339_340delAG variant predicted to cause premature termination of the protein after 57 alternative amino acid residues was identified in 3/860 families who tested negative for BRCA1 and BRCA2 mutations and in 1/84 sporadic breast cancer cases. However, the variant was also detected in 2/182 families with known BRCA1 or BRCA2 mutations and in 2/464 non-cancer controls. Furthermore, loss of the mutant allele was detected in 2/2 breast tumors. Our data suggest that pathogenic mutations in KLLN are rare in breast cancer families and the c.339_340delAG variant does not represent a high-penetrance breast cancer risk allele.
Breast Cancer Research and Treatment 05/2012; 134(2):543-7. · 4.43 Impact Factor
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ABSTRACT: Epidemiological studies have shown that Asian populations display a lower incidence of hormone-dependant cancers, cardiovascular
disease, osteoporosis, and menopausal ailments compared to Western societies. Available data support the proposal that lower
incidence is associated with the high dietary consumption of isoflavones, such as genistein. This study used two-dimensional
electrophoresis to characterize the effect of genistein on the proteome of an endometrial tumor cell model, namely the Ishikawa
cell line. Proteome maps displaying approx 1800 proteins were obtained from cells treated with vehicle or genistein at physiologically
attainable concentrations of 0.5, 5, or 50 μM or supra-physiological concentration, 500 μM. The effects of genistein on protein expression were characterized using image analysis software. A total 65 protein spots
displayed a significant decrease in expression and 32 proteins displayed a significant increase in expression. Of these protein
spots, 29 were randomly selected for characterization by matrix assisted laser desorption/ionization tandem mass spectrometry,
yielding 18 different proteins. This type of analysis enabled the characterization of a wide range of cellular proteins and
allowed for the identification of functional and biochemical pathways that may be regulated or affected by genistein, including
cellular transcription, cell proliferation, stress response, or modulation of oncogenic pathways.
Clinical Proteomics 04/2012; 2(3):153-167.
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ABSTRACT: MOTIVATION: In light of the increasing adoption of targeted resequencing (TR) as a cost-effective strategy to identify disease-causing variants, a robust method for copy number variation (CNV) analysis is needed to maximize the value of this promising technology. RESULTS: We present a method for CNV detection for TR data, including whole-exome capture data. Our method calls copy number gains and losses for each target region based on normalized depth of coverage. Our key strategies include the use of base-level log-ratios to remove GC-content bias, correction for an imbalanced library size effect on log-ratios, and the estimation of log-ratio variations via binning and interpolation. Our methods are made available via CONTRA (COpy Number Targeted Resequencing Analysis), a software package that takes standard alignment formats (BAM/SAM) and outputs in variant call format (VCF4.0), for easy integration with other next-generation sequencing analysis packages. We assessed our methods using samples from seven different target enrichment assays, and evaluated our results using simulated data and real germline data with known CNV genotypes.
Bioinformatics 04/2012; 28(10):1307-13. · 5.47 Impact Factor
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ABSTRACT: To compare the prevalence of pulmonary restriction on the basis of a vital capacity (VC) below the lower limit of normal (LLN) and a normal or high forced expiratory volume in 1 second (FEV(1))/VC ratio with the criterion standard of total lung capacity (TLC) less than LLN in individuals with spinal cord injury (SCI) and able-bodied (AB) controls.
Method comparison with criterion standard.
University research center.
Individuals with cervical SCI (n=12; injury level, C5-7) and AB controls (n=12) matched for age, stature, and body mass.
None.
TLC via plethysmography; FEV(1) and VC via spirometry; and maximum inspiratory and expiratory pressures (P(Imax) and P(Emax)).
All participants with SCI exhibited a VC less than LLN and a normal-to-high FEV(1)/VC ratio, whereas significantly fewer (8 of 12) participants with SCI exhibited a TLC less than LLN (P=.046). For the AB group, no participant exhibited a VC or TLC less than LLN. Percent-predicted VC was lower than the percent-predicted TLC in SCI (P=.013), whereas percent-predicted VC was higher than percent-predicted TLC in AB controls (P=.001). Percent-predicted P(Imax) was higher than P(Emax) in SCI (P=.001) but not AB controls (P=.146).
A VC less than LLN with a normal-to-high FEV(1)/VC ratio does not accurately predict pulmonary restriction in cervical SCI. When using spirometry to infer pulmonary restriction in cervical SCI, we recommend using a VC below 60% of the AB predicted value.
Archives of physical medicine and rehabilitation 02/2012; 93(8):1463-5. · 2.18 Impact Factor
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Kathryn M Kinross,
Karen G Montgomery,
Margarete Kleinschmidt,
Paul Waring,
Ivan Ivetac,
Anjali Tikoo,
Mirette Saad,
Lauren Hare,
Vincent Roh,
Theo Mantamadiotis, [......],
Georgina L Ryland, Ian G Campbell,
Kylie L Gorringe,
James G Christensen,
Carleen Cullinane,
Rodney J Hicks,
Richard B Pearson,
Ricky W Johnstone,
Grant A McArthur,
Wayne A Phillips
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ABSTRACT: Mutations in the gene encoding the p110α subunit of PI3K (PIK3CA) that result in enhanced PI3K activity are frequently observed in human cancers. To better understand the role of mutant PIK3CA in the initiation or progression of tumorigenesis, we generated mice in which a PIK3CA mutation commonly detected in human cancers (the H1047R mutation) could be conditionally knocked into the endogenous Pik3ca locus. Activation of this mutation in the mouse ovary revealed that alone, Pik3caH1047R induced premalignant hyperplasia of the ovarian surface epithelium but no tumors. Concomitantly, we analyzed several human ovarian cancers and found PIK3CA mutations coexistent with KRAS and/or PTEN mutations, raising the possibility that a secondary defect in a co-regulator of PI3K activity may be required for mutant PIK3CA to promote transformation. Consistent with this notion, we found that Pik3caH1047R mutation plus Pten deletion in the mouse ovary led to the development of ovarian serous adenocarcinomas and granulosa cell tumors. Both mutational events were required for early, robust Akt activation. Pharmacological inhibition of PI3K/mTOR in these mice delayed tumor growth and prolonged survival. These results demonstrate that the Pik3caH1047R mutation with loss of Pten is enough to promote ovarian cell transformation and that we have developed a model system for studying possible therapies.
The Journal of clinical investigation 01/2012; 122(2):553-7. · 15.39 Impact Factor
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ABSTRACT: MicroRNAs are key regulators of gene expression and have been shown to have altered expression in a variety of cancer types, including epithelial ovarian cancer. MiRNA function is most often achieved through binding to the 3'-untranslated region of the target protein coding gene. Mutation screening using massively-parallel sequencing of 712 miRNA genes in 86 ovarian cancer cases identified only 5 mutated miRNA genes, each in a different case. One mutation was located in the mature miRNA, and three mutations were predicted to alter the secondary structure of the miRNA transcript. Screening of the 3'-untranslated region of 18 candidate cancer genes identified one mutation in each of AKT2, EGFR, ERRB2 and CTNNB1. The functional effect of these mutations is unclear, as expression data available for AKT2 and EGFR showed no increase in gene transcript. Mutations in miRNA genes and 3'-untranslated regions are thus uncommon in ovarian cancer.
PLoS ONE 01/2012; 7(4):e35805. · 4.09 Impact Factor
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Ella R Thompson,
Samantha E Boyle,
Julie Johnson,
Georgina L Ryland,
Sarah Sawyer,
David Y H Choong,
kConFab,
Georgia Chenevix-Trench,
Alison H Trainer,
Geoffrey J Lindeman,
Gillian Mitchell,
Paul A James, Ian G Campbell
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ABSTRACT: There is strong evidence that overtly inactivating mutations in RAD51C predispose to hereditary breast and ovarian cancer but the prevalence of such mutations, and whether they are associated with a particular clinical phenotype, remains unclear. Resolving these questions has important implications for the implementation of RAD51C into routine clinical genetic testing. Consequently, we have performed a large RAD51C mutation screen of hereditary breast and ovarian cancer families, and the first study of unselected patients diagnosed with ovarian cancer. Our data confirm a consistent but low frequency (2/335 families) of inactivating RAD51C mutations among families with a history of both breast and ovarian cancer and an absence of mutations among breast cancer only families (0/1,053 families). Our data also provide support for the designation of the missense variant p.Gly264Ser as a moderate penetrance allele.
Human Mutation 01/2012; 33(1):95-9. · 5.69 Impact Factor
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Sally M Hunter,
Michael S Anglesio,
Raghwa Sharma,
C Blake Gilks,
Nataliya Melnyk,
Yoke-Eng Chiew,
Anna deFazio,
Teri A Longacre,
David G Huntsman,
Kylie L Gorringe, Ian G Campbell
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ABSTRACT: Serous ovarian carcinomas are the predominant epithelial ovarian cancer subtype and it has been widely believed that some or all of these may arise from precursors derived from the ovarian surface epithelium or fimbriae, although direct molecular evidence for this is limited. This study aimed to conduct copy number (CN) analysis using a series of benign and borderline serous ovarian tumors to identify underlying genomic changes that may be indicative of early events in tumorigenesis.
High resolution CN analysis was conducted on DNA from the epithelial and fibroblast components of a cohort of benign (N = 39) and borderline (N = 24) serous tumors using the Affymetrix OncoScan assay and SNP6.0 arrays.
CN aberrations were detected in the epithelium of only 2.9% (1 of 35) of serous cystadenomas and cystadenofibromas. In contrast, CN aberrations were detected in the epithelium of 67% (16 of 24) of the serous borderline tumors (SBT). Unexpectedly, CN aberrations were detected in the fibroblasts of 33% (13 of 39) of the benign serous tumors and in 15% (3 of 20) of the SBTs. Of the 16 cases with CN aberrations in the fibroblasts, 12 of these carried a gain of chromosome 12.
Chromosome 12 trisomy has been previously identified in pure fibromas, supporting the concept that a significant proportion of benign serous tumors are in fact primary fibromas with an associated cystic mass. This is the first high resolution genomic analysis of benign serous ovarian tumors and has shown not only that the majority of benign serous tumors have no genetic evidence of epithelial neoplasia but that a significant proportion may be more accurately classified as primary fibromas.
Clinical Cancer Research 12/2011; 17(23):7273-82. · 7.74 Impact Factor
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ABSTRACT: Ductal carcinoma in situ (DCIS) is a non-obligate precursor to invasive ductal carcinoma (IDC). Annotation of the genetic differences between the two lesions may assist in the identification of genes that promote the invasive phenotype. Synchronous DCIS and IDC cells were microdissected from FFPE tissue and analysed by molecular inversion probe (MIP) copy number arrays. Matched IDC and DCIS showed highly similar copy number profiles (average of 83% of the genome shared) indicating a common clonal origin although there is evidence that the DCIS continues to evolve in parallel with the co-existing IDC. Four chromosomal regions of loss (3q, 6q, 8p and 11q) and four regions of gain (5q, 16p, 19q and 20) were recurrently affected in IDC but not in DCIS. CCND1 and MYC showed increased amplitude of gain in IDC. One region of loss (17p11.2) was specific to DCIS. IDC-specific regions include genes with previous links to breast cancer progression and potential therapeutic targets such as AXL, SPHK1 and PLAUR.
Breast Cancer Research and Treatment 11/2011; 133(3):889-98. · 4.43 Impact Factor
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Ella R. Thompson,
Samantha E. Boyle,
Julie Johnson,
Georgina L. Ryland,
Sarah Sawyer,
David Y.H. Choong,
kConFab,
Georgia Chenevix-Trench,
Alison H. Trainer,
Geoffrey J. Lindeman,
Gillian Mitchell,
Paul A. James, Ian G. Campbell
[show abstract]
[hide abstract]
ABSTRACT: There is strong evidence that overtly inactivating mutations in RAD51C predispose to hereditary breast and ovarian cancer but the prevalence of such mutations, and whether they are associated with a particular clinical phenotype, remains unclear. Resolving these questions has important implications for the implementation of RAD51C into routine clinical genetic testing. Consequently, we have performed a large RAD51C mutation screen of hereditary breast and ovarian cancer families, and the first study of unselected patients diagnosed with ovarian cancer. Our data confirm a consistent but low frequency (2/335 families) of inactivating RAD51C mutations among families with a history of both breast and ovarian cancer and an absence of mutations among breast cancer only families (0/1,053 families). Our data also provide support for the designation of the missense variant p.Gly264Ser as a moderate penetrance allele. Hum Mutat 33:95–99, 2012. © 2011 Wiley Periodicals, Inc.
Human Mutation 11/2011; 33(1):95 - 99. · 5.69 Impact Factor
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Marjan E Askarian-Amiri,
Joanna Crawford,
Juliet D French,
Chanel E Smart,
Martin A Smith,
Michael B Clark,
Kelin Ru,
Tim R Mercer,
Ella R Thompson,
Sunil R Lakhani,
Ana C Vargas, Ian G Campbell,
Melissa A Brown,
Marcel E Dinger,
John S Mattick
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ABSTRACT: Long noncoding RNAs (lncRNAs) are increasingly recognized to play major regulatory roles in development and disease. To identify novel regulators in breast biology, we identified differentially regulated lncRNAs during mouse mammary development. Among the highest and most differentially expressed was a transcript (Zfas1) antisense to the 5' end of the protein-coding gene Znfx1. In vivo, Zfas1 RNA is localized within the ducts and alveoli of the mammary gland. Zfas1 intronically hosts three previously undescribed C/D box snoRNAs (SNORDs): Snord12, Snord12b, and Snord12c. In contrast to the general assumption that noncoding SNORD-host transcripts function only as vehicles to generate snoRNAs, knockdown of Zfas1 in a mammary epithelial cell line resulted in increased cellular proliferation and differentiation, while not substantially altering the levels of the SNORDs. In support of an independent function, we also found that Zfas1 is extremely stable, with a half-life >16 h. Expression analysis of the SNORDs revealed these were expressed at different levels, likely a result of distinct structures conferring differential stability. While there is relatively low primary sequence conservation between Zfas1 and its syntenic human ortholog ZFAS1, their predicted secondary structures have similar features. Like Zfas1, ZFAS1 is highly expressed in the mammary gland and is down-regulated in breast tumors compared to normal tissue. We propose a functional role for Zfas1/ ZFAS1 in the regulation of alveolar development and epithelial cell differentiation in the mammary gland, which, together with its dysregulation in human breast cancer, suggests ZFAS1 as a putative tumor suppressor gene.
RNA 04/2011; 17(5):878-91. · 5.09 Impact Factor
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Paul D P Pharoah,
Rachel T Palmieri,
Susan J Ramus,
Simon A Gayther,
Irene L Andrulis,
Hoda Anton-Culver,
Natalia Antonenkova,
Antonis C Antoniou,
David Goldgar,
Mary S Beattie, [......],
Ignace Vergote,
Robert A Vierkant,
Allison F Vitonis,
Christine Walsh,
Shan Wang-Gohrke,
Barbara Wappenschmidt,
Anna H Wu,
Argyrios Ziogas,
Andrew Berchuck,
Harvey A Risch
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ABSTRACT: An assay for the single-nucleotide polymorphism (SNP), rs61764370, has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3'-UTR miRNA binding site of the KRAS oncogene and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published article, analyzing fewer than 1,000 subjects in total, has examined this association.
Risk association was evaluated in 8,669 cases of invasive EOC and 10,012 controls from 19 studies participating in the Ovarian Cancer Association Consortium, and in 683 cases and 2,044 controls carrying BRCA1 mutations from studies in the Consortium of Investigators of Modifiers of BRCA1/2. Prognosis association was also examined in a subset of five studies with progression-free survival (PFS) data and 18 studies with all-cause mortality data.
No evidence of association was observed between genotype and risk of unselected EOC (OR = 1.02, 95% CI: 0.95-1.10), serous EOC (OR = 1.08, 95% CI: 0.98-1.18), familial EOC (OR = 1.09, 95% CI: 0.78-1.54), or among women carrying deleterious mutations in BRCA1 (OR = 1.09, 95% CI: 0.88-1.36). There was little evidence for association with survival time among unselected cases (HR = 1.10, 95% CI: 0.99-1.22), among serous cases (HR = 1.12, 95% CI = 0.99-1.28), or with PFS in 540 cases treated with carboplatin and paclitaxel (HR = 1.18, 95% CI: 0.93-1.52).
These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer. Use of this SNP for ovarian cancer clinical risk prediction, therefore, seems unwarranted.
Clinical Cancer Research 03/2011; 17(11):3742-50. · 7.74 Impact Factor
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Michael S Anglesio,
Joshy George,
Hagen Kulbe,
Michael Friedlander,
Danny Rischin,
Charlotte Lemech,
Jeremy Power,
Jermaine Coward,
Prue A Cowin,
Colin M House, [......],
Kylie L Gorringe, Ian G Campbell,
Aikou Okamoto,
Michael J Birrer,
David G Huntsman,
Anna de Fazio,
Steve E Kalloger,
Frances Balkwill,
C Blake Gilks,
David D Bowtell
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ABSTRACT: Ovarian clear cell adenocarcinoma (OCCA) is an uncommon histotype that is generally refractory to platinum-based chemotherapy. We analyze here the most comprehensive gene expression and copy number data sets, to date, to identify potential therapeutic targets of OCCA.
Gene expression and DNA copy number were carried out using primary human OCCA tumor samples, and findings were confirmed by immunohistochemistry on tissue microarrays. Circulating interleukin (IL) 6 levels were measured in serum from patients with OCCA or high-grade serous cancers and related to progression-free and overall survival. Two patients were treated with sunitinib, and their therapeutic responses were measured clinically and by positron emission tomography.
We find specific overexpression of the IL6-STAT3-HIF (interleukin 6-signal transducer and activator of transcription 3-hypoxia induced factor) pathway in OCCA tumors compared with high-grade serous cancers. Expression of PTHLH and high levels of circulating IL6 in OCCA patients may explain the frequent occurrence of hypercalcemia of malignancy and thromboembolic events in OCCA. We describe amplification of several receptor tyrosine kinases, most notably MET, suggesting other potential therapeutic targets. We report sustained clinical and functional imaging responses in two OCCA patients with chemotherapy-resistant disease who were treated with sunitinib, thus showing significant parallels with renal clear cell cancer.
Our findings highlight important therapeutic targets in OCCA, suggest that more extensive clinical trials with sunitinib in OCCA are warranted, and provide significant impetus to the growing realization that OCCA is molecularly and clinically distinct to other forms of ovarian cancer.
Clinical Cancer Research 02/2011; 17(8):2538-48. · 7.74 Impact Factor
