# US 8,288,091 B2 · Transcription infidelity, detection and uses thereof

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- Number: US 8,288,091 B2
- Document ID: US8288091B2
- Status: Granted
- Kind: B2
- Application number: 12/374,431
- Filed: 2007-07-20
- Published: 2009-12-24
- Granted: 2012-10-16
- Earliest claimed: 2006-07-20
- Assignees: Transmedi SA
- Inventors: Bernard Bihain
- Web page: https://patentgrep.com/patent/US8288091B2

## CPC

- C12Q 1/68: involving nucleic acids
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12Q 1/6827: for detection of mutation or polymorphism
- C12Q 2600/158: Expression markers
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to the identification of a novel mechanism of transcription infidelity in cells. The invention provides compositions and methods to detect the level of transcript ion infidelity in a sample, as well as the use thereof, e.g., for therapeutic, diagnostic, pharmacogenomic or drug design. As will be disclosed, the invention is particularly suited for detecting, monitoring or treating proliferative cell disorders, for the design and/or screening of drugs, for patient or disease profiling, prediction of disease severity and evaluation of drug efficacy.

## Claims

### Claim 1

A method to diagnose the presence of a cancer in a subject, the method comprising the following steps:
(a) detecting in vitro or ex vivo the presence or rate of transcription infidelity in a sample from said subject, wherein said transcription infidelity introduces sequence variations into an RNA primary transcript during transcription of DNA to RNA, and
(b) diagnosing the presence of cancer in said subject, said presence or rate of transcription infidelity is an indication of the presence of a cancer in said subject.

### Claim 2 (depends on 1)

The method of claim 1, wherein transcription infidelity is detected using at least one ligand specific for a transcription infidelity site of a protein or nucleic acid.

### Claim 3 (depends on 1)

The method of claim 1, wherein transcription infidelity is detected by hybridization of the nucleic acid in the sample with a nucleic acid probe specific for a transcription infidelity domain.

### Claim 4 (depends on 3)

The method of claim 3, wherein the transcription infidelity domain comprises at least one modification encoded by a nucleic acid alteration according to the following rules:
A is substituted when A is preceded or followed by C,
T is substituted when T is preceded or followed by G,
C is substituted when C is preceded or followed by G or A, and
G is substituted when G is preceded or followed by A.

### Claim 5 (depends on 1)

The method of claim 1, wherein transcription infidelity is detected by amplification of the nucleic acid in the sample with a nucleic acid primer specific for a transcription infidelity domain.

### Claim 6 (depends on 5)

The method of claim 5, wherein the transcription infidelity domain comprises at least one modification encoded by a nucleic acid alteration according to the following rules:
A is substituted when A is preceded or followed by C,
T is substituted when T is preceded or followed by G,
C is substituted when C is preceded or followed by G or A, and
G is substituted when G is preceded or followed by A.

### Claim 7 (depends on 1)

The method of claim 1, wherein transcription infidelity is detected in a nucleic acid encoding a cell surface protein or a secreted protein.

### Claim 8 (depends on 7)

The method of claim 7, wherein the nucleic acid encodes a plasma protein or a receptor.

### Claim 9 (depends on 1)

The method of claim 1, which comprises detecting in vitro or ex vivo the presence or rate of one or more sequence variations in nucleotide molecules in a sample from said subject, said variation(s) being selected from nucleotide base deletions, insertions or base family changes.

### Claim 10 (depends on 9)

The method of claim 9, wherein the base family change(s) is/are selected from A→C, T→G, G→T, A→T, A→U, G→C, G→U, T→A, C→A, or C→G.

### Claim 11 (depends on 10)

The method of claim 10, wherein the base family change(s) is A→C.

### Claim 12 (depends on 10)

The method of claim 10, wherein the base family change(s) is T→G.

### Claim 13 (depends on 1)

The method of claim 1, wherein the cancer is breast cancer or colon cancer.

### Claim 14 (depends on 1)

The method of claim 1, wherein said transcription infidelity does not arise from a post-transcriptional base change in a mRNA molecule.

### Claim 15 (depends on 1)

The method of claim 1, which comprises detecting in vitro or ex vivo the presence or rate of:
a) one or more sequence variations in nucleotide molecules in a sample from said subject, said variation(s) being selected from A→C or T→G nucleotide base changes; and/or
b) one or more protein modifications resulting from sequence variations of step a);
wherein said sequence variations are introduced into the RNA primary transcript during transcription of DNA to RNA by transcription infidelity (TI) and said presence or rate of sequence variations and/or protein modifications is an indication of the presence of a cancer in said subject.