PVT1 dependence in cancer with MYC copy-number increase

doi:10.1038/nature13311

. 2014 Aug 7;512(7512):82-6.

doi: 10.1038/nature13311. Epub 2014 Jun 22.

PVT1 dependence in cancer with MYC copy-number increase

Yuen-Yi Tseng¹, Branden S Moriarity², Wuming Gong³, Ryutaro Akiyama⁴, Ashutosh Tiwari⁵, Hiroko Kawakami⁴, Peter Ronning¹, Brian Reuland¹, Kacey Guenther¹, Thomas C Beadnell⁶, Jaclyn Essig¹, George M Otto⁷, M Gerard O'Sullivan⁷, David A Largaespada⁸, Kathryn L Schwertfeger⁹, York Marahrens¹⁰, Yasuhiko Kawakami¹¹, Anindya Bagchi⁸

Affiliations

¹ Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
² 1] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2].
³ 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [3].
⁴ 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Stem Cell Institute, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
⁵ 1] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Center for Bio-Design, Translational Health Science and Technology Institute, Gurgaon 122016, India.
⁶ Department of Laboratory Medicine and Pathology, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
⁷ Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
⁸ 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
⁹ 1] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Department of Laboratory Medicine and Pathology, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [3].
¹⁰ 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2].
¹¹ 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Stem Cell Institute, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [3].

PMID: 25043044
PMCID: PMC4767149
DOI: 10.1038/nature13311

PVT1 dependence in cancer with MYC copy-number increase

Yuen-Yi Tseng et al. Nature. 2014.

. 2014 Aug 7;512(7512):82-6.

doi: 10.1038/nature13311. Epub 2014 Jun 22.

Authors

Affiliations

¹ Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
² 1] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2].
³ 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [3].
⁴ 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Stem Cell Institute, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
⁵ 1] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Center for Bio-Design, Translational Health Science and Technology Institute, Gurgaon 122016, India.
⁶ Department of Laboratory Medicine and Pathology, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
⁷ Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
⁸ 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
⁹ 1] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Department of Laboratory Medicine and Pathology, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [3].
¹⁰ 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2].
¹¹ 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Stem Cell Institute, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [3].

PMID: 25043044
PMCID: PMC4767149
DOI: 10.1038/nature13311

Abstract

'Gain' of supernumerary copies of the 8q24.21 chromosomal region has been shown to be common in many human cancers and is associated with poor prognosis. The well-characterized myelocytomatosis (MYC) oncogene resides in the 8q24.21 region and is consistently co-gained with an adjacent 'gene desert' of approximately 2 megabases that contains the long non-coding RNA gene PVT1, the CCDC26 gene candidate and the GSDMC gene. Whether low copy-number gain of one or more of these genes drives neoplasia is not known. Here we use chromosome engineering in mice to show that a single extra copy of either the Myc gene or the region encompassing Pvt1, Ccdc26 and Gsdmc fails to advance cancer measurably, whereas a single supernumerary segment encompassing all four genes successfully promotes cancer. Gain of PVT1 long non-coding RNA expression was required for high MYC protein levels in 8q24-amplified human cancer cells. PVT1 RNA and MYC protein expression correlated in primary human tumours, and copy number of PVT1 was co-increased in more than 98% of MYC-copy-increase cancers. Ablation of PVT1 from MYC-driven colon cancer line HCT116 diminished its tumorigenic potency. As MYC protein has been refractory to small-molecule inhibition, the dependence of high MYC protein levels on PVT1 long non-coding RNA provides a much needed therapeutic target.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

**Extended Data Figure 1**
Genetic elements shared between human and mouse in the *MYC*–*GSDMC* interval.

**Extended Data Figure 2. Generating the mouse strains**
**a–c**, Chromosome engineering of Hprt-deficient mouse AB2.2 embryonic stem cells was used to develop mouse strains containing an extra copy of *Myc* (*gain(Myc)*) (a), *Pvt1/Ccdc26/Gsdmc* (*gain(Pvt1,Ccdc26,Gsdmc)*) (b) and *Myc/Pvt1/Ccdc26/ Gsdmc* (*gain(Myc,Pvt1,Ccdc26,Gsdmc)*) (c). Gene targeting was performed in AB2.2 with targeting vectors obtained from the Mutagenic Insertion and Chromosome Engineering Resource (MICER) that were modified to facilitate detection of correctly targeted clones by PCR. These electroporated embryonic stem cells were cultured in G418 (G, 180 µg ml⁻¹) or puromycine (P, 3 µg ml⁻¹) for 7–10 days. Correctly targeted clones were identified by PCR analysis. Double-targeted embryonic stem cells were electroporated with the transient Cre-recombinase expression vector pOG231. After subsequent selection of recombinants by using hypoxanthine aminopterin thymidime (H) media for 7 days and then recovery of recombinants by using hypoxanthines and thymidine media for 2 days, the H^RG^RP^R clones containing one mouse chromosome 15 with the targeted region duplication (dp) and the other mouse chromosome 15 with the targeted region deletion (df) were identified. d, Summary of gene targeting of mouse genome at the MycL, MycR and GsdmcR loci. e, FISH analysis of *gain/loss Myc,Pvt1,Ccdc26,Gsdmc* embryonic stem cells with balanced allele for the *Myc/Pvt1/Ccdc26/Gsdmc* region. Metaphase and interphase preparations from the engineered cells were probed with BAC clone specific for chromosome 15 and located outside (RP23-18H8, red) and within (RP24-78D24, green) the engineered region. The alleles containing the deletion and the duplication are marked.

**Extended Data Figure 3. Histopathology of mammary adenocarcinomas and lung metastasis in *gain(Myc,Pvt1, Ccdc26,Gsdmc), MMTVneu*/+ and *gain(Myc,Pvt1,Ccdc26,Gsdmc)* respectively**
a, b, Mammary adenocarcinoma in gain(Myc,Pvt1,Ccdc26,Gsdmc),MMTVneu/+ mice. Representative histopathology of mammary tumours from gain(Myc,Pvt1,Ccdc26,Gsdmc),MMTVneu/+ mice. Image shows a solid, expansile tumour that is invading a small blood vessel (arrow; bar, 1000 µm) (a), and numerous mitotic figures (arrows; bar, 100 µm) (b). c, Summary of histopathology showing early onset of mammary adenocarcinoma in gain(Myc,Pvt1,Ccdc26,Gsdmc),MMTVneu/+ mice compared with *MMTVneu/*+ mice. d, Image of lung metastasis in gain(Myc,Pvt1,Ccdc26,Gsdmc) with spontaneous mammary adenocarcinoma (YYT 528,). e, Histopathology summary of spontaneous, low-penetrance tumour onset in *gain(Myc,Pvt1,Ccdc26,Gsdmc)* mice.

**Extended Data Figure 4. Abnormal oncogenic stress, proliferation and differentiation in *gain(Myc,Pvt1,Ccdc26, Gsdmc)* mammary ducts**
a, b, Western blot analysis of p53 (a) and phospho-Erk1/2 (b) in total protein lysates from mammary glands of indicated genotypes. The relative densities of p53 and p-ERK1/2 were calculated by normalizing against the GAPDH and total ERK1/2 protein levels respectively. c, Immunofluorescence analysis of ERα (green) on sections of mammary ducts. Cell nuclei positive for ERα are presented as the percentage of total epithelial cell nuclei (DAPI, blue). Images shown are representative three mice per genotype. d, Haematoxylin and eosin staining of the mammary ducts from wild type and gain (M,P,C,G) mice showed precocious alveolar-like phenotype in the latter. This aberrant structure is shown at higher magnification in the right row. e, Immunofluorescence co-staining for DAPI (blue), luminal marker K8 (red) and myoepithelial marker K14 (green) in mice. Arrowheads indicate co-expression of K8 and K14. DAPI-stained nuclei in blue. Mean ± s.e.m. for **a–c** (n = 3). *P < 0.05, ***P < 0.001 by two-tailed Student’s t-test; error bars, s.e.m.

**Extended Data Figure 5. Gasdermin expression in mouse mammary tissues**
a, Gsdmc is not expressed in mouse mammary tissue. Semi-quantitative RT–PCR of Gsdmc transcript in mouse colon and mammary tissues. PCR was performed using equal amount of cDNAs derived from colon and mammary tissues, for cycles as indicated. –RT indicates samples treated without reverse transcriptase. β-actin used as a loading control. NC, negative control (water). **b–d**, Representative RT–qPCR analysis of Gsdmc2 (b), Gsdmc3 (c) and Gsdmc4 (d) mRNA in 10-week-old virgin mouse mammary tissues of all genotypes. Mean ± s.e.m. for **b–d** (n = 3); error bars, s.e.m.

**Extended Data Figure 6. PVT1 depletion results into reduction in proliferation in SK-BR-3 and MDA-MB-231 breast cancer cell lines**
**a, b,** Proliferation assay of human breast cancer cell lines SK-BR-3 (a) and MDA-MB-231 (b) growing in three-dimensional culture after the cell lines were transfected with siCtrl, siMYC, siPVT1 and both (siMYC + siPVT1). Transfection efficiency in each cell line was confirmed as mentioned in the text. Mean ± s.e.m. for a and b (n = 3). **P < 0.01, ***P < 0.001 by two-tailed Student’s t-test. c, d, Inhibition of miRNA expression coded by the *PVT1* locus shows no loss of proliferation in SK-BR-3 cells. SK-BR-3 cells transfected with antisense miRNAs were grown in three-dimensional culture as described before. c, Relative expression of individual miRNA in cells treated with its corresponding inhibitor, normalized to the control experiments Each data point represents the mean ± s.e.m. (n = 3, except for miR-1207, where n = 6). d, Percentage of Ki-67 positive cells denotes the proliferation index. Bar graph, mean ±.e.m. (n = 3); error bars, s.e.m.

**Extended Data Figure 7. PVT1 regulates MYC protein level in MDA-MB-231 breast cancer cells**
a, RT–qPCR measurement of MYC (left) and PVT1 (right) RNA levels in MDA-MB-231 cells 48 h after transfection with the indicated siRNAs. b, Reduction in MYC protein in PVT1-depleted MDA-MB-231. Western blot analysis for MYC protein in the total lysates obtained from the MDA-MB-231 cell line transfected with different siRNAs. The relative density for each category was determined by normalizing against the intensity of the GAPDH band. c, Stability assay for MYC protein in MDA-MB-231 cells. Cells were transfected with siCtrl and siPVT1 and then treated with 10 μM cycloheximide for different time points (top panel). The relative density was determined by comparing against the GAPDH level (bottom panel). Mean ± s.e.m. for **a–c** (n = 3). *P < 0.05, **P < 0.01, ***P < 0.001 by two-tailed Student’s t-test. Error bars, s.e.m.

**Extended Data Figure 8. PVT1 and MYC co-localize in the SK-BR-3 nuclei**
a, Specificity of fluorescent-labelled anti-PVT1 RNA probe in SK-BR-3 cells. Fluorescent images of SK-BR-3 cells treated with no probe, sense and anti-sense PVT1 RNA probe. DAPI (blue) stain is shown in the lower panel. **b, c,** Expression and co-localization of MYC and PVT1 in SK-BR-3 nuclei. Representative fluorescent images of SK-BR-3 cells treated with fluorescently labelled anti-MYC antibody (green) and anti-PVT1 RNA (magenta) (b). DAPI indicating cell nuclei is shown in blue. Cells expressing MYC and PVT1 are indicated by red arrows whereas those expressing low levels of MYC and PVT1 are indicated by white arrows. Merge panel represents overlapping images of DAPI, MYC and PVT1 panels. The nuclei with co-localization of MYC and PVT1 are shown by red arrows. c, Quantification of SK-BR-3 nuclei with co-localization of MYC and PVT1 (n = 87).

**Extended Data Figure 9. Incidence *MYC* and *PVT1* co-gain in human cancers**
a, Number of 8q24 gain-associated human cancers showing gain of *MYC* but not *PVT1* (blue), gain of *PVT1* but not *MYC* (orange) and co-gain of *MYC* + *PVT1* (green) in TCGA (left) and Progenetix copy-number database (right). b, Pie chart showing breast cancer samples in TCGA expressing high *HER2* transcript with or without co-gain of *MYC* + *PVT1*. c, The ratio of *MYC* + *PVT1* + *CCDC26* and *MYC* + *PVT1* + *GSDMC* co-amplification among *MYC* + *PVT1* co-gained TCGA samples at different amplification levels (segment mean cutoff). d, The ratio of *MYC* + *PVT1* co-amplification among *MYC*-gained cancers on different segment mean cutoffs. **e, f,** Tissue microarray analysis of PVT1 RNA and MYC protein expression in primary human tumours. Images of 32 primary human tumours showing *in situ* hybridization using digoxigenin-labelled PVT1 probe (purple, top panel) and MYC immunohistochemistry using anti-MYC antibody (brown, bottom panel) (e). f, Specification of multiple organ normal and diseased tissue microarray, single core per case, eight types of tumour (breast, colon, oesophagus, kidney, liver, lung, rectum, stomach) (BC00119).

**Extended Data Figure 10. Generating the Δ*PVT1* HCT116**
a, Schematic representation of CRISPR-mediated deletion of 307 kilobase PVT1 gene in HCT116. Black triangles denote CRISPR specific for upstream of exon 1 and downstream of exon 8 of *PVT1*. PCR primers F1, F2 and R1 are denoted. b, A CRISPR-mediated deletion of *PVT1* (Δ*PVT1*) can be detected by PCR amplicon using primers F1 and R1, whereas the control with *PVT1* locus intact (*PVT1*+) can be screened by using F2 and R1. c, RT–qPCR analysis of *PVT1* transcript in *PVT1*+ and Δ*PVT1* HCT116 cells (n = 3). d, Relative cellular proliferation abilities of *PVT1*+ and Δ*PVT1* HCT116 cells were evaluated by MTS assays. Data are mean ± s.e.m. for c and d (n = 3). *P < 0.05, **P < 0.01, ***P < 0.001 by two-tailed Student’s t-test. Error bars, s.e.m. e, Luciferase-based images of the presence of tumour lesions detected 3–17 days after subcutaneous implantation of *PVT1*+ and Δ*PVT1* HCT116 cells in nude mice.

**Figure 1. Gain of *Myc* promotes tumorigenesis only if downstream sequence is co-gained**
a, Map of an approximately 2 Mb genomic region in 8q24.21 commonly gained in human tumours. Chr., chromosome. **b–d**, Generation of mice containing gain of *Myc* (b), gain of *Pvt1*, *Ccdc26* and *Gsdmc* (c) and gain of *Myc*, *Pvt1*, *Ccdc26*, *Gsdmc* (d). WT, wild type. e, Mammary tumour-free survival analysis of the different genotypes (***P<0.001, log-rank test, compared with *MMTVneu*).

**Figure 2. Pre-cancerous phenotypes in mouse *gain*(*Myc, Pvt1, Ccdc26, Gsdmc)* mammary glands**
**a, b**, Fluorescence images and quantification of γ-H2AX foci (a) and BrdU-incorporation (b) in mammary ducts of indicated genotype (n = 3). c, Wholemount analysis of mammary glands (higher magnification, bottom). Inset, schematic of mammary gland. Branch points were enumerated at a 25-mm² area near the lymph node (n = 3). d, e, Rescue of aberrant proliferation (d), and enhanced lateral branching (e) in the *gain(Myc, Pvt1, Ccdc26, Gsdmc)* mammary ducts by corresponding *loss* allele. M, *Myc; P*, *Pvt1; C*, *Ccdc26; G*, *Gsdmc* (n = 3). Results are shown as mean ± s.e.m. (*P<0.05, **P<0.01, ***P<0.001, two-tailed Student’s t-test). Scale bar on a, b, d, 10 μm; c, e, 1 mm (top), 5 mm (bottom); error bars, s.e.m.

**Figure 3. *Pvt1/PVT1* co-gained with *Myc/MYC* elevates Myc/MYC protein levels**
a, RT–qPCR measurement of *Myc* (left) and *Pvt1* (right) RNA levels in *gain(Myc, Pvt1, Ccdc26, Gsdmc), MMTVneu/*+ mammary tumour cells transfected with indicated siRNAs (n = 3). b, Proportions of primary tumour cells positive for Ki-67 after the indicated siRNA treatments (n = 3). c, RT–qPCR of *Myc* (left) and *Pvt1* (right) transcript levels (n = 3), and d, western blot analysis (top) and quantification (bottom) of Myc protein in mammary tissue (n = 3). GAPDH, Glyceraldehyde 3-phosphate dehydrogenase. **e–h**, Analyses of human breast cancer cell line SK-BR-3. e, RT–qPCR measurement of *MYC* (left) and *PVT1* (right) transcripts in cells 48 h after transfection with the indicated siRNA(s) (n = 3). f, g, Western blot analysis of the MYC protein in SK-BR-3 after siRNA transfection (n = 3) (f), and siRNA transfection and cycloheximide (CHX) treatment for times indicated (n = 3) (g). h, Western blot analysis of MYC(p-T58), MYC(p-S62), MYC, FBW7 and AXIN1 protein levels in SK-BR-3 treated with siRNAs (left). Ratios of T58/total MYC and p-S62/total MYC (right) (n = 3). i, Immunofluorescence staining of MYC (green) and RNA FISH of PVT1 (magenta) showing nuclear co-localization of MYC and PVT1 (white). 4′,6-Diamidino-2-phenylindole (DAPI) is shown in blue. The marked cell in the upper panel is shown in the lower panels in single channels and MYC + PVT1 overlay. j, RT–PCR using PVT1 and GAPDH specific primers of total SK-BR-3 RNA (input), immunoprecipitated using MYC antibody (IP MYC) and IgG (IP IgG). PVT1–RT indicates samples not treated with reverse transcriptase. Results are shown as mean ± s.e.m. (*P<0.05, **P<0.01, ***P<0.001, two-tailed Student’s t-test). Scale bar, 10 μm; error bars, s.e.m.

**Figure 4. PVT1 dependence in MYC-driven tumours**
**a, b**, Proportion of all tumours harbouring gain of *MYC* but not *PVT1* (blue), *PVT1* but not *MYC* (orange) and *MYC* + *PVT1* (green) in the Progenetix (left) and TCGA databases (right) (a) and among different cancer types in the TCGA database (b). c, Tissue microarray analysis showing nuclear expression of PVT1 (dark purple) and MYC (dark brown) in primary human tumours. Lower panels represent × 10 magnification of regions shown by arrow in the upper panel. d, Cartoons showing that stabilized mutant β-catenin (β-cat) upregulates *MYC* transcription through the recruitment of T-cell factor (TCF) in human colorectal cancer line HCT116. e, Schematic of CRISPR-mediated excision of *PVT1* to obtain the Δ*PVT1* allele. DNA sequence of a PCR amplicon containing the junction sequence of the deletion product is shown. f, Images of colonies formed by *PVT1*+ and Δ*PVT1* HCT116 cells in soft agar assay (top). The insets are ×3 magnification of the areas marked in each plate. Quantification of the respective colonies (bottom, n = 3). g, Tumour volume measurements from xenograft transplants of *PVT1*+ and Δ*PVT1* HCT116 cells. Bioluminescent imaging at 3, 7, 10, 13 and 17 days after inoculation (left). Δ*PVT1* HCT116 inoculation at the left flank where the tumour failed to grow is designated by white circle (dashed). Mean tumour volumes are quantified (n = 6) (right). h, Western blot of MYC and GAPDH protein in three *PVT1*+ and Δ*PVT1* HCT116 clones. Quantification of relative MYC protein levels in *PVT1*1 and *PVT1*D HCT116 cells is shown (n = 3). i, Predicted outlook for an 8q24 cancer patient after inhibition of PVT1. Results are shown as mean ± s.e.m. (*P<0.05, **P<0.01, ***P<0.001, two-tailed Student’s t-test). Scale bar, 500 μm (c, top two rows of panels), 50 μm (c, bottom two rows of panels); error bars, s.e.m.

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Expanding the functional role of long noncoding RNAs.
Johnsson P, Morris KV. Johnsson P, et al. Cell Res. 2014 Nov;24(11):1284-5. doi: 10.1038/cr.2014.104. Epub 2014 Aug 8. Cell Res. 2014. PMID: 25104732 Free PMC article.

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References

1. Huppi K, Pitt JJ, Wahlberg BM, Caplen NJ. The 8q24 gene desert: an oasis of non-coding transcriptional activity. Front Genet. 2012;3:69. - PMC - PubMed
1. Haverty PM, Hon LS, Kaminker JS, Chant J, Zhang Z. High-resolution analysis of copy number alterations and associated expression changes in ovarian tumors. BMC Med Genomics. 2009;2:21. - PMC - PubMed
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1. Borg A, Baldetorp B, Ferno M, Olsson H, Sigurdsson H. c-myc amplification is an independent prognostic factor in postmenopausal breast cancer. Int J Cancer. 1992;51:687–691. - PubMed

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[1] Huppi K, Pitt JJ, Wahlberg BM, Caplen NJ. The 8q24 gene desert: an oasis of non-coding transcriptional activity. Front Genet. 2012;3:69. - PMC - PubMed

[2] Huppi K, Pitt JJ, Wahlberg BM, Caplen NJ. The 8q24 gene desert: an oasis of non-coding transcriptional activity. Front Genet. 2012;3:69. - PMC - PubMed

[3] Haverty PM, Hon LS, Kaminker JS, Chant J, Zhang Z. High-resolution analysis of copy number alterations and associated expression changes in ovarian tumors. BMC Med Genomics. 2009;2:21. - PMC - PubMed

[4] Haverty PM, Hon LS, Kaminker JS, Chant J, Zhang Z. High-resolution analysis of copy number alterations and associated expression changes in ovarian tumors. BMC Med Genomics. 2009;2:21. - PMC - PubMed

[5] Guan Y, et al. Amplification of PVT1 contributes to the pathophysiology of ovarian and breast cancer. Clin Cancer Res. 2007;13:5745–5755. - PubMed

[6] Guan Y, et al. Amplification of PVT1 contributes to the pathophysiology of ovarian and breast cancer. Clin Cancer Res. 2007;13:5745–5755. - PubMed

[7] van Duin M, et al. High-resolution array comparative genomic hybridization of chromosome 8q: evaluation of putative progression markers for gastroesophageal junction adenocarcinomas. Cytogenet Genome Res. 2007;118:130–137. - PubMed

[8] van Duin M, et al. High-resolution array comparative genomic hybridization of chromosome 8q: evaluation of putative progression markers for gastroesophageal junction adenocarcinomas. Cytogenet Genome Res. 2007;118:130–137. - PubMed

[9] Borg A, Baldetorp B, Ferno M, Olsson H, Sigurdsson H. c-myc amplification is an independent prognostic factor in postmenopausal breast cancer. Int J Cancer. 1992;51:687–691. - PubMed

[10] Borg A, Baldetorp B, Ferno M, Olsson H, Sigurdsson H. c-myc amplification is an independent prognostic factor in postmenopausal breast cancer. Int J Cancer. 1992;51:687–691. - PubMed

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PVT1 dependence in cancer with MYC copy-number increase

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PVT1 dependence in cancer with MYC copy-number increase

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