CN105018588A - Bi-color FISH method and kit used for screening lung cancer ALK-EML4 fused gene - Google Patents
Bi-color FISH method and kit used for screening lung cancer ALK-EML4 fused gene Download PDFInfo
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Abstract
The invention relates to a FISH detection method for an ALK-EML4 fused gene. The method includes the steps that a lung cancer tissue paraffin section is pretreated conventionally, two sets of bi-color FISH probes are adopted for two-step in-situ hybridization in sequence, and whether ALK gene splitting and ALK-EML4 gene fusing exist or not is judged according to detected fluorescence signals. The FISH detection method for the ALK fused gene related to the lung cancer is designed comprehensively and overcomes the detect that an existing ALK gene FISH diagnosis kit in the market detects ALK gene splitting only and is incapable of judging ALK-EML4 gene fusing. The method is high in specificity and sensitivity, capable of fast, accurately and visually detecting the ALK fused gene related to the lung cancer, and suitable for large-scale utilization and popularization, and detection results are accurate and reliable.
Description
Technical field
The present invention relates to disease related gene detection technique field, concrete, relate to lung cancer correlation fusion technical field of gene detection, refer to a kind of lung cancer correlation fusion gene FISH detection method and correlation detection probe and test kit especially.
Background technology
It is the fastest that lung cancer is that M & M increases, to one of population health and the maximum malignant tumour of life threat.The many countries of immediate and mid-term all report that the M & M of lung cancer all obviously increases, and male lung cancer M & M all accounts for first of all malignant tumours, and women's sickness rate accounts for second, and mortality ratio accounts for second.The cause of disease of lung cancer is still not exclusively clear and definite so far, and great mass of data shows, long-term a large amount of smoking and lung cancer have very close relationship.
According to the growth of lung cancer, infringement and transport velocity and scope and to chemotherapeutics and radiocurable susceptibility, clinically lung cancer is divided into small cell lung cancer (SCLC) and nonsmall-cell lung cancer (NSCLC), the latter accounts for lung cancer morbidity rate about 80%.Only have methods such as rationally applying operation, radiotherapy, chemotherapy, targeted therapy, better inverse amplification factor could be obtained, extend lifetime.
In the past few decades, although scientists constantly explores the method for nonsmall-cell lung cancer (NSCLC) chemotherapy and radiation, but the achievement obtained still can not be satisfactory, the mean survival time of such as Patients with Advanced Lung Cancer is not yet more than 1 year, uncertain therapeutic efficacy is fixed, and some patients there will be some toxic side effecties, as gastrointestinal reactions such as Nausea and vomiting, have impact on quality of life, even therapy discontinued.It is " fighting the enemy 1,000; from damaging 800 " that traditional Cytotoxic Chemical can be compared to, thus many patients are that the look of what is said or talked about becomes to this, and targeted therapy just scientists be devoted to the clinical study achievement differentiating molecular biology difference between cancer cells and normal cell in decades.
So-called targeted therapy, is exactly the selection by gene or molecule, kills malignant cell targetedly, and affect normal cell hardly.The feature of this epoch-making tumor therapy can be summarized as 4 words: " high-efficiency low-toxicity ".On the one hand, targeted therapy substantially increases the curative effect of oncotherapy; On the other hand, targeted therapy reduces patient's side effect in the treatment, improves the quality of living.
Targeted therapy refers on the basis of diagnosis of molecular biology, utilize the difference existed between lung carcinoma cell and normal cell, suppress lung cancer cell growth and propagation targetedly, such as, adopt the methods such as the signal transduction pathway of the blood vessel needed for the growth of antagonism acceptor, Tumor suppression and blocking-up tumor growth to suppress lung cancer cell growth and propagation, thus reach therapeutic purpose.
ALK-EML4 fusion gene is targeted therapy of lung cancer new lover.ALK-EML4 fusion gene is found in kinds of tumors, such as primary cutaneous type, inflammatory myofibroblast knurl, neuroblastoma and nonsmall-cell lung cancer (NSCLC) etc., it is caused by No. 2 the short arm of a chromosome gene fragment transversion (Inversion).The discovery of ALK-EML4, represents the molecular isoform of a kind of NSCLC, and this group patient has unique Clinical symptoms: can not benefit from EGFR-TKI targeted therapy.The wild-type patient accepting EGFR-TKI treatment compares with ALK positive patient, and the latter more easily may produce resistance.The discovery of ALK-EML4 impels lung cancer therapy to step a step near towards the target of " individuation ".Although ALK-EML4 fusion gene only has the positive rate of 4%-10%, in the patient of the ALK-EML4 fusion gene positive, the curative effect of its inhibitor C rizotinib can reach more than 60%.U.S. FDA ratifies rapidly Crizotinib listing, and the patient for the ALK-EML4 fusion gene positive is a Gospel.Due to the positive rate that this gene is lower, so should gene test be carried out before use, only just advise using in the patient of the positive.
ALK gene, a modification lymphom kinase gene, is positioned karyomit(e) 2p23.FISH can detect the chromosome translocation relevant to ALK gene, comprises EML4, TFG and KIF5B and other gene fusion.Abbott Laboratories Vysis ALK bi-color branch is first adjoint diagnostic reagent for the novel subclass of Patients with Non-small-cell Lung from probe reagent box, is applicable to that formalin is fixed, paraffin-embedded Non-Small Cell Lung Carcinoma section sample.The prerequisite of XALKORI (crizotinib) pharmacological agent is selected to be the nonsmall-cell lung cancer that FISH detects the ALK positive.Abbott Laboratories Vysi s ALK bi-color branch obtains U.S. FDA approval from the XALKORI (crizotinib) of probe reagent box and Pfizer simultaneously.In addition, this probe also can be used for an auxiliary diagnosis for modification large celllymphoma.
But, the ALK FISH detection kit (Abbott Laboratories' Vysis ALK bi-color branch is from probe reagent box) of current U.S. FDA approval only can detect the fracture of ALK gene, but whether merge with EML4 after ALK fracture can not be judged, therefore the information being supplied to clinician is comprehensive not, is unfavorable for accurate molecular somatotype and the targeted therapy of lung cancer.
Summary of the invention
Main purpose of the present invention is exactly for above Problems existing and deficiency, provides modification method, probe and test kit that a kind of lung cancer correlation fusion gene FISH detects.This method design thorough, simple to operate, specificity and susceptibility high, can be quick, accurately, measure lung cancer intuitively and to be correlated with ALK-EML4 fusion gene, detected result accurately and reliably, thus can be used as doctor carries out molecule parting reference frame to lung cancer, is applicable to large-scale promotion application.
To achieve these goals, in a first aspect of the present invention, provide a kind of lung cancer correlation fusion gene FISH detection method, be characterized in, conventional pre-treatment is carried out to cancerous lung tissue paraffin section, then adopt two groups of double-color probe successively to carry out in situ hybridization, judge whether to there is described lung cancer correlation fusion gene according to the fluorescent signal detected.Specifically, the double-colored separate probe of the first step ALK gene is hybridized, and determines whether ALK gene ruptures.Second step, selects the sample of ALK gene fracture, carries out second time hybridization check with the double-colored fusion probe of ALK-EML4.Whether fusion gene is defined with EML4 gene after determining ALK fracture.
Preferably, described two groups of double-color probe are the double-colored separate probe of (1) ALK gene, the double-colored fusion probe of (2) ALK-EML4.
More preferably, the double-colored separate probe of (1) ALK gene adopts ALK gene 3 ' to hold probe red fluorescence element mark, and ALK gene 5 ' holds probe green fluorescein mark.(2) the double-colored fusion probe of ALK-EML4 adopts ALK gene red fluorescence element mark, and EML4 gene green fluorescein marks.
In a second aspect of the present invention, provide a kind of two groups of double-color probe for above-mentioned lung cancer correlation fusion gene FISH detection method, be characterized in, two groups of described double-color probe are the double-colored separate probe of (1) ALK gene, the double-colored fusion probe of (2) ALK-EML4.
Preferably, the double-colored separate probe of described (1) ALK gene adopts ALK gene 3 ' to hold probe red fluorescence element mark, and ALK gene 5 ' holds probe green fluorescein mark.(2) the double-colored fusion probe of ALK-EML4 adopts ALK gene red fluorescence element mark, and EML4 gene green fluorescein marks.
In a third aspect of the present invention, provide a kind of lung cancer correlation fusion gene FISH detection kit, it is characterized in that, described two groups of double-color probe are the double-colored separate probe of (1) ALK gene, the double-colored fusion probe of (2) ALK-EML4.
Preferably, two groups of described FISH double-color probe, is characterized in that: the double-colored separate probe of (1) ALK gene adopts ALK gene 3 ' to hold probe red fluorescence element mark, and ALK gene 5 ' holds probe green fluorescein mark.(2) the double-colored fusion probe of ALK-EML4 adopts ALK gene red fluorescence element mark, and EML4 gene green fluorescein marks.
Beneficial effect of the present invention
Be: lung cancer correlation fusion gene FISH detection method of the present invention is by carrying out conventional pre-treatment to cancerous lung tissue paraffin section, then adopt two groups of double-color probe to carry out in situ hybridization, judge whether to there is described lung cancer correlation fusion gene according to the fluorescent signal detected.This law design thorough, simple to operate, specificity and susceptibility high, can be quick, accurately, visually detect lung cancer and to be correlated with ALK-EML4 fusion gene, detected result accurately and reliably, thus can be used as doctor carries out accurate molecular somatotype reference frame to lung cancer, is suitable for large-scale promotion application.
Embodiment
Content for a better understanding of the present invention, is described further below in conjunction with specific embodiment.The main agents that following specific embodiment adopts, instrument and operation steps as follows:
One, the acquisition of DNA probe
1) streak inoculation: will the BAC bacterial classification streak inoculation of ALK gene and EML4 be carried on the agar plate containing microbiotic (paraxin), 37 DEG C of overnight incubation (about 14 hours).
2) initial incubation: the good mono-clonal bacterial classification of picking growth conditions next day, is inoculated in 2ml and contains in the LB liquid nutrient medium of microbiotic (paraxin), put into 37 DEG C of shaking tables, arrange shaking table speed and be about 200rpm, cultivates 6-8 hour.
3) incubated overnight: every 1ml bacterium liquid is transferred to 200ml culture system, is positioned over 37 DEG C of shaking tables, rotating speed 200rpm, overnight incubation (about 14-16 hour).
4) extract test kit operation instructions in a large number according to QIAGEN company plasmid next day and carry out a large amount of Isolation and purification of DNA.
Two, probe mark
1. enzyme cuts DNA:
1) carry out enzyme according to following reaction system to target DNA to cut
| xμl | DNA(lμg) |
| 5μl | 10×HS |
| 0.5μl | 0.1％BSA |
| 0.5μl | EcoR1 |
| (44.5-x)μl | H 2O |
| 50μl |
Hatch 1 hour for 37 DEG C, add ethylenediamine tetraacetic acid (EDTA) (Ethylene Diamine TetraaceticAcid, EDTA) (PH7.5) termination reaction of the 0.5M of 1l, mixing, brief centrifugation.
2) precipitate DNA: the 3M sodium acetate adding 1/10 volume, 2 times of volume 100% ethanol (-20 DEG C), mixing, brief centrifugation, precipitates about 2 hours by-70 DEG C.
3) centrifugal 14000rpm, 4 DEG C, 20 minutes.Abandon supernatant with careful suction of rifle point, add 100ul70% ethanol (4 DEG C), mixing, centrifugal 14000rpm, 4 DEG C, 15 minutes.
4) supernatant is abandoned, drying precipitated 10 minutes with careful suction of rifle point.Shake at least 5 hours continuously on the oscillator after resuspended with the Tris-HCl (PH8.5) of the 10mM of 10l, rotating speed 800, the DNA dissolved is placed on 4 DEG C and preserves until ligation.
2. ligation:
Nick-translation method is adopted to carry out fluorescein-labelled to the DNA that enzyme cuts.
Method is as follows:
Get the EP pipe of lucifuge, first add water, finally add DNase (10ng/1) and DNA polymerase (enzyme be placed on all the time ice chest or on ice) by following reaction system liquid feeding:
Mixing, brief centrifugation, 14 DEG C of overnight incubation (9-12 hour).
Add EDTA (PH7.5) termination reaction of the 0.5M of 5ul next day, mixing, brief centrifugation, the DNA connected is placed on-20 DEG C and keeps in Dark Place.
3. precipitate DNA:
1) DNA probe marked is precipitated: adding deionized water to cumulative volume is 300l, then add the sodium acetate (1/20 cumulative volume) of 3M, then add 100% ethanol (-20 DEG C) mixing, brief centrifugation ,-20 DEG C, precipitates overnight.
2) next day centrifugal 14000rpm, 4 DEG C, 20 minutes.Abandon supernatant with careful suction of rifle point, add 70% ethanol (4 DEG C) of 100ul, mixing, centrifugal 14000rpm, 4 DEG C, 15 minutes.Supernatant is abandoned, drying precipitated 10 minutes of room temperature lucifuge with careful suction of rifle point.
3) add the hybridization buffer of 10ul, shake at least 6 hours continuously on the oscillator, rotating speed 800, the probe dissolved is placed on 4 DEG C and preserves until subsequent experimental.
4) by 3) probe made takes out, puts into 56 DEG C and hatch 1 hour, the centrifugal 14000rpm of room temperature from 4 DEG C, 20 minutes, centrifugal good probe is transferred in a new lucifuge EP pipe, preserves in 4 DEG C, if should-20 DEG C be stored in without probe for a long time.
Three, hybridization
1. cancerous lung tissue paraffin section preprocessor:
1) slide glass to be immersed in 2%3-aminopropyltriethoxywerene werene acetone soln 5 minutes.Rinsing in acetone and distilled water subsequently, seasoning slide glass.
2) fix paraffin-embedded cancerous lung tissue from formalin and obtain polylith 4 micron sections, be placed in above on the slide glass of aminopropyltriethoxywerene werene process respectively.
3) to spend the night at tissue being placed in 65 DEG C baking
4) tissue slice to be immersed in dimethylbenzene room temperature dewaxing 2 times.Each 10 minutes.To immerse subsequently in 100% ethanol 5 minutes.
5) 100% ethanol is placed in by under tissue slice successively room temperature, 85% ethanol, each 2 minutes rehydrations in 70% ethanol.Tissue slice room temperature is immersed deionized water 3 minutes, dry with lint-free paper handkerchief examination.
6) tissue slice 20-30 minute is processed with 30% (w/v) sodium bisulfite (Sodium bisulfite) under 50C.
7) rinsing 2 times in 2XSSC solution under room temperature, each 5 minutes.
8) get 0.4ml Proteinase K storage liquid (20mg/ml) to be dissolved in 40ml2XSSC and to obtain Proteinase K working fluid (200g/m1).Tissue slice to be immersed in Proteinase K working fluid 37 DEG C and hatch 20-30 minute
9) tissue slice is after Proteinase K process, rinsing 2 times in 2XSSC, each 5 minutes.
10) tissue slice is immersed soaking at room temperature 5-10 minute in 0.1MHCL.Rinsing 2 times in 2XSS solution, each 5 minutes.
11) tissue section slide is immersed successively 70%, 85% of-20 DEG C of precoolings, dehydration in each 2 minutes in 100% ethanol.
12) tissue slice room temperature is immersed acetone soln 2 minutes.
13) seasoning slide.
14) slide to 56 DEG C is heated.
2. hybridize:
Slide is put into hybridization instrument, 84-90 DEG C of sex change 5 minutes, 47 DEG C of hybridized overnight.
3. wash:
The slice, thin piece of hybridized overnight is removed cover glass, is placed in the 4 × SSPE of 47 DEG C and washs 5 minutes, wash 10 minutes in the 4 × SSPE of 55 DEG C.
4. dewater (70%, 85%, 2 × 100% ethanol) in graded ethanol, 3 minutes/gradient.
5. put into hexane: Virahol (60: 40) mixed solution 10 minutes, then put into Virahol 5 minutes, finally put into the ethanol 5 minutes of 100%.
6. air drying slice, thin piece adds the DAPI of 8-10l after about 10 minutes, adds cover glass, avoids producing bubble, nail varnish mounting.
7. microscopy:
At fluorescence microscopy Microscopic observation, utilize blue filter to observe green, utilize green filter to observe danger signal, utilize two channels filter to observe the yellow signal of red green fusion.Select clean background, hybridization signal is strong, and the homogeneous zero lap of nucleus size, nuclear boundary is clear, the region Taking Pictures recording that DAPI dyes homogeneous.
8. result judges:
1) the double-colored separate probe of ALK gene: the double-colored separate probe of ALK gene adopts ALK gene 3 ' to hold probe red fluorescence element mark, and ALK gene 5 ' holds probe green fluorescein mark.The lung carcinoma cell of ALK feminine gender can be observed the signal that 2 red greens merge (fusion part presents yellow); And the signal that a red green merges (fusion part presents yellow) can be observed on the lung carcinoma cell of the ALK positive, other 2 redness and green be separated, this result shows that ALK presents breaking state.
2) ALK is presented to the lung cancer sample of breaking state, then carry out the detection of second group of double-colored fusion probe of ALK-EML4.The double-colored fusion probe of ALK-EML4 adopts ALK gene red fluorescence element mark, and EML4 gene green fluorescein marks.The cell of ALK-EML4 fusion gene feminine gender presents 2 redness and green be separated.Gene after ALK gene fracture is described and beyond EML4 gene defines fusion gene.The lung carcinoma cell of the ALK-EML4 fusion gene positive then presents the signal that a red green merges (fusion part presents yellow), with the signal that other 2 red greens are separated, this result after showing ALK gene fracture really and EML4 gene define fusion gene.
In this description, the present invention is own is described with reference to its specific embodiment.But, still can make various amendment and conversion obviously and not deviate from the spirit and scope of the present invention.
Claims (7)
1. a lung cancer correlation fusion gene FISH detection method, it is characterized in that, conventional pre-treatment is carried out to cancerous lung tissue paraffin section, then adopts two groups of double-color probe successively to carry out in situ hybridization, judge whether to there is described lung cancer correlation fusion gene according to the fluorescent signal detected.
2. lung cancer correlation fusion gene FISH detection method according to claim 1, is characterized in that, described two groups of double-color probe are the double-colored separate probe of (1) ALK gene, the double-colored fusion probe of (2) ALK-EML4.
3. lung cancer correlation fusion gene FISH detection method according to claim 2, it is characterized in that: the double-colored separate probe of (1) ALK gene adopts ALK gene 3 ' to hold probe (ALK breakage hot spot 3 ' end) red fluorescence element mark, and ALK gene 5 ' holds probe (ALK breakage hot spot 5 ' end) green fluorescein mark; (2) the double-colored fusion probe of ALK-EML4 adopts ALK gene red fluorescence element mark, and EML4 gene green fluorescein marks.
4. two groups of double-colored FISH probe for lung cancer correlation fusion gene FISH detection method according to claim 1, it is characterized in that, two groups of described double-color probe are the double-colored separate probe of (1) ALK gene, the double-colored fusion probe of (2) ALK-EML4.
5. two groups of FISH double-color probe according to claim 4, is characterized in that: the double-colored separate probe of (1) ALK gene adopts ALK gene 3 ' to hold probe red fluorescence element mark, and ALK gene 5 ' holds probe green fluorescein mark; (2) the double-colored fusion probe of ALK-EML4 adopts ALK gene red fluorescence element mark, and EML4 gene green fluorescein marks.
6. a lung cancer correlation fusion gene FISH detection kit, is characterized in that, two groups of described double-color probe are the double-colored separate probe of (1) ALK gene, the double-colored fusion probe of (2) ALK-EML4.
7. two groups of FISH double-color probe according to claim 6, is characterized in that: the double-colored separate probe of (1) ALK gene adopts ALK gene 3 ' to hold probe red fluorescence element mark, and ALK gene 5 ' holds probe green fluorescein mark; (2) the double-colored fusion probe of ALK-EML4 adopts ALK gene red fluorescence element mark, and EML4 gene green fluorescein marks.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105368962A (en) * | 2015-12-18 | 2016-03-02 | 河南赛诺特生物技术有限公司 | Fluorescence probe for rapid detection of lung cancer ALK gene rearrangement and preparation method |
| CN105803063A (en) * | 2016-04-25 | 2016-07-27 | 苏州达麦迪生物医学科技有限公司 | Marking method of probe for detecting EML4/ALK gene fusion under single channel |
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2014
- 2014-04-29 CN CN201410184329.8A patent/CN105018588A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105368962A (en) * | 2015-12-18 | 2016-03-02 | 河南赛诺特生物技术有限公司 | Fluorescence probe for rapid detection of lung cancer ALK gene rearrangement and preparation method |
| CN105803063A (en) * | 2016-04-25 | 2016-07-27 | 苏州达麦迪生物医学科技有限公司 | Marking method of probe for detecting EML4/ALK gene fusion under single channel |
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