# US 11,306,364 B2 · TERT promoter mutations in gliomas and a subset of tumors

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- Number: US 11,306,364 B2
- Document ID: US11306364B2
- Status: Granted
- Kind: B2
- Application number: 16/928,164
- Filed: 2020-07-14
- Published: 2020-12-24
- Granted: 2022-04-19
- Earliest claimed: 2012-02-18
- Assignees: Duke University; The Johns Hopkins University
- Applicants: Duke University; The Johns Hopkins University
- Inventors: Hai Yan; Bert Vogelstein; Nickolas Papadopoulos; Kenneth W. Kinzler; Yuchen Jiao; Chetan Bettegowda; Darell D. Bigner; Zachary J. Reitman; Patrick J. Killela
- Web page: https://patentgrep.com/patent/US11306364B2

## CPC

- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- C12Q 2600/112: Disease subtyping, staging or classification
- C12Q 2600/156: Polymorphic or mutational 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

## Abstract

We surveyed 1,230 tumors of 60 different types and found that tumors could be divided into types with low (<15%) and high (≥15%) frequencies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas (including 83% of primary glioblastoma, the most common brain tumor type). TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages. In addition to their implications for understanding the relationship between telomeres and tumorigenesis, TERT mutations provide a biomarker for the early detection of urinary tract and liver tumors and aid in the classification and prognostication of brain tumors.

## Claims

### Claim 1

A method of identifying a mutation in a human subject and treating a human subject, comprising:
subjecting a nucleic acid sample obtained from a tumor of the human selected from the group consisting of: glioma, astrocytoma, oligodendroglioma, and oligoastrocytoma, to a reaction whereby reaction products are formed;
detecting in the reaction products from the human tumor a somatic mutation at nucleotide chr5 1,295,250 in hg19; and
administering to the subject with the somatic mutation a therapy selected from the group consisting of chemotherapy, radiotherapy, biological therapy, or surgery.

### Claim 2 (depends on 1)

The method of claim 1, wherein the tumor is a glioma.

### Claim 3 (depends on 1)

The method of claim 1, wherein the tumor is an astrocytoma.

### Claim 4 (depends on 1)

The method of claim 1, wherein the tumor is an oligodendroglioma.

### Claim 5 (depends on 1)

The method of claim 1, wherein the tumor is an oligoastrocytoma.

### Claim 6 (depends on 1)

The method of claim 1, wherein the tumor is a primary glioblastoma.

### Claim 7 (depends on 1)

The method of claim 1, wherein the reaction comprises amplifying the promoter or part of the promoter of a telomerase reverse transcriptase (TERT) gene to form an amplicon.

### Claim 8 (depends on 7)

The method of claim 7, wherein the amplicon is sequenced.

### Claim 9 (depends on 7)

The method of claim 7, wherein the amplicon is hybridized to a mutation specific oligonucleotide.

### Claim 10 (depends on 7)

The method of claim 7, wherein the reaction employs mutation-specific amplification primers.

### Claim 11 (depends on 1)

The method of claim 1, wherein the reaction is a nucleic acid hybridization reaction.

### Claim 12 (depends on 11)

The method of claim 11, wherein the reaction employs a mutation-specific hybridization probe.

### Claim 13 (depends on 1)

The method of claim 1, wherein the reaction is a nucleic acid sequencing reaction.

### Claim 14 (depends on 1)

The method of claim 1, wherein the nucleic acid sample is obtained from a primary tumor.

### Claim 15 (depends on 1)

The method of claim 1, wherein prior to the step of subjecting, nucleic acids are extracted from a primary tumor sample.

### Claim 16 (depends on 1)

The method of claim 1, further comprising:
subjecting a nucleic acid sample obtained from a non-tumor tissue of the human to the reaction; and
confirming that the somatic mutation detected in the tumor tissue is not in the nucleic acid sample obtained from the non-tumor tissue.

### Claim 17 (depends on 1)

The method of claim 1, wherein the therapy is chemotherapy.

### Claim 18 (depends on 1)

The method of claim 1, wherein the therapy is radiotherapy.

### Claim 19 (depends on 1)

The method of claim 1, wherein the therapy is biological therapy.

### Claim 20 (depends on 1)

The method of claim 1, wherein the therapy is surgery.

### Claim 21

A method of detecting a mutation in a human subject and treating a human subject, comprising:
subjecting nucleic acid samples obtained from a plurality of tumors of a plurality of humans to a reaction to form reaction products wherein the plurality of tumors are selected from the group consisting of: glioma, astrocytoma, oligodendroglioma, and oligoastrocytoma;
detecting in the reaction products of at least one of the plurality of nucleic acid samples obtained from the plurality of tumors a somatic mutation at nucleotide chr5 1,295,250 in hg19; and
administering a therapy to at least one of the human subjects in whose tumor the somatic mutation was detected, wherein the therapy is selected from the group consisting of chemotherapy, radiotherapy, biological therapy, or surgery.

### Claim 22 (depends on 21)

The method of claim 21, wherein the nucleic acid samples obtained from the plurality of tumors are obtained from primary tumors.

### Claim 23 (depends on 21)

The method of claim 21, wherein prior to the step of subjecting nucleic acid samples obtained from the plurality of tumors, nucleic acids are extracted from primary tumor samples.

### Claim 24 (depends on 21)

The method of claim 21, wherein the tumors are gliomas.

### Claim 25 (depends on 21)

The method of claim 21, wherein the tumors are primary glioblastomas.

### Claim 26 (depends on 21)

The method of claim 21, wherein the tumors are astrocytomas.

### Claim 27 (depends on 21)

The method of claim 21, wherein the tumors are oligodendrogliomas.

### Claim 28 (depends on 21)

The method of claim 21, wherein the tumors are oligoastrocytomas.

### Claim 29 (depends on 21)

The method of claim 21, wherein the reaction comprises amplifying the promoter or part of the promoter to form an amplicon.

### Claim 30 (depends on 29)

The method of claim 29, wherein the reaction employs mutation-specific amplification primers.

### Claim 31 (depends on 29)

The method of claim 29, wherein the amplicon is sequenced.

### Claim 32 (depends on 29)

The method of claim 29, wherein the amplicon is hybridized to a mutation specific oligonucleotide.

### Claim 33 (depends on 21)

The method of claim 21, wherein the reaction is a nucleic acid hybridization reaction.

### Claim 34 (depends on 21)

The method of claim 21, wherein the reaction is a nucleic acid sequencing reaction.

### Claim 35 (depends on 21)

The method of claim 21, wherein the therapy is chemotherapy.

### Claim 36 (depends on 21)

The method of claim 21, wherein the therapy is radiotherapy.

### Claim 37 (depends on 21)

The method of claim 21, wherein the therapy is biological therapy.

### Claim 38 (depends on 21)

The method of claim 21, wherein the therapy is surgery.

### Claim 39 (depends on 21)

The method of claim 21, further comprising:
subjecting a plurality of nucleic acid samples obtained from a plurality of non-tumor tissues of the plurality of humans to the reaction; and
confirming that the somatic mutation detected in the tumor tissue of the at least one human subject is not present in the nucleic acid sample obtained from the non-tumor tissue of the at least one human subject.