WO2013037118A1 - Biomarqueurs du cancer de la prostate, cibles thérapeutiques et leurs utilisations - Google Patents

Biomarqueurs du cancer de la prostate, cibles thérapeutiques et leurs utilisations Download PDF

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WO2013037118A1
WO2013037118A1 PCT/CN2011/079709 CN2011079709W WO2013037118A1 WO 2013037118 A1 WO2013037118 A1 WO 2013037118A1 CN 2011079709 W CN2011079709 W CN 2011079709W WO 2013037118 A1 WO2013037118 A1 WO 2013037118A1
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prostate cancer
gene
primers
fusion
long
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PCT/CN2011/079709
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English (en)
Chinese (zh)
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孙颖浩
彭智宇
任善成
易康
毛建华
张纪斌
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上海长海医院
深圳华大基因科技有限公司
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Priority to PCT/CN2011/079709 priority Critical patent/WO2013037118A1/fr
Priority to CN201180073445.7A priority patent/CN103797120B/zh
Publication of WO2013037118A1 publication Critical patent/WO2013037118A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57434—Specifically defined cancers of prostate

Definitions

  • the invention relates to the field of cancer, in particular prostate cancer.
  • the present invention relates to the use of next generation sequencing techniques to find biomarkers for the diagnosis, prognosis and prediction of therapeutic response and pharmaceutical targets for the effective treatment of prostate cancer, particularly biomarkers for prostate cancer.
  • the RNA-Seq technique which is a transcriptome sequencing technique for analyzing the transcriptome of prostate cancer tissues and adjacent normal tissues, reveals a complete transcriptional map of prostate cancer in Chinese. Background technique
  • prostate cancer In developed countries, prostate cancer remains the highest incidence of cancer, and it ranks second among male cancer-related deaths. The incidence of prostate cancer is increasing worldwide, but the incidence varies widely among countries and races. The highest incidence is in Western countries, such as the United States; the lowest incidence is in East Asian countries, such as China, and this difference may be partly due to genetic differences between different ethnic groups.
  • prostate cancer is a heterogeneous disease. Each tumor varies greatly in tumor evolution and biological behavior (such as tumor dormancy, local growth, distant spread, response to treatment, and recurrence). Therefore, patients with histopathologic staging and Gleason scores with the same treatment regimen may have very different clinical outcomes and tumor progression history. In some patients, the tumor is dormant and confined to the prostate. It can survive for more than 10 years, while other patients die from distant metastasis of the tumor 2-3 years after diagnosis. Evidence suggests that the heterogeneity of clinical behavior of prostate cancer is caused by differences in its underlying molecular mechanisms during tumor progression.
  • NGS Next Generation Sequencing
  • NGS data can analyze genomes from multiple perspectives, such as mutations, transcription, structural variation, and post-transcriptional regulation (such as methylation).
  • mutations such as mutations, transcription, structural variation, and post-transcriptional regulation (such as methylation).
  • post-transcriptional regulation such as methylation
  • RNA-Seq ie, transcriptome sequencing technology
  • USP9Y-TTTY15 CTAGE5-KHDRBS3, RAD50-PDLIM4, and SDK1-AMACR. High frequency fusion genes and dozens of other fusion genes are reported, see Table 1 below.
  • Fusion genes expressed in cancer tissues are highly specific prostate cancer markers, detected by real time PCR in blood and urine, prostate puncture Tissue and postoperative tissues were used to detect the presence of fusion genes by FISH, for early diagnosis, molecular typing and prognosis of patients with prostate cancer, and fusion gene can be used as a target for targeted therapy.
  • long-chain non-coding RNAs were found to be involved in transcriptional regulation.
  • 23 long-chain non-coding RNAs are significantly associated with hundreds of genes in the whole genome, while most other genes are only related to several genes or are not related at all. This suggests that long-chain non-coding RNA may have functions other than transcriptional regulation, such as regulation at the post-transcriptional level.
  • almost all long-chain non-coding RNAs are positively correlated with gene expression, suggesting that these long-chain non-coding RNAs may promote gene expression.
  • long-chain non-coding RNA was selected four long-chain non-coding RNAs (two known: DD3 and MALAT1; two new findings: FR257520 and FR348383), and qRT-PCR in both groups. Their expression levels were examined in prostate specimens. The first group was 40 pairs of prostate cancer tissues and their matched adjacent normal tissues, and the second group was 15 normal human prostate tissues and 15 prostate cancer tissues. There is a strong correlation between qRT-PCR and RNA-seq results. Consistent with the RNA-Seq results, PCA3, MALAT1 and FR348383 were overexpressed in most prostate cancer specimens, while FR257520 expression was decreased. The results of PCA3 overexpression were similar to those previously thought to be new diagnostic markers, but we first found that MALAT1, FR257520, and FR348383 were significantly different in prostate cancer from normal prostate.
  • Prostate cancer mutation spectrum We found an average of 1725 point mutations in prostate cancer tissue. However, only a small fraction (on average 1.5%) is located in the coding region of the gene. Interestingly, some point mutations are located in long-chain non-coding RNA. The vast majority of mutations (91.7%) are mutations from T:A to C:G. A reasonable solution to this finding is that this point mutation occurs during RNA editing, and RNA editing changes the adenosine nucleoside to the hypoxanthine nucleoside, which is read as a guanosine nucleoside when translated. This results in a change in a particular RNA nucleotide.
  • RNA-Seq mutations were 96.7% (cDNA level) and 90% (genome level), respectively.
  • DNA is extracted from prostate puncture tissue or post-operative tissue, and PCR is performed to send sequencing to detect the presence of SNPs and point mutations. It is used for molecular prophylaxis and drug treatment targets of prostate cancer patients to judge the prognosis of patients.
  • the 194 mutations of the 183 genes provided by the present invention are shown in Table 3, wherein the preferred 30 gene mutations are shown in Table 8. Table 3. Prostate cancer-specific gene mutations
  • AS Alternative splicing
  • CDK11B 984 chrl 1637645-1637775 1633563-1633726 1633563-1633699
  • TRPT1 83707 chrl l 63748591-63748765 63748843-63749018 63748849-63749018
  • Figure 1 Flow chart of systemic tumor transcriptome analysis.
  • Figure 2 Schematic diagram of the fusion gene.
  • Figure 2c is a schematic diagram of the CTAGE5-khdrbs3 fusion gene, the 23rd exon of ctage5 is fused to the 8th exon of khdrbs3;
  • Figure 2d is a schematic diagram of the Tmprss2-erg fusion gene, the first exon of Tmprss2 and ERG The fourth exon is fused together;
  • Figure 2e shows the frequency of occurrence of the five fusion genes.
  • FIG. 3a Schematic diagram of the fusion gene.
  • Fig. 3a is a fusion diagram of USP9Y-TTTY15, and the third exon of USP9Y is fused together with the fourth exon of TTTY15;
  • Fig. 3b is the result of RT-PCR of USP9Y-TTTY15.
  • Figure 4 Schematic diagram of the fusion gene.
  • Figure 4a RAD50-PDLIM4 fusion gene RT-PCR and Sanger sequencing results;
  • Figure 4b is the results of the SDK1-AMACR fusion gene RT-PCR and Sanger sequencing.
  • Figure 5c shows differential expression of long-chain non-coding RNA DD3 MALAT1 FR0257520 FR0348383 in 40 pairs of cancer and adjacent tissues;
  • Figure 5d is long-chain non-coding RNA: DD3, MALAT1, FR0257520 and FR0348383 in prostate cancer and benign prostatic hyperplasia The difference in expression.
  • the invention provides a biological marker for prostate cancer, comprising the fusion gene shown in Table 1, the long-chain non-coding RNA shown in Table 2, the gene mutation shown in Table 3, and the mutation shown in Table 4. One or more of selective shearing.
  • the biological marker of the present invention can further be used as an early diagnostic marker for prostate cancer, a drug treatment effectiveness judgment marker or a patient prognosis marker.
  • the fusion gene comprises one or more of the 83 fusion genes of Table 6, preferably including 35 underlined in Table 6.
  • One or more of the fusion genes are particularly preferred.
  • the fusion gene comprises one or more of USP9Y-TTTY15, CTAGE5-KHDRBS3, RAD50-PDLIM4, and SDK1-AMACR, preferably a fusion gene USP9Y-TTTY15, CTAGE5-KHDRBS3, RAD50-PDLIM4, and SDK1-AMACR were amplified using the primers described in Table 5.
  • the long-chain non-coding RNA comprises one or more of DD3, MALAT1, FR0257520, FR0348383, preferably the long-chain non-coding RNA : DD3, MALAT1, FR0257520, FR0348383 were amplified using the primers described in Table 7.
  • the gene mutation comprises one or more of 30 gene mutations as shown in Table 8, preferably 30 genes shown in Table 8. Mutations were amplified using the primers described in Table 9.
  • the selective cleavage comprises PSA or AMACR, preferably selectively cleavage of PSA or AMACR using the primers described in Table 10 for amplification.
  • Another aspect of the present invention provides the use of the biological marker as a target for diagnosing prostate cancer or a drug for treating prostate cancer, in particular as an early diagnostic marker for prostate cancer, and for judging the effectiveness of drug treatment Use of markers or patient prognostic markers.
  • the invention further provides a primer for amplifying the biological marker or a probe of the biological marker for use in preparing a reagent for diagnosing prostate cancer.
  • the primer can be used to specifically amplify the biological marker, the probe specifically binding to the biological marker, thereby indicating the The presence of biological markers.
  • a primer for amplifying the biological marker wherein the primer preferably comprises the primer described in Table 5 for the fusion gene USP9Y-TTTY15, CTAGE5-KHDRBS3 , RAD50-PDLIM4, SDK1-AMACR; primers shown in Table 7, which were used to amplify long-chain non-coding RNAs: DD3, MALAT1, FR0257520, FR0348383; primers shown in Table 9, which were used to amplify Table 8. The 30 gene mutations shown; the primers shown in Table 10, which were used to amplify the selective shear PSA or AMACR.
  • the use of the primers described in Table 5 for the preparation of a medicament for the diagnosis of prostate cancer is provided.
  • the use of the primers shown in Table 7 for the preparation of a medicament for diagnosing prostate cancer is provided.
  • the use of the primers shown in Table 9 for the preparation of a medicament for diagnosing prostate cancer is provided.
  • RNA-Seq 14 pairs of prostate cancer tissues and adjacent normal tissues for RNA-Seq were taken from Shanghai Changhai Hospital. 54 pairs of samples for gene fusion verification: 23 pairs from Shanghai Changhai Hospital, 17 pairs from Jiangsu Provincial Hospital, and 14 pairs from Zhongshan University Third affiliated Hospital. A group of 40 pairs of prostate cancer and cancer for selective shear, long-chain non-coding RNA validation The adjacent organization was taken from Shanghai Changhai Hospital. Another group of 15 tumor samples and 15 BPH (benign prostatic hyperplasia) samples for long-chain non-coding RNA validation were taken from Jiangsu Provincial Hospital and Shanghai Changhai Hospital. The RNA-Seq protocol and its follow-up trials were approved by three hospital ethics committees. All patients completed written informed consent and authorized us to use their samples.
  • Hepatic tissue and adjacent normal tissues were subjected to HE staining (hematoxylin-eosin staining) and examined by the pathologist of the study to ensure that the selected tissue cancer tissue density exceeded 80%, and there was no cancer in the adjacent normal tissues. organization. All pathological samples were reviewed by another pathologist. If there is an inconsistent conclusion, the two pathologists will jointly discuss to determine the conclusion.
  • Oligomeric deoxythymidine magnetic beads were used to separate poly A mRNA from total RNA.
  • the purified mRNA was fragmented with fragmentation buffer. Using these short fragments as templates, the first fragment of cDN A was synthesized using a random hexamer.
  • the second strand of the cDNA strand was synthesized using buffer, dNTPs, RNase H and DNA polymerase I.
  • the short double-stranded cDNA fragment was purified using QIAQuick PCR extraction kit (vendor) and eluted with EB buffer to repair the end and add "A". The short segments are then connected to the Illumina sequencing adaptors.
  • the DNA of the target fragment size was purified by tapping for PCR amplification.
  • the amplified library was sequenced using Illumina HiSeqTM 2000.
  • the cDNA library was constructed using Illumina's mRNA-Seq 8-Sample Prep Kit (Cat. No.: RS-100-0801). The specific protocol was: Oligo-deoxythymidine magnetic beads for separation and aggregation from total RNA. A mRNA. The purified mRNA was fragmented with a fragmentation buffer. Use these short clips as templates, Random hexamer primers were used to synthesize the first stretch of cDNA strands. The second stretch of cDNA strand was synthesized using buffer, dNTPs, RNase H and DNA polymerase I.
  • Short double-stranded cDNA fragments were purified using QIAQuick PCR extraction kit (Qiagen) and eluted with EB buffer to repair the ends and add "A". The short segments are then attached to the Illumina sequencing adaptors.
  • the DNA of the target fragment size was purified by tapping for PCR amplification.
  • the quality of the cDNA library was determined by using an Agilent 2100 Bioanalyzer Bioanalyzer and a Stepone plus fluorescence quantitative PCR machine (according criteria: PCR amplification product size was 322 ⁇ 20 bp, with a short fragment size of 200 ⁇ 20 bp, library Moore concentration of not less than 1.3nM), using sequenced using Illumina HiSeq TM 2000 amplified library.
  • the images generated by the sequencer are subjected to base calling processing through the accompanying sequencer control software.
  • the original sequence is stored in fastq format. Remove dirty readings before analyzing the data. We use three criteria to remove dirty readings:
  • the readings were located on the human genome and transcriptome.
  • SOAP2 Short Oligonucleotide Analysis Package (SOAP) aligner (SOAP2); Li R, Yu C, Li Y, Lam TW, Yiu SM, et al. (2009) SOAP2: an improved ultrafast tool for short read alignment. Bioinformatics 25 : 1966-1967) Method will be read after finishing The numbers were compared to the genome and transcriptome, respectively. The number of mismatches per reading cannot exceed three.
  • Readings that can be localized to a particular gene are used to calculate expression levels.
  • the level of gene expression is the number of reads per kilobase length from a gene per million reads. The formula is as follows:
  • C is the copy number of the selected gene reading
  • N is the copy number of all read genes
  • L is the total length of the exon of the selected gene.
  • the RPKM method can eliminate the effects of different gene lengths and sequence differences on gene expression calculations. Therefore, RPKM can be directly used to compare gene expression differences between samples.
  • the shorter segment length is not shorter than 8 bp
  • TMPRSS2-ERG was verified by RT-PCR and sequencing. We validated the gene fusion obtained by RNA-Seq at the transcriptional level. We designed gene fusion-specific PCR primers. After PCR and agarose electrophoresis, all RT-PCR amplified fragments (Qiagen QIAquick Gel Extraction kit) were sequenced in parallel with Sanger. In this way, we verified five fusion genes, TMPRSS2-ERG, USP9Y-TTTY15, SDKl-AMACR, CTAGE5-KHDRBS3, RAD50-PDLIM4, among which the other four fusion genes except TMPRSS2-ERG are the inventors. Newly discovered.
  • the four newly discovered fusion genes are:
  • the uppercase letters indicate the sequence of the first gene, and the lowercase letters indicate the sequence of the second gene.
  • the amplification primers for these five fusion genes are shown in Table 5 below.
  • the PCR conditions were: 95 X: 10 seconds; 60*C 30 seconds; 90 seconds; 38-43 cycles.
  • PCR product purification was carried out using PCR purification kit PCR Cleanup Kit 50 -prep (AXYGEN> Cat No. AP-PCR-50, Lot No. KB10101204-G), and the PCR product was subjected to 2% agarose gel electrophoresis using gel recovery.
  • the kit DNA Gel Extraction Kit 50-prep (AXYGEN, Cat No. AP-GX-50, Lot No. KE10101204-G) was subjected to strand recovery.
  • Electrophoresis images with fusion genes are shown in Figure 2d (TMPRSS2-ERG and CTAGE5-KHDRBS3), Figures 3a and b (USP9Y-TTTY15) and Figure 4a (RAD50-PDLIM4), Figure 4b ( SDK1-AMACR).
  • RNA from all samples was first extracted and reverse transcribed into cDNA.
  • the RT-PCR primers were identical to the validation primers described above.
  • the cDNA of the sequenced sample was used as a positive control.
  • Prostate cancer gene fusion map Transcriptome sequencing was first used to detect gene fusion in prostate cancer. Using paired end readings, we found a total of 84 gene fusions. In addition to the well-known TMPRSS2-ERG gene fusion, we found 83 new gene fusions that were not reported in previous studies against whites. 35 new and one previously well-known gene fusions were found only in prostate cancer tissues but not in matched normal tissues (see underlined fusion genes), and fusion genes were expressed in normal tissues adjacent to the cancer (see bold black body). Partly), the specific biological significance is temporarily unknown, and the following four fusion genes are found in cancer and cancer.
  • KLK2 KLK3 chrl9 chrl 9 56072113 56055040 fwd, fwd Gene fusion expressed only in cancer is defined as tumor-specific gene fusion.
  • the number of gene fusions for each cancer tissue sample ranged from 1 to 6 respectively.
  • the 83 new genes were fused as shown in Table 6, and 35 new gene fusions were underlined.
  • USP9Y-TTTY15 located on the Y chromosome. USP9Y encodes a protein similar to a ubiquitin-specific protease, while TTTY15 is a non-coding RNA. The deletion or mutation of the USP9Y gene is associated with male infertility. However, previous studies have not revealed that these two genes are involved in tumorigenesis.
  • long-chain non-coding RNA and genes were used to calculate the correlation coefficient R.
  • qRT-PCR validates long-chain non-coding RNA (we performed qRT-PCR on Applied Biosystems Step One Plus using Power SYBR Green Mastermix reagent. GAPDH primer was used as internal reference. A group of 40 pairs of prostate cancer as described above) The adjacent tissues were taken from Shanghai Changhai Hospital, and the other group was used for 15 tumor samples and 15 BPH samples taken from Jiangsu Provincial Hospital and Shanghai Changhai Hospital for long-chain non-coding RNA verification.
  • PCA3 also known as DD3
  • MALAT1 MALAT1
  • FR0348383 FR0257520 expression decreased (Fig. 5).
  • the results of PCA3 overexpression are similar to those previously thought to be new diagnostic markers, but we first found that the frequency of overexpression of MALAT1 is high in prostate cancer.
  • the invention provides 137 long-chain non-coding RNAs for diagnosis and judgment of patients Prognosis and drug response, as well as therapeutic targets, see Table 2.
  • Example 4. Discovery and validation of single nucleotide polymorphisms and point mutations
  • Table 8 The 30 mutations that have been verified, the rightmost column is the template used for CDNA and DNA, S for success and F for failure.
  • the present invention provides 183 mutations which can be used as diagnostic markers, prognostic judgments, drug efficacy judgments, and therapeutic targets. See Table 3 for details.
  • RT-PCR verified selective splicing.
  • the PCR conditions are: seconds; 60 ⁇ 30 seconds; 72* €90 seconds; 33-36 cycles.
  • two gene primers are as follows:
  • the invention provides tumor-specific selective scission as shown in Table 4, which can be used as a diagnostic marker for blood, urine and tissue, as well as for prognosis and treatment.
  • the marker can also be used as a target for cancer treatment.

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Abstract

L'invention concerne un groupe de biomarqueurs du cancer de la prostate, lesquels comprennent des gènes de fusion, des ARN non codants à chaîne longue, une mutation génique et des complexes d'épissage sélectifs. L'invention concerne également l'utilisation de ces biomarqueurs en tant que réactifs pour le diagnostic du cancer de la prostate ou comme cibles des médicaments utilisés pour le traitement de ce cancer.
PCT/CN2011/079709 2011-09-16 2011-09-16 Biomarqueurs du cancer de la prostate, cibles thérapeutiques et leurs utilisations WO2013037118A1 (fr)

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CN104611336B (zh) * 2015-02-09 2017-06-23 上海长海医院 融合基因ttty15‑usp9y及其作为前列腺癌标志物的应用
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US10760132B2 (en) 2011-09-15 2020-09-01 University of Pittsburgh—of the Commonwealth System of Higher Education Methods for diagnosing prostate cancer and predicting prostate cancer relapse
US10344338B2 (en) 2013-12-30 2019-07-09 University of Pittsburgh—of the Commonwealth System of Higher Education Fusion genes associated with progressive prostate cancer
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CN104805178A (zh) * 2014-05-20 2015-07-29 吴松 Tacc3-fgfr3融合基因序列、其检测方法以及其在检测膀胱癌中的应用
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US11053218B2 (en) 2017-08-23 2021-07-06 Novartis Ag 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
US10414755B2 (en) 2017-08-23 2019-09-17 Novartis Ag 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
US11833142B2 (en) 2018-07-10 2023-12-05 Novartis Ag 3-(5-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof
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