WO2013033169A1 - Procédés d'identification de translocations génomiques associées au cancer - Google Patents

Procédés d'identification de translocations génomiques associées au cancer Download PDF

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WO2013033169A1
WO2013033169A1 PCT/US2012/052805 US2012052805W WO2013033169A1 WO 2013033169 A1 WO2013033169 A1 WO 2013033169A1 US 2012052805 W US2012052805 W US 2012052805W WO 2013033169 A1 WO2013033169 A1 WO 2013033169A1
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nci
gene
copy number
translocation
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Hong Liu
Chang Hahn
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Sanofi
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    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2565/00—Nucleic acid analysis characterised by mode or means of detection
    • C12Q2565/50—Detection characterised by immobilisation to a surface
    • C12Q2565/501—Detection characterised by immobilisation to a surface being an array of oligonucleotides
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the invention provides methods for evaluating and detecting translocation mutations in different cancers using SNP array data.
  • Recent high-throughput data platforms also provide opportunities to discover novel fusions.
  • expression data based analysis such as Cancer Outlier Profile Analysis (COPA) (MacDonald and Ghosh 2006) identified novel fusions, including TMPRSS2-ERG and TMPRSS2-ETV1 in prostate cancer (Tomlins, Rhodes et al. 2005).
  • COPA Cancer Outlier Profile Analysis
  • TMPRSS2-ERG TMPRSS2-ERG
  • TMPRSS2-ETV1 in prostate cancer
  • Deep sequencing of cDNA libraries led to the discovery of the EML4-ALK fusion in non- small-cell lung cancer (NSCLC) (Soda, Choi et al. 2007), and integrative analysis of high-throughput long- and short-read
  • transcriptome sequencing identified several gene fusions in prostate cancer cell lines (Maher, Kumar-Sinha et al. 2009). However, since these methods are based on information from RNA transcripts, the fusion identified might be due to alternative splicing, or transcript level re-arrangement. Identifying translocations at the
  • chromosomal level remains a challenging task.
  • Chromosomal translocations by definition, alter genomic sequences, and may generate fusion proteins or dysregulate gene expression. Chromosomal translocations elicit DNA repair processes, which involve mis-repair of double-strand ends. Cloning genomic junctions in various chromosome translocations in leukemia shows that there are deletions, duplications, and insertions at the breakpoints in many translocations (Nickoloff, De Haro et al. 2008). The sizes of deletions and duplications range from a few bp to a few hundred bp. Many fusion genes are also reported to have multiple copies. These will result in copy number variation (CNV) between segments retained in the fusion gene and its neighboring genomic sequences.
  • CNV copy number variation
  • High density SNP arrays are useful tools, not only to study SNP-based genetic linkage, but also to detect DNA CNV across the whole genome.
  • the current Affymetrix SNP array 6.0 contains 1.8 million markers for genetic variation, and has a median inter-marker distance of less than 700 bases.
  • extensive efforts have been dedicated to SNP array profiling on tumor samples and cell lines. For example, the Sanger Institute has profiled over 800 cancer cell lines on the Affymetrix SNP array 6.0.
  • the disclosure provides, herein, a method for diagnosing a patient suspected of having a gene translocation-associated cancer including the step of detecting the presence of a copy number variation (CNV) breakpoint signature in a gene of a subject, wherein the presence of the signature in the gene is indicative of the subject having the gene translocation-associated cancer.
  • the method can also include a step of determining the nucleic acid sequence of the gene containing the copy number variation breakpoint signature to confirm the presence of an associated gene translocation.
  • the method can also include using first or first or second steps described above for diagnosing the subject as having a gene translocation-associated cancer; and administering to the subject a compound that inhibits the activity of the gene or a polypeptide encoded by the gene if said copy number variation (CNV) breakpoint signature or said associated gene translocation is present thereby treating the patient having the gene translocation- associated cancer.
  • CNV copy number variation
  • the disclosure also provides a method for selecting therapy for a patient having a gene translocation-associated cancer, including the steps of determining whether said cancer exhibits a gene having a copy number variation breakpoint signature; and if said cancer exhibits the gene having the copy number variation breakpoint signature, selecting for said patient a therapy that comprises the administration of a compound that inhibits the activity of the gene or a polypeptide encoded by the gene.
  • the method can further include determining the nucleic acid sequence of the gene containing the copy number variation breakpoint signature to confirm the presence of an associated gene translocation.
  • the copy number variation breakpoint signature can be detected using a single nucleotide polymorphism (SNP) array.
  • the gene translocation-associated cancer can include a balanced or an unbalanced translocation.
  • the copy number variation breakpoint signature can include a region of copy number variation within the boundary of the gene; a region of increased copy number flanked by copy number variation breakpoints; or a region of decreased copy number flanked by copy number variation breakpoints.
  • the gene can be an oncogene or a proto- oncogene.
  • the gene can be FYN, MMEL1, RAB8A, VAV2, BRAF, ERBB2, ETV6, FLU, MET, NAE1, NTRK3, PVT1, RAB31, RAB3A, RAB40C, or
  • the gene can be the gene can be ERBB4, FER, AKT3, ERG, ABL2, ALK, BCL2, EFCAB2, EGFR, ETS2, ETV6, ETV7, FGFRIOP, ISY1, NTRK3, PDGFB, PVT1, RABIA, RAB27B, RAB40B, RAB6B, RAB7A, RAF1, RAPGEF1, RUNX1, SET, TAF8, THRB, or TMEM50A.
  • the disclosure also provides an isolated nucleic acid comprising a gene fusion of any of FYN, MMEL1, RAB8A, VAV2, BRAF, ERBB2, ETV6, FLU, MET, NAE1, NTRK3, PVT1, RAB31, RAB3A, RAB40C, or THRB.
  • the disclosure also provides an isolated nucleic acid comprising a gene fusion of any of PVT1, THRB, AKT3, RAB3C, AKAP13, VAV2, ABL2, ERBB4, AKT2, NTRK3, ALK, VAV3, BRAF, KIT, BCL2, EGFR, ERG, ETV6, EWSR1, RET, RUNX1, FER, RAF1, ERBB2, MKRN2,
  • RAB31 relieveRAB5A, RAPGEF1, ETS1, MERTK, KRAS, RAB2A, CRKL, FYN, ABL1, EFCAB2, RAP1A, FLU, RAB40B, ROS1, VAV1, CSF1R, ERBB3, LYN, MYB, RAB28, RAB40C, TETl, FGFR10P2, RAB10, RABIA, RAB30, RRAS2, TET2, USP6, DEK, MET, RALA, RAPIB, SH3D19, TTC23, SRC, TAF8, ECT2, RAB22A, RAB4A, RAB7A, SKIL, TET3, THRA, TPR, ETS2, ETV7, HEXB, RAB18, RAB27A, RAB38, RAB6A, RALB, TMEM50A, CDON, CSDE1, ENTPD5, MYBL1, NAE1, NTRK1, PDGFB, RAB17,
  • the disclosure also provides an isolated nucleic acid comprising a gene fusion of any of ERBB4, FER, AKT3, ERG, ABL2, ALK, BCL2, EFCAB2, EGFR, ETS2, ETV6, ETV7, FGFRIOP, ISY1, NTRK3, PDGFB, PVT1, RABIA, RAB27B, RAB40B, RAB6B, RAB7A, RAF1, RAPGEF1, RUNX1, SET, TAF8, THRB, and TMEM50A.
  • the disclosure also provides a method for detecting the presence of a
  • chromosomal translocation in a tumor sample including the step of detecting the presence of a copy number variation breakpoint signature in a gene, wherein the presence of the signature in the gene is indicative of a chromosomal translocation.
  • the disclosure also provides a method for identifying a gene containing a chromosomal translocation in a tumor sample including the step of detecting the presence of a copy number variant breakpoint signature in a gene, wherein the presence of the copy number variant breakpoint signature in the gene identifies the gene as containing a chromosomal translocation.
  • the disclosure also provides a method for identifying a translocation gene fusion including the step of detecting the presence of a copy number variation breakpoint signature in a gene, wherein the presence of the copy number variant breakpoint signature in the gene identifies the gene as a translocation gene fusion.
  • the disclosure also provides a method for identifying a gene deletion including the step of detecting the presence of a copy number variation breakpoint signature in a gene, wherein the presence of the copy number variant breakpoint signature in the gene identifies the gene as a gene deletion.
  • the disclosure also provides a method for identifying a gene amplification including the step of detecting the presence of a copy number variation breakpoint signature in a gene, wherein the presence of the copy number variant breakpoint signature in the gene identifies the gene as a gene amplification.
  • the gene can be a tumor suppressor gene.
  • the gene can be RUNX3, HRPT2, FH, FHIT, RASSF1A, TGFBR2, VHL, hCDC4, APC, NKX3.1, Pl6 mKM , Pl ⁇ , PTC, TSC1, BMPR1, PTEN, WT1, MEN1, ⁇ 5 ⁇ ⁇ 2 , TIMP3, IGFBP, CDKN2A/pl6 INK4A ,
  • CDKN2B/pl5 INK4B Pl ⁇ , P53, P73, GSTP1, MGMT, CDH1, DAPK, MLH1, THBS1, RB, CASP8, APAF1, or CTMP.
  • Figure 1 depicts genomic level CNV analysis of BCR and ABL1 genes using Affymetrix SNP 6.0 array® data for eight CML cell lines. Copy number states are divided into the following categories: 0 -homozygous deletion; 1 - heterozygous deletion; 2 - normal diploid; 3 - single copy gain; and 4 - multiple copy gain. Arrows highlight both amplified (blue) and deleted (red) genomic segments. The black arrow indicates the direction of the transcript. Affymetrix Genotyping Console software was used for this analysis.
  • Figure 2 depicts an Affymetrix Genotyping Console Browser® view of BCR and ABL1 genes for two non-CML cell lines that possess copy number breakpoints in both BCR and ABL1 genes. Copy number states are divided into the following categories: 0 -homozygous deletion; 1 - heterozygous deletion; 2 - normal diploid; 3 - single copy gain; and 4 - multiple copy gain. Arrows highlight both amplified (blue) and deleted (red) genomic segments. The black arrows indicate the direction of the transcript.
  • Figure 3 depicts an Affymetrix Genotyping Console Browser® view of the segment deletion between TMPRSS2 and ERG in prostate cancer samples. Copy number states are divided into the following categories: 0 -homozygous deletion; 1 - heterozygous deletion; 2 - normal diploid; 3 - single copy gain; and 4 - multiple copy gain. Red arrows demarcate deleted genomic segments, while black arrows designate the directions of the two transcripts.
  • Figure 4 depicts an Affymetrix Genotyping Console Browser® view of EML4 and ALK genes in six lung cancer cell lines that contain copy number breakpoints in both genes. Copy number states are divided into the following categories: 0 - homozygous deletion; 1 - heterozygous deletion; 2 - normal diploid; 3 - single copy gain; and 4 - multiple copy gain. Arrows highlight both amplified (blue) and deleted (red) genomic segments. Black arrows indicate the directions of the transcripts.
  • Figure 5 depicts a boxplot view of the numbers of gene-linked copy number breakpoints in 820 cancer cell lines from different cancer origins. The numbers in brackets indicate the number of cell lines mapped to each cancer type. Cancer types with less than 5 cell lines are not included.
  • Y axis the number of gene-linked copy number breakpoints. Median: bolded line inside the box; 25 percentile: top line of the box; 75 percentile: bottom line of the box; Maximum (excluding outliers): top bar outside of the box; Minimum (excluding outliers): lowest bar outside of the box; Outlier: O Detailed Description of the Invention
  • the invention provides methods for evaluating and detecting translocation mutations in different cancers using SNP array data.
  • the present invention is based, in part, on the discovery that genomic deletion or duplication at the breakpoint/junction site of a gene fusion event or amplification of a fusion gene during tumorigenesis can be detected by high-resolution SNP arrays.
  • the methods of the invention were validated by analyzing three well-known genetic fusions in cancer: BCR-ABL1, TMPRSS2-ERG, and EML4-ALK using high density SNP array data from related patient samples and cancer cell lines.
  • the copy number breakpoint near or at the junction of each fusion gene as examined and two aspects were evaluated: (i) whether a deletion or amplification in copy number could be detected, and (ii) the distance relative to the specific fusion junction.
  • a search tool was developed to identify additional cancer cell lines that contain interesting fusion genes by examining the SNP array data of Sanger's 820 cancer cell lines.
  • the distribution of gene-linked copy number breakpoints in cancer cell lines was also evaluated.
  • breakpoints in the genes FYN, MMEL1, RAB8A, VAV2, BRAF, ERBB2, ETV6, FLU, MET, NAE1, NTRK3, PVT1, RAB31, RAB3A, RAB40C, and THRB are associated with prostate cancer.
  • RABL3, RAP2A, SET and TMED9 are associated with lung cancer.
  • Breakpoints in the genes ERBB4, FER, AKT3, ERG, ABL2, ALK, BCL2, EFCAB2, EGFR, ETS2, ETV6, ETV7, FGFRIOP, ISY1, NTRK3, PDGFB, PVT1, RAB1A, RAB27B, RAB40B, RAB6B, RAB7A, RAF1, RAPGEF1, RUNX1, SET, TAF8, THRB, and TMEM50A are associated with leukemia.
  • transcript start and end positions were retrieved from the hgl8 human genome assembly RefGene table.
  • transcript start position was based on the first transcript start site
  • transcript end position was based on the last transcript end site on the chromosome.
  • chromosomes or on un-assembled segments; (2) genes were on either the X or Y chromosomes; (3) the transcript sequence length was less than 0.
  • 19,642 genes meet the above criteria, and among them, 224 genes were annotated as oncogenes based on Affymetrix "HG-U133_Plus_2.na27.annot.txt" annotation table.
  • the start position for the coding sequences was based on the last start site, and the end position was based on the first end site on the chromosome, provided that the resulting coding sequence length was larger than 0.
  • There are total 17,609 genes in the genome that meet these criteria and 205 genes were annotated as oncogenes.
  • SNP array data were analyzed using Affymetrix Genotyping Console 3.0.2 and Birdseed v2 genotype algorithm. All of the arrays passed quality control requirements, with contrast QC and MAPD values within boundaries. If there were no paired samples, samples were normalized against default Affymetrix normal samples. For the copy number analysis, we used regional GC correction and required 5 markers to be found within the changed region and the size of the region to be at least 100 kb. Genotyping Console Browser (Affymetrix) was used to illustrate copy number changes detected.
  • SNP array data of 38 unique HapMap normal cell lines downloaded from GEO were profiled on the Affymetrix SNP Array 6.0 set.
  • SNP array data of 20 paired prostate tumor samples with matched normal samples were downloaded from GEO (GSE12702), and were profiled on the Affymetrix Mapping 500K Array set. Samples were normalized against the matched normal samples.
  • SNP array data of 25 GIST cancer samples were downloaded from GEO (dataset GSE20709) and were profiled on the Affymetrix SNP Array 6.0 set.
  • Genotyping Console 3.0.2 which contains CNV segment information, including copy number state, chromosome location, start position, and end position. The information was utilized to search for copy number breakpoint in an interested gene.
  • the BCR-ABL gene fusion also referred to as the Philadelphia chromosome or Philadelphia translocation, is the best known chromosomal abnormality resulting from a reciprocal translocation between chromosome 9 and 22.
  • the fusion contains 5 'end sequences from BCR and 3'end sequences from ABL1, which contains the kinase domain.
  • the chimeric BCR-ABL protein has constitutively elevated tyrosine
  • the copy number at its 3 'end is lower than that of its 5 'end, while in ABL1, the copy number at its 3'end is always higher than that of its 5'end, thus favoring presence of BCR-ABL fusion protein.
  • breakpoints were detected in either BCR, ABL1, or in the neighboring regions. For example, in CMLT-1 cells, a copy number breakpoint was found in ABL1, while in KU812 a micro-deletion was found in ABL1.
  • CNV were found in the neighbor genes of BCR in all three cell lines.
  • the copy number breakpoint resides within the transcript of the oncogene in these eight CML cell lines. As shown in Table 1, ABL1 contains copy number breakpoints in six out of the eight CML cell lines. The frequency (75%) is the highest compared to other oncogenes. Table 1. Oncogenes that contain copy number breakpoints in eight CML cell lines.
  • Breakpoint is within the transcript, regardless of the location or whether it was associated with amplification or deletion.
  • NCI-H747 the CNV was consistent with what was observed in the other CML cell lines: namely, the copy number at 3 'end is lower than that of 5' end for BCR, and the copy number at 3' end is higher than that of 5' end for ABLl.
  • the CNV in ABLl is different, with the 3'end (containing the kinase domain) at lower copy number relative to the 5' end. Whether these cell lines contain a functional BCR-ABL fusion is yet to be determined.
  • ERG contains copy number breakpoints in three out of the 20 prostate cancer samples. The frequency (15%) is the highest compared to other oncogenes. Table 2. Oncogenes that contain copy number breakpoints in 20 prostate cancer samples. Breakpoint is within the transcript, regardless of the location or whether it was associated with amplification or deletion.
  • the TMPRSS2-ERG fusion is known to exist in the prostate cell line VCaP (Maher, Kumar-Sinha et al. 2009). However, publicly available SNP array data for this cell line could not be located. Instead, prostate cell lines profiled by Sanger Institute were investigated. Among 820 cancer cell lines, five prostate cancer cell lines are represented: 22RV, BPH-1, DU-145, LNCaP, PC-3. None of these lines possess segmental deletions between TMPRSS2 and ERG, nor is the copy number of ETV1 amplified (data not shown).
  • TMPRSS2-ERG fusion In order to assess whether the TMPRSS2-ERG fusion is unique to prostate cancers, a search was performed to identify other cell line containing segmental deletions between ERG and TMPRSS2. Specifically, a deletion segment was queried for with one end anchored either within TMPRSS2 or between TMPRSS2 and its neighbor RIPK4, and the other end anchored either within the 5' end of ERG or between ERG and its neighbor gene ETS2. This type of deletion has the potential to create a fusion gene that utilizes the promoter of TMPRSS2 and links to the coding of ERG. However, among the 820 cell lines that the Sanger Institute profiled, none contains such deletion. This is suggestive that the TMPRSS2-ERG fusion is restricted to specific subtypes of prostate cancers.
  • EML4-ALK fusion was identified in a NSCLC sample by full-length cDNA cloning. It was also detected in other lung cancers with a frequency of 9.1% (3 out of 33) (Soda, Choi et al. 2007).
  • both EML4 and ALK were examined for potential copy number breakpoints in Sanger's 140 lung cancer cell lines. Among these 140 lung cancer cell lines, six (4%) were found to carry breakpoints for both EML4 and ALK. As shown in Figure 4, most of the copy number breakpoints in EML4 are caused by the amplification of the 5'end of the gene, while breakpoints in ALK are closer to its 3'end.
  • ALK contains copy number breakpoints in 22 out of the 140 lung cancer cell lines. Its frequency (15.7%) is among the highly ranked but the not the highest compared to other oncogenes.
  • PVT1 t(2;8) and t(8;22) in Burkitt lymphoma
  • AKT3 (t(l;13)(q44;q32) in microcephaly and agenesis of the corpus callosum) (Boland, Clayton-Smith et al. 2007), VAV2 (t(l;9)(p36.32;q34.2) in cryptic imbalance) (Gajecka, Glotzbach et al. 2006), ABL2 (t(l;12)(q25;pl3) in AML) (Iijima, Ito et al. 2000), and NTRK3 (t(12; 15)(pl3;q25) in salivary gland tumors and AML) (Skalova, Vanecek et al. 2010) (Eguchi, Eguchi-Ishimae et al. 1999), were reported to be involved in reciprocal translocation.
  • AKT3 34 DV-90_4562#NCI-H596_4344#COR-L279_4273#NCI-H1648_4312#NCI-
  • RAPGEF1 16 DMS-114_4227#NCI-H1563_4211#NCI-H2030_4239#NCI- H2228_3820#NCI-H446_4347#SHP-77_4328#NCI-H2009_3428#NCI- H2291_3688#NCI-H510A_3653#NCI-H524_5003#EKVX_4697#NCI- H 1355_4439#NCI-H 1417_4944#NCI-H 146_4505#NCI- H250_3661#RERF-LC-MS_4233
  • RRAS2 8 LC-lF_4261#NCI-H2342_4234#COLO-668_3773#COR-L23_4214#HT- 29_3963#NCI-H128_3423#NCI-H2227_4338#NCI-H522_3920
  • TET2 8 Calu-6_4277#NCI-H 1770_3420#NCI-H214 l_4957#NCI-H345_4962#Calu- 3_3575#PC-14_4279#NCI-H748_4932#NCI-H82_4355
  • NTRK1 3 NCI-H 1770_3420#NCI-H526_4337#NCI-H 1355_4439
  • RNASEH2A 3 NCI-H 128_3423#NCI-H2107_3667#NCI-H 1618_3689
  • a proto-oncogene can become an oncogene as a consequence of a relatively small modification such as mutations or increased expression. Chromosomal rearragement can lead to the increased gene expression, or the expression of a constitutively active hybrid protein (Croce 2008).
  • AKT2 8 NCI-H 1792_4298#Calu-6_4277#HuH-7_4226#KYSE- gb:AA448167
  • /UG_TITLE HER2 neu receptor ⁇ 3 region, alternatively spliced ⁇ (human, breast cancer cell line, mRNA Partial,
  • /DEF HER2neu receptor ⁇ 3 region, alternatively spliced ⁇ (human, breast cancer cell line, mRNA Partial,
  • /DEF Homo sapiens colony stimulating factor 1 receptor, formerly
  • DKFZp434D0215 (from clone DKFZp434D0215); partial cds
  • liver cancers and mesotheliomas possess medians of greater than 600 genes containing copy number breakpoints.
  • hematopoietic cancers exhibited a median of 70 genes containing copy number breakpoints (Figure 5).
  • BCR-ABL1 breakpoints in both BCR and ABL1 were observed in 5 out of 8 CML cell lines. However, it should be noted that for the other three CML cell lines, breakpoints were present in either BCR, ABL1, or in the neighboring genes. Additional searches identified two non-leukemia cancer cell lines that also contain copy number breakpoints in BCR and ABL1. It will be of interest to confirm whether these two cell lines do contain BCR-ABL1 fusions since BCR-ABL1 has only been reported in leukemias to date.
  • TMPRSS2-ERG For TMPRSS2-ERG, based on the 20 paired prostate patient samples, the SNP array data reveal that some of the fusions are likely results of genomic sequence deletion. As for other Ets family members, such as ETV1, the altered expression may be due to different genetic mutations, such as gene amplification. Alternatively, the frequency of TMPRSS2-ETV1 translocation fusions may be much lower than for TMPRSS2-ERG. In this limited data set, the samples that contain amplified ETV1 and fusion ERG were mutually exclusive, which implies that the over-expression of one of the Ets genes may contribute to initiation or progression of prostate cancer.
  • transcript read-through fusion transcript mechanisms, such as transcript read-through, which can not be captured by SNP array data at the DNA level. This is all the more possible given that TMPRSS2 and ERG are closely located on the same chromosome, and that read-through fusion transcripts were identified in prostate cancer (Maher, Kumar-Sinha et al. 2009).
  • EML4-ALK fusion 6 lung cancer cell lines, and 18 cell lines from other cancer origins with copy number breakpoints were identified. This is in agreement with a report by Lin et al., where a RT-PCR assay was used to examine a panel of 124 cell lines from breast cancer, colorectal cancer, and NSCLC for fusion transcripts of EML4- ALK. With this panel, 9 cell lines, including a known positive control (H2228), were identified to harbor the EML4-ALK fusion. Since the detailed information of the 124 cell lines was not available in the publication, it was not possible to compare them with the copy number analysis. However, based on some of the positive and negative cell lines listed in the paper, nine cell lines that were common could be evaluated. Among them, two cell lines (H2228 and SW1417) are positive, and five cell lines (T47D,
  • CAL120, HCT116, H1299, and H838) are negative supported by both methods.
  • the frequencies of the copy number breakpoint for ABL1 (75%), ERG (15%) and ALK (15.7%) are high in the eight CML cell lines, 20 prostate cancer samples, and 140 lung cancer cell lines, respectively.
  • the frequency for ERG may be underestimated since the SNP array data of the prostate cancer samples were generated from Affymetrix 500K array Set, whose probe coverage is less than one third of the Affymetrix array 6.0 used for the Sanger panel.
  • the frequencies of copy number breakpoint for ABL1 and ERG, respectively were ranked top compared to other oncogenes.
  • the lung cancer cell lines there are several oncogenes whose copy number breakpoint frequencies are higher than that of ALK. Some of them were reported to be involved in reciprocal translocation in other cancers or developmental diseases.
  • Genome- wide copy number breakpoint analysis was also performed in the 820 Sanger cell lines. It had identified genes that contain copy number breakpoints in Sanger cancer cell lines, but not in the 38 Hapmap normal cell lines. The top ten genes that are highly linked with copy number breakpoints only in the cancer cell lines were evaluated (Table 6). The genomic sizes of these genes tend to be very large, which may increase the chance for them to link with a copy number breakpoint. Nevertheless, it is interesting to note that five out of the ten genes: MACROD2 (Stephens, McBride et al. 2009), FHIT (Gemmill, West et al. 1998), CNTNAP2 (Belloso, Bache et al. 2007), MAGI2 (Berger, Lawrence et al. 2011), LRP1B (Moller, Kubart et al. 2008), were reported to be involved in genomic sequence re-arrangement/translocation.
  • CNTNAP 237 ALL-PO_3996#BC-3_4230#CCF-STTG1_3880#D- 2,305 2 392MG_3614#DMS-

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  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

L'invention concerne des procédés pour l'évaluation et la détection de mutations de translocation dans différents cancers, à l'aide de données de matrice SNP et en particulier par détermination des variations de nombre de copies (CNV) dans les gènes qui sont impliqués dans ladite translocation, ou à proximité de ceux-ci.
PCT/US2012/052805 2011-08-31 2012-08-29 Procédés d'identification de translocations génomiques associées au cancer WO2013033169A1 (fr)

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CN106834490A (zh) * 2017-03-02 2017-06-13 上海亿康医学检验所有限公司 一种鉴定胚胎平衡易位断裂点和平衡易位携带状态的方法
CN108866209A (zh) * 2018-08-28 2018-11-23 扬州大学 肝用鹅肥肝重的辅助选择标记及利用分子标记辅助选择方法
CN109082475A (zh) * 2018-08-28 2018-12-25 扬州大学 肝用鹅腹脂重的辅助选择标记及利用分子标记辅助选择方法
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WO2016080750A1 (fr) * 2014-11-18 2016-05-26 사회복지법인 삼성생명공익재단 Panel de gènes permettant la détection d'un mutant dans le génome lié au cancer
WO2016208826A1 (fr) * 2015-06-24 2016-12-29 사회복지법인 삼성생명공익재단 Procédé et dispositif pour analyse de gène
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CN106834490B (zh) * 2017-03-02 2021-01-22 上海亿康医学检验所有限公司 一种鉴定胚胎平衡易位断裂点和平衡易位携带状态的方法
WO2019206341A1 (fr) * 2018-04-28 2019-10-31 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） Lignée de gènes de fusion rab22a-noefs pour le diagnostic et/ou le traitement de l'ostéosarcome, et son application
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KR20200027242A (ko) * 2018-09-04 2020-03-12 재단법인 아산사회복지재단 방사선 피폭 진단용 바이오마커 및 이를 이용한 방법
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