CN109321653B - Probe combination for diagnosing PRCC-MITF translocation kidney cancer and application thereof - Google Patents
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Abstract
The invention discloses a probe combination for diagnosing PRCC-MITF translocation renal cancer and application thereof. A probe combination for diagnosing PRCC-MITF translocation renal cancer is BAC clone probe RP11-867E4 and BAC clone probe RP11-963H 1. Wherein RP11-867E4 is located at one side of PRCC centromere and is marked as fluorescence of any color; RP11-963H1 localized to the telomeric side of MITF and was labeled with a fluorescence different in color from that labeled on the centromeric side of PRCC. The probe is applied to preparation of a diagnostic reagent for the MITF translocation renal cancer. The specificity and the sensitivity of the probe combination diagnosis reach 100 percent.
Description
Technical Field
The invention belongs to the field of application of fluorescent in-situ hybridization probes, and relates to a fluorescent in-situ hybridization (FISH) fusion gene probe combination for diagnosing PRCC-MITF translocation kidney cancer and application thereof in preparation of a PRCC-MITF translocation kidney cancer diagnostic reagent.
Background
The new version of the pathohistological classification of WHO renal tumors in 2016 added one new renal cell carcinoma type: MiT family of translocating renal cell carcinomas. The MiT family is an abbreviation for microphthalmia-associated transcription factor family, members of which include MITF, TFE3, TFEB, and TFEC genes.
The currently discovered MiT family translocating renal cell carcinomas include renal cell carcinomas related to Xp11.2 translocation/TFE 3 gene fusion and renal carcinomas related to t (6; 11) (p 21; q12) translocation/TFEB gene fusion. Tumors translocated by the MITF and TFEC genes have never been reported in the literature worldwide.
The pathogenesis of the MiT family translocation renal cell carcinoma is clear and clear, and the translocation of MiT family member genes (TFE3/TFEB) is a key pathogenic factor: the tumor is related to MiT family member gene translocation with other chromosomes and fusion genes formed by the translocation, TFE3/TFEB fusion protein is highly expressed by promoter transformation, and TFE3/TFEB is used as a transcription factor, and the transcription regulation and control of in vivo multiple gene expression are combined with a specific DNA structure to finally cause diseases. At present, at least 10 different translocation partners and fusion genes have been reported, including ASPL-TFE3, PRCC-TFE3, SFPQ-TFE3, NONO-TFE3, CLTC-TFE3, LUC7L3-TFE3, KHSRP-TFE3, PARP14-TFE3, DVL2-TFE3, RBM10-TFE3 and MALAT1-TFEB, etc., with only a single translocation form present in each tumor.
The MiT family of translocating renal cell carcinomas is a rare type of tumor, with kidney carcinomas translocating from the TFE3 gene accounting for approximately 1.6% to 4% of all renal cell carcinomas, and relatively more rarely, from the TFEB gene. However, the disease is characterized by a low age of onset, accounts for 40% of the renal cell carcinoma in children, and causes an extremely heavy burden on the family and society. Furthermore, there is clear evidence that patients with MiT family of translocating renal cell carcinomas are susceptible to Vascular Endothelial Growth Factor Receptor (VEGFR) or mammalian rapamycin (mTOR) molecule targeted therapies. Another study shows that MET tyrosine kinase is a target gene of ASPL-TFE3 fusion gene and is expected to be a therapeutic target of TFE3 translocation tumor. Therefore, it is very important to accurately diagnose such tumors.
The group of the invention detects the PRCC-MITF fusion gene in a case of morphologically conforming to the characteristics of the translocation renal cell carcinoma of the MiT family by a high-throughput sequencing technology, the fusion gene type is discovered for the first time, no report is found at home and abroad, and the discovery is the first international discovery of the translocation-related renal cell carcinoma of the MITF gene. Since there has been no detection means for this gene translocation, it has been assumed that the conventional renal cell carcinoma associated with MITF gene translocation has been misdiagnosed or missed.
At present, high-throughput sequencing is the only detection means capable of determining unknown translocation sites, but high-throughput sequencing is expensive in cost, long in detection period, scarce in detection platforms, high in requirement on sample quality, not beneficial to popularization and is not the preferred detection means for most patients.
The Fluorescence In Situ Hybridization (FISH) of the chromosome starts from the combination of the traditional cytogenetics and DNA technology, is quick, sensitive and good in specificity, and can detect hidden or tiny chromosome aberration and complex karyotype; and various fluorescent markers can be used for displaying the relative positions and directions of the DNA fragments and the genes, and the spatial positioning is accurate. In addition, the FISH method can be used for retrospective research on paraffin-embedded samples, and greatly reduces the requirements on the research samples. At present, no report is available at home and abroad on a method for detecting a PRCC-MITF fusion gene by Fluorescence In Situ Hybridization (FISH).
Disclosure of Invention
The present invention has been made in view of the above problems, and an object of the present invention is to provide a probe set for diagnosing MITF-translocating renal cancer.
The invention also aims to provide application of the probe combination in preparing a diagnostic reagent for the MITF translocation renal cancer.
It is still another object of the present invention to provide a diagnostic kit comprising the above probe combination.
The purpose of the invention is realized by the following technical scheme:
the team of the invention detects the PRCC-MITF fusion gene in one case of which the morphology accords with the characteristics of the MiT family translocation renal cell carcinoma through a high-throughput sequencing technology, and finds that the gene is formed by fusing PRCC exon 5 and MITF exon 4. The MITF and PRCC gene sequences are from GeneBank, sequence version number grch38.p7, PRCCtranscript _ id ═ XM _005245313.1, MITF transcript _ id ═ NM _198159.2 ".
The invention designs a probe combination for diagnosing PRCC-MITF translocation renal carcinoma aiming at the novel fusion gene of the MiT family translocation renal cell carcinoma.
A probe combination for diagnosing PRCC-MITF translocation renal cancer is BAC clone probe RP11-867E4 and BAC clone probe RP11-963H 1.
The probe combination, wherein, the BAC clone probe RP11-867E4 is positioned at one side of PRCC centromere and is marked as fluorescence of any color; BAC cloning probe RP11-963H1 was located at the telomeric side of MITF and labeled with a fluorescence different from the color of the label at the centromeric side of PRCC.
The probe combination, wherein RP11-867E4 is preferably marked as green fluorescence, and RP11-963H1 is preferably marked as red fluorescence; the fluorescence colors of the labels may be interchanged.
The probe is applied to preparation of a diagnostic reagent for the MITF translocation renal cancer.
A diagnostic kit for an MITF translocation renal cancer comprises the probe combination.
The following is a detailed description of the technical scheme of the invention:
the probe combination adopted by the invention is used for detecting PRCC-MITF fusion gene by using FISH method for the first time at home and abroad, and is a preferable scheme adopted based on analysis of distribution position, size and the like of different BAC clone probe binding sites at the centromere side of PRCC gene and the telomere side of MITF gene on chromosome.
In the invention, the PRCC centromere side BAC cloning probe is RP11-867E4 (fragment length 222kb), the MITF telomere side BAC cloning probe is RP11-963H1 (fragment length 196kb), the fragments are Bacterial Artificial Chromosome (BAC) clones, the positioning of the BAC clones on human chromosome is disclosed, and RP11-867E4 is positioned on chromosome 1 156414562 and 1566363636320, and RP11-963H1 is positioned on chromosome 3 15170790 and 70348243 respectively. The PRCC gene was mapped to chromosome 1, 156737274-156770609. The location of the MITF gene is chromosome 3 69788586-70017488. The connection sequence of the BAC clone probe and the PRCC gene is PRCC, RP11-867E4, chromosome 1 centromere; the connection sequence of the BAC clone probe and the MITF gene is chromosome 3 centromere, MITF, RP11-963H 1.
The BAC clone probe is combined with a sequence at a corresponding position on a chromosome to be marked with fluorescence, and the position of the fragment keeps a certain distance from the PRCC and MITF genes without overlapping (the distance is maximally 134kb and minimally 101kb in the invention), so that the broken rearrangement in the PRCC and MITF genes does not influence the combination of the BAC clone fragment and the corresponding position of the chromosome. In addition, the farthest distance between BAC clone probes at telomere side of MITF gene and at centromere side of PRCC gene is controlled within 1500 kb. Thus, when the PRCC-MITF fusion gene does not exist in the non-MITF translocation kidney cancer, the red and green fluorescence is far away, and the far-away red and green signals can be seen without amplification during observation; when the PRCC-MITF fusion gene exists in the MITF translocation kidney cancer, the red and green fluorescence is relatively close, and a red and green fusion signal (represented as red and green connection or a yellow signal point) appears during observation, so that the MITF translocation kidney cancer is easy to observe.
The 2 BAC cloning probes were selected for several considerations: the sizes of 2 BAC cloning probes are similar, and the method has the following advantages: the fluorescence intensity of each end is kept consistent, so that the phenomenon that one end is too strong and the other end is too weak to influence observation is prevented; in addition, the in situ hybridization conditions can be kept consistent. Secondly, the position of the BAC clone probe keeps a certain distance from the PRCC and MITF genes without overlapping, so that the combination of the BAC clone probe and the corresponding position of the chromosome can not be influenced by the internal fragmentation rearrangement of the PRCC and MITF genes. And thirdly, the farthest distance between BAC clone probes at the telomere side of the MITF gene and the centromere side of the PRCC gene is controlled within 1500kb, when the two genes are fused, a fusion signal (such as red-green connection or yellow signal points) is presented, and when the MITF gene and the PRCC gene are not fused, the two fluorescence colors are far separated and are easy to observe. Otherwise, if the farthest distance between BAC cloning probes at the telomere side of the MITF gene and the centromere side of the PRCC gene is too large, such as more than 1500kb or even larger, two types of fluorescence which are obviously separated are observed no matter whether the two genes are fused, and whether the PRCC-MITF fusion gene exists is difficult to judge.
The invention has the beneficial effects that:
according to the characteristics of the MITF translocation kidney cancer, the invention designs and combines the fluorescence labeling DNA probe combination at the telomere side of the MITF gene and the centromere side of the PRCC gene, carries out in-situ hybridization on the basis of paraffin embedded tissue sections, detects fusion and separates signals, and can greatly improve the accuracy of diagnosing the tumor. Provides basis for diagnosis and typing and molecular targeted therapy. According to the experimental results, the specificity and the sensitivity of the combined diagnosis of the probe reach 100 percent, and the operation object only needs to be carried out on the paraffin-embedded tissue section for only two working days. The probe combination provided by the invention is used for detecting the MITF translocation renal cell carcinoma, is convenient, rapid and reliable, has high success rate, can be used for preparing an MITF translocation renal cell carcinoma diagnostic kit, and provides a new tool for rapid and accurate diagnosis of the MITF translocation renal cell carcinoma.
Drawings
FIG. 1: map of BAC clone probe localization pattern.
FIG. 2: the RT-PCR method detects the fusion gene of the MITF translocation renal carcinoma. Sequencing results show that translocation exists between chromosome 1 and chromosome 3 to form PRCC-MITF fusion gene (PRCC exon 5 is connected with MITF exon 4);
FIG. 3: the PRCC-MITF fusion probe FISH detection result shows that a fusion signal exists in the tumor and is marked as a positive result.
FIG. 4: FISH detection of the control group hyaline cell carcinoma tissue by using a PRCC-MITF3 fusion probe shows that no fusion signal exists in the tissue, and the result is marked as negative result.
FIG. 5: FISH detection of normal tissues by using a PRCC-MITF fusion probe shows that no fusion signal exists in the tissues and is marked as a negative result.
Detailed Description
The invention is further illustrated by the following examples.
The probe described in the examples is a BAC cloning fragment, which may also be called BAC cloning probe.
Example 1: preparation of DNA Probe combination:
2 BAC cloning fragments which can be respectively connected at the telomere side of the MITF gene of the No. 3 chromosome and the centromere side of the PRCC gene of the No. 1 chromosome are selected, the farthest distance between probes at two ends is controlled within 1500kb, certain distance is kept between the BAC cloning fragments, the BAC cloning fragments are not overlapped, and the sizes of the BAC cloning fragments are similar. The cloning fragment came out from the human BAC cloning center of Empiregenomics (http:// www.empiregenomics.com/hellixhq/clonecentral/search/human). PRCC centromere side BAC clone fragment is RP11-867E4 (fragment length 222kb), MITF telomere side BAC clone fragment is RP11-963H1 (fragment length 196kb), these fragments are Bacterial Artificial Chromosome (BAC) clones, the location of which on human chromosome is disclosed, RP11-867E4 locates at No. 1 chromosome 156414562 and 156636320), RP11-963H1 locates at No. 3 chromosome 70151790 and 70348243 respectively. The PRCC gene was mapped to chromosome 1, 156737274-156770609. The location of the MITF gene is chromosome 3 69788586-70017488. The connection sequence of the BAC clone probe and the PRCC gene is PRCC, RP11-867E4, chromosome 1 centromere; the connection sequence of the BAC clone probe and the MITF gene is chromosome 3 centromere, MITF, RP11-963H 1. The positioning structure of the probe assembly is shown in fig. 1. Marking the BAC clone probe at the side of the MITF telomere into red fluorescence, and marking the BAC clone probe at the side of the PRCC centromere into green fluorescence with the BAC clone probe at the side of the MITF telomere; the fluorescence colors of the two end markers can also be interchanged. These methods are well known to those skilled in the art (these services are offered by Empire genomics, USA). The PRCC centromere side BAC clone probe is a green fluorescence signal under a fluorescence microscope and represents the PRCC gene centromere side. The BAC clone probe at the telomere side of the MITF is a red fluorescent signal under a fluorescent microscope and represents the telomere side of the MITF gene. The fluorescence colors of the two end markers can be interchanged. Normally, red and green signals are separated, and when PRCC-MITF gene translocation exists in tumors, fusion signals are observed.
Furthermore, the prepared probe combination can be used for verifying whether the positioning and/or diagnosis effect is reliable in the MITF translocation renal cell carcinoma, the non-MITF translocation renal cell carcinoma and the paraneoplastic normal tissues by adopting a fluorescence in situ hybridization method.
Example 2: fluorescence in situ hybridization process:
1 example of MITF translocation renal cancer was diagnosed by high-throughput sequencing and RT-PCR detection fusion gene results (FIG. 2, the reliability of the experiment was better reflected by the correspondence with the experiment results), and 30 examples of diagnosed renal cell carcinoma in Nanjing general hospital of Legionnaire district were collected as a control group by two experienced pathologists referring to the classification standard of WHO 2016 urinary and male reproductive system.
Wax block 3 μm thick slice, after dewaxing, sequentially placed in 100%, 85%, 70% ethanol for 2min each, then immersed in deionized water in 100 deg.C water bath for 15 min. Placing the tissue slices in pepsin K solution (0.1g pepsin, 40ml 0.01M HCL) at 37 deg.C for 15 min; rinsing with 2 XSSC (sodium chloride, sodium citrate) for 2 times, each for 5min, soaking the slices in 0.1mol/L HCl at room temperature for 10min, rinsing with 2 XSSC for 2 times, each for 5 min; dehydrating with 70%, 85%, and 100% ethanol for 2min, and drying in air; add 10. mu.l of probe mix (1. mu.l each for 2 probes, 2. mu.l each, and 8. mu.l of hybridization buffer containing human Cot1DNA, supplied by Empire genomics at the time of probe purchase) to the tissue area, cover the slide, and seal the edge with rubber; denaturation at 88 ℃ for 6min and then overnight at 37 ℃ In an In Situ hybridization apparatus (GeneAmp In Situ PCR System 1000) (16 h); removing the cover glass, placing the glass slide in 0.4 XSSC (sodium chloride, sodium citrate, 0.3% NP-40) solution, and rinsing at 69 deg.C for 1 min; rinsing with 2 XSSC (sodium chloride, sodium citrate, 0.1% NP-40) solution for 1min, adding 70% ethanol for 3min, and drying at room temperature in dark; mu.l of 4',6-diamidino-2-phenylindole (4',6-diamidino-2-phenylindole DAPI) was added dropwise to the target region, and the result was observed with a fluorescence microscope after mounting the sample on a glass cover.
And (4) judging a result:
normal cells see 2 red signals and 2 green signals. All signals are independent signals (each cell is diploid, so normally two red and two green).
A PRCC-MITF translocated tumor cell can see a pair of red and green fused abnormal signals and 1 red and green wild type signals respectively.
To exclude false positives and false negatives, 100 cells were counted per sample and only when 4 fluorescence signals were present were included in the counted subjects (we would see 4 single signals (two green and two red) for both normal and tumor, except that the red and green signals were separate in normal cells and appeared to be composed of four single signals. The distance between the red and green fluorescence signals is measured as a fusion signal when the signal width is less than one. When the abnormal signal is more than 10%, the abnormal signal is marked as positive. The above results were determined according to the criteria of evaluation conducted by many similar commercial probes on the market, such as the probes of Vysis and Dako.
As a result:
among 31 cases of kidney cancer, 1 case of MITF-translocated kidney cancer, 6 cases of TFE 3-translocated kidney cancer, 4 cases of TFEB-translocated kidney cancer, 10 cases of clear cell carcinoma, and 10 cases of papillary kidney cancer were examined. Results 1 example of the MITF-translocating kidney cancer detected a positive fusion signal, the range of the number of positive cells was 85%, and no fusion signal was detected in all of the other control tumor tissues and the paracancerous normal kidney tissues (fig. 3-5 show representative positive pictures of MITF-translocating kidney cancer, negative pictures of other tumors such as clear cell carcinoma, and negative pictures of normal kidney tissues). The specificity and the sensitivity of detecting the MITF translocation kidney cancer by using the probe are both 100 percent
The number of patients with renal carcinoma with susceptibility to both true yang and all MITF translocation is 100%;
specificity x 100% of the number of non-MITF translocating renal cancer tumor patients;
evaluation:
the number of cloned fragments used in this set of probes is relatively small and the sizes of the cloned fragments are relatively consistent. The design takes into account both the economy and the consistency of the in situ hybridization conditions. In addition, the specificity and sensitivity of the fluorescent in situ hybridization probe in the experiment reach 100%. The diagnosis of the MITF translocation renal cell carcinoma is rapid, reliable and high in success rate by using the FISH technology and the PRCC-MITF double-color fusion fluorescence in-situ hybridization probe, is a new technology for diagnosing the MITF translocation renal cell carcinoma, and is worthy of popularization.
Claims (6)
1. A probe combination for diagnosing PRCC-MITF translocating renal cancer, which is characterized by consisting of a BAC clone probe RP11-867E4 and a BAC clone probe RP11-963H 1; the fragment of BAC clone probe RP11-867E4 is 222kb in length and is positioned on chromosome 1 156414562-156636320, and the fragment of BAC clone probe RP11-963H1 is 196kb in length and is positioned on chromosome 3 70151790-70348243.
2. The probe combination of claim 1, wherein the BAC cloning probe RP11-867E4 is located on the side of the PRCC centromere and labeled as fluorescence of any color; the BAC clone probe RP11-963H1 is positioned at the telomere side of MITF and is marked with fluorescence of different colors from that marked at the centromere side of PRCC.
3. The probe combination of claim 1, wherein the BAC clone probe RP11-867E4 is labeled green fluorescence and the BAC clone probe RP11-963H1 is labeled red fluorescence.
4. The probe combination of claim 1, wherein the BAC clone probe RP11-867E4 is labeled red fluorescence and the BAC clone probe RP11-963H1 is labeled green fluorescence.
5. Use of a combination of probes according to any one of claims 1 to 4 in the preparation of a diagnostic reagent for MITF-translocating renal cancer.
6. A diagnostic kit for MITF-translocating kidney cancer, characterized in that it comprises the probe combination according to any one of claims 1 to 4.
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