CA2327542A1 - Method and probes for the detection of chromosome aberrations - Google Patents

Method and probes for the detection of chromosome aberrations Download PDF

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Publication number
CA2327542A1
CA2327542A1 CA002327542A CA2327542A CA2327542A1 CA 2327542 A1 CA2327542 A1 CA 2327542A1 CA 002327542 A CA002327542 A CA 002327542A CA 2327542 A CA2327542 A CA 2327542A CA 2327542 A1 CA2327542 A1 CA 2327542A1
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Prior art keywords
nucleic acid
probes
peptide nucleic
acid sequences
hybridisation
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CA002327542A
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French (fr)
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CA2327542C (en
Inventor
Karl-Johan Pluzek
Kirsten Vang Nielsen
Kim Adelhorst
Jacobus Johannus Maria Van Dongen
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Dako Denmark ApS
Original Assignee
Dako A/S
Karl-Johan Pluzek
Kirsten Vang Nielsen
Kim Adelhorst
Jacobus Johannus Maria Van Dongen
Dakocytomation Denmark A/S
Dako Denmark A/S
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Publication of CA2327542A1 publication Critical patent/CA2327542A1/en
Application granted granted Critical
Publication of CA2327542C publication Critical patent/CA2327542C/en
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    • 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
    • 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
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6827—Hybridisation assays for detection of mutation or polymorphism
    • 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
    • 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
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6841—In situ hybridisation
    • 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
    • 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
    • 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

Abstract

A novel method for detecting chromosome aberrations is disclosed. More specifically, chromosome aberrations are detected by in situ hybridisation using at least two sets of hybridisation probes, at least one set comprising one or more peptide nucleic acid probes capable of hybridising to specific nucleic acid sequences related to a potential aberration in a chromosome, and at least one set comprising two or more peptide nucleic acid probes capable of hybridising to specific nucleic acid sequences related to another potential aberration in a chromosome. In particular, the method may be used for detecting chromosome aberrations in the form of breakpoints.

Claims (25)

Method and probes for the detection of chromosome aberrations
1. A method of determining the presence of chromosome aberrations in a sample of eukaryotic origin using in site hybridisation, comprising the steps of a) producing a preparation of the sample, whereby the sample will be subject to a fixation, b) contacting said preparation with a hybridisation solution comprising at least two sets of hybridisation probes, at least one set comprising one or more peptide nucleic acid probes capable of hybridising to specific nucleic acid sequences related to a potential aberration in a chromosome, and at least one set comprising one or more peptide nucleic acid probes capable of hybridising to specific nucleic acid sequences related to another or the same potential aberration in a chromosome, and optionally a hybrid destabilising agent in an amount effective, to decrease the melting temperature of hybrids formed between said nucleic acid sequences and said peptide nucleic acid probes so as to increase the ratio between specific and non-specific binding, c) removing any unbound and any non-specifically bound peptide nucleic acid probe, and d) determining the presence of peptide nucleic acid probe in the preparation.
2. A method according to claim 1, wherein each set of hybridisation probes hybridise to specific nucleic acid sequences related to the same potential chromosome aberration.
3. A method according to claim 1 or 2, wherein the potential aberration is a potential breakpoint.
4. A method according to claim 1, comprising the steps of a) producing a preparation of the sample, whereby the sample will be subject to a fixation, b) contacting said preparation with a hybridisation solution comprising at least two sets of hybridisation probes, at least one set comprising one or more peptide nucleic acid probes capable of hybridising to specific nucleic acid sequences flanking one side of a potential breakpoint in a chromosome, and at least one set comprising one or more peptide nucleic acid probes capable of hybridising to specific nucleic acid sequences flanking ,the other side of the potential breakpoint and optionally a hybrid destabilising agent in an amount effective to decrease the melting temperature of hybrids formed between said nucleic acid sequences and said peptide nucleic acid probes so as to increase the ratio between specific and non-specific binding, c) removing any unbound and any non-specifically bound peptide nucleic acid probe, and d) determining the presence of peptide nucleic acid probe in the preparation.
5. A method according to claim 1, comprising the steps of a) producing a preparation of the sample, whereby the sample will be subject to a fixation, b) contacting said preparation with a hybridisation solution comprising at least two sets of hybridisation probes, one set comprising one or more peptide nucleic acid probes capable of hybridising to specific nucleic acid sequences flanking one side of a potential breakpoint in a chromosome, and one set comprising one or more peptide nucleic acid probes capable of hybridising to specific nucleic acid sequences flanking the other side of the potential breakpoint and optionally a hybrid destabilising agent in an amount effective to decrease the melting temperature of hybrids formed between said nucleic acid sequences and said peptide nucleic acid probes so as to increase the ratio between specific and non-specific binding, c) removing any unbound and any non-specifically bound peptide nucleic acid probe, and d) determining the presence of peptide nucleic acid probe in the preparation.
6. A method according to claim 4 or 5, wherein each set of hybridisation probes hybridise to said specific nucleic acid sequences flanking a potential breakpoint in a chromosome within a genomic distance of no more than 100 kb, preferably no more than 50 kb from the potential breakpoint.
7. A method according to any one of claims 1 to 6 wherein each peptide nucleic acid probe contains from 8 to 40 polymerised moieties.
8. A method according to any one of claims 1 to 7 wherein the peptide nucleic acid probe comprises polymerised moieties of formula (I) wherein Y designates O or S, each X independently designates O or S, each Q independently designates a ligand that is a naturally occurring nucleobase, a non-naturally occurring nucleobase, an intercalator, a nucleobase-binding group, a label or H,, a is an integer from 0, or 1 to 5, p and s independently designate 0 or 1, q and r independently designate 0 or 1, t designates 0 or 1, R1 and R10 independently designate H or C1-4 alkyl, R2, R3, R4, R5, R6, R7, R8 and R9 independently designate H, the side chain of a naturally occurring amino acid, or the side chain of a non-naturally occurring amino acid.
9. A method according to claim 8, wherein Y, X, Q, u, p, q, r, s, R2, R5, R7 and R8 are as defined in claim 8, t is O, R1 designates H or CH3, and each of R3, R4, R6 and R9 designates H.
10. A method according to claim 8, wherein the peptide nucleic acid probe comprises polymerised moieties of formula (II), which are moieties of the general formula (I) wherein r is 0 and q and s are 1, wherein Y, X, Q, p, t, u, R2, R5 and R7 are as defined in claim 7, and R1 and R10 independently designate H or CH3.
11. A method according to claim 8, wherein the peptide nucleic acid probe comprises polymerised moieties of formula (III), which are moieties of the general formula (I) wherein p, r and t are 0, and q and s are 1 6~
wherein Y, X, Q, u, R2, R5 and R7 are as defined in claim 8.
12. A method according to claim 8, wherein the peptide nucleic acid probe comprises polymerised moieties selected among those of formulas (IV)-(VI), which are moieties of the general formula (I) wherein p, r and t are 0, and u, s and q are 1, wherein R2, R5 and R7 are as defined in claim 7, and each Q independently designates a naturally occurring nucleobase, a non-naturally occurring nucleobase, an intercalator or a nucleobase-binding group.
13. A method according to claim 12, wherein R2, R5 and R7 designate H or the side chain of Ala, Asp, Cys, Glu, His, HomoCys, Lys, Orn, Ser or Thr, and Q designates thymine, adenine, cytosine, guanine, uracil or hypoxanthine.
14. A method according to claim 8, wherein the peptide nucleic acid probe comprises polymerised moieties of formula (VII), which are moieties of formula (I) wherein p, r and t are 0, and u, s and q are 1:
wherein Q designates thymine, adenine, cytosine, guanine, uracil or hypoxanthine.
15. A method according to any one of claims 12 to 14, wherein polymerised moieties of formulas (IV)-(VII) constitute at least 75% by weight of the peptide nucleic acid probe.
16. A method according to any one of claims 1 to 15, wherein the hybrid destabilising agent is selected from the group consisting of formamide, urea, guanidine, ethylene glycol, and glycerol.
17. A method according to any one of claims 1 to 16, wherein the concentration of the hybrid destabilising agent is above 10%.
38. A method according to any one of claims 1 to 17 wherein each peptide nucleic acid probe is labelled directly or indirectly with at least one detectable label.
19. A method according to claim 18 wherein the label is selected from the group consisting of enzymes, chromophores, fluorochromes, haptens, dyes and spin labels.
20. A method according to claim 19 wherein the label is selected from the group consisting of fluorescein labels, biotin, digoxigenin, dinitro benzoic acid, peptide labels, rhodamine, R-phycoerythrine and cyanine dyes.
21. A method according to any one of claims 18 to 20 wherein the detectable label of one set of hybridisation probes is different from the detectable label of at least one other set of hybridisation probes.
22. A method according to any one of claims 1 to 21, wherein two sets of hybridisation probes are used.
23. A method according to any one of claims 1 to 21, wherein each set of hybridisation probes comprises from 1 to 500, from 1 to 250, from 1 to 100, or from 1 to 35 peptide nucleic acid probes.
24. A method according to any one of claims 1 to 23, wherein the sample is a tissue section, a cell smear, a cell suspension, or a chromosome spread.
25. A pair of sets of hybridisation probes, one set hybridising to specific nucleic acid sequences related to a potential aberration of a chromosome, and one set hybridising to specific nucleic acid sequences related to another or the same potential aberration of a chromosome, each set comprising one or more peptide nucleic acid probes of formula (I) to (VII).
26. A pair of sets of hybridisation probes according to claim 25, each set capable of hybridising to nucleic acid sequences related to different potential chromosome aberrations.
27. A pair of sets of hybridisation probes according to claim 25 or 26, each set of hybridisation probe hybridising to said specific nucleic acid sequences related to the same potential aberration.
28. A pair of sets of hybridisation probes according to claim 27, each set of probes hybridising to nucleic acid sequences related to a potential breakpoint.
29. A pair of sets of hybridisation probes according to claim 25, one set hybridising to specific nucleic acid sequences flanking one side of a potential breakpoint in a chromosome and another set hybridising to specific nucleic acid sequences flanking the other side of the potential breakpoint and each set comprising one or more peptide nucleic acid probes of formula (I) to (VII).
30. A pair of sets of hybridisation probes according to claim 29, each set hybridising to specific nucleic acid sequences flanking either side of a potential breakpoint in a chromosome within a genomic distance of no more than 100 kb, preferably no more than 50 kb from the potential breakpoint.
31. A pair of sets of hybridisation probes according to
claim 25 to 30 characterised in that each set comprises from 1 to 500, from 1 to 250, from 1 to 100, from 1 to 35 peptide nucleic acid probes.
CA2327542A 1998-05-04 1999-05-04 Method and probes for the detection of chromosome aberrations Expired - Lifetime CA2327542C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DK61598 1998-05-04
DK0615/98 1998-05-04
PCT/DK1999/000245 WO1999057309A1 (en) 1998-05-04 1999-05-04 Method and probes for the detection of chromosome aberrations

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CA2327542A1 true CA2327542A1 (en) 1999-11-11
CA2327542C CA2327542C (en) 2011-11-22

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US (3) US7105294B2 (en)
EP (1) EP1078098A1 (en)
JP (1) JP2002513587A (en)
AU (1) AU3516899A (en)
CA (1) CA2327542C (en)
WO (1) WO1999057309A1 (en)

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US7368245B2 (en) 2008-05-06
US20040043383A1 (en) 2004-03-04
US7105294B2 (en) 2006-09-12
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US7642057B2 (en) 2010-01-05
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US20060160106A1 (en) 2006-07-20
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US20080187934A1 (en) 2008-08-07

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