Genetic alterations in isocitrate dehydrogenase and other genes in malignant glioma

Patent metadata

Field	Value
Publication number	US-10704108-B2
Application number	US-201816132928-A
Country	US
Kind code	B2
Filing date	Sep 17, 2018
Priority date	Sep 3, 2008
Publication date	Jul 7, 2020
Grant date	Jul 7, 2020

Abstract

We found mutations of the R132 residue of isocitrate dehydrogenase 1 (IDH1) in the majority of grade II and III astrocytomas and oligodendrogliomas as well as in gliblastomas that develop from these lower grade lesions. Those tumors without mutations in IDH1 often had mutations at the analogous R172 residue of the closely related IDH2 gene. These findings have important implications for the pathogenesis and diagnosis of malignant gliomas.

First claim

The invention claimed is:

1. A method of treating a mutant isocitrate dehydrogenase 1 (IDH1) enzyme-associated central nervous system cancer in a subject comprising:
detecting the presence of an isocitrate dehydrogenase 1 (IDH1) mutation in a nucleic acid present in a sample obtained from the subject, wherein the IDH1 mutation is present in a mutant codon that corresponds to a wild type codon that encodes amino acid 132 in the wild type IDH1 polypeptide of SEQ ID NO: 130; and
administering to the subject a chemotherapeutic agent to treat the cancer.

2. The method of claim 1 , wherein the mutant codon that includes the IDH1 mutation encodes an amino acid selected from the group consisting of: histidine (H), cysteine (C), serine (S), leucine (L), and glycine (G).

3. The method of claim 1 , wherein the presence of an IDH1 mutation in the sample is detected using an amplification primer, a hybridization probe, or both.

4. The method of claim 3 , wherein:
the amplification primer comprises at least 10 but fewer than 600 contiguous nucleotide residues of a coding sequence of a IDH1 protein found in a tumor of the subject, or its complement, the at least 10 contiguous nucleic acid residues comprising:
a first nucleotide that is present at a position in a mutant codon that corresponds to a wild type codon that encodes amino acid 132 in the wild type IDH1 polypeptide of SEQ ID NO: 130, wherein the mutant codon comprising the first nucleotide encodes an amino acid selected from the group consisting of: histidine (H), cysteine (C), serine (S), leucine (L), and glycine (G), wherein the amplification primer is labeled with a detectable label;
the hybridization probe comprises at least 10 but fewer than 600 contiguous nucleotide residues of a coding sequence of a IDH1 protein found in a tumor of the subject, or its complement, the at least 10 contiguous nucleic acid residues comprising:
a second nucleotide that is present at a position in a mutant codon that corresponds to a wild type codon that encodes amino acid 132 in the wild type IDH1 polypeptide of SEQ ID NO: 130, wherein the mutant codon comprising the second nucleotide encodes an amino acid selected from the group consisting of: histidine (H), cysteine (C), serine (S), leucine (L), and glycine (G), wherein the hybridization probe is labeled with a detectable label; or
both.

5. The method of claim 1 , wherein the chemotherapeutic agent is a small molecule.

6. The method of claim 1 , wherein the IDH1 mutation results in the subject expressing a mutant IDH1 polypeptide comprising an amino acid substitution at position 132.

7. The method of claim 6 , wherein the mutant IDH polypeptide comprises a R132C or a R132H amino acid substitution.

8. A method of treating a mutant isocitrate dehydrogenase 1 (IDH1) enzyme-associated central nervous system cancer in a subject identified as having an isocitrate dehydrogenase 1 (IDH1) mutation that is present in a nucleic acid wherein the IDH1 mutation is present in a mutant codon that encodes amino acid 132 in the wild type IDH1 polypeptide of SEQ ID NO: 130, the method comprising:
administering to the subject a chemotherapeutic agent to treat the cancer.

9. The method of claim 8 , wherein the mutant codon that includes the IDH1 mutation encodes an amino acid selected from the group consisting of: histidine (H), cysteine (C), serine (S), leucine (L), and glycine (G).

10. The method of claim 8 , wherein the subject is identified as having an isocitrate dehydrogenase 1 (IDH1) mutation by a method that employs an amplification primer, a hybridization probe, or both.

11. The method of claim 10 , wherein:
the amplification primer comprises at least 10 but fewer than 600 contiguous nucleotide residues of a coding sequence of a IDH1 protein found in a tumor of the subject, or its complement, the at least 10 contiguous nucleic acid residues comprising:
a first nucleotide that is present at a position in a mutant codon that corresponds to a wild type codon that encodes amino acid 132 in the wild type IDH1 polypeptide of SEQ ID NO: 130, wherein the mutant codon comprising the first nucleotide encodes an amino acid selected from the group consisting of: histidine (H), cysteine (C), serine (S), leucine (L), and glycine (G), wherein the amplification primer is labeled with a detectable label;
the hybridization probe comprises at least 10 but fewer than 600 contiguous nucleotide residues of a coding sequence of a IDH1 protein found in a tumor of the subject, or its complement, the at least 10 contiguous nucleic acid residues comprising:
a second nucleotide that is present at a position in a mutant codon that corresponds to a wild type codon that encodes amino acid 132 in the wild type IDH1 polypeptide of SEQ ID NO: 130, wherein the mutant codon comprising the second nucleotide encodes an amino acid selected from the group consisting of: histidine (H), cysteine (C), serine (S), leucine (L), and glycine (G), wherein the hybridization probe is labeled with a detectable label; or both.

12. The method of claim 8 , wherein the chemotherapeutic agent is a small molecule.

13. The method of claim 8 , wherein the IDH1 mutation results in the subject expressing a mutant IDH1 polypeptide comprising an amino acid substitution at position 132.

14. The method of claim 13 , wherein the mutant IDH polypeptide comprises a R132C or a R132H amino acid substitution.

15. A method of treating a mutant isocitrate dehydrogenase 1 (IDH1) enzyme-associated central nervous system cancer in a subject identified as having an isocitrate dehydrogenase 1 (IDH1) mutation that is present in a nucleic acid, wherein the IDH1 mutation results in the subject expressing an IDH1 polypeptide comprising a R132C or a R132H amino acid substitution, the method comprising:
administering to the subject a small molecule chemotherapeutic agent to treat the cancer.

16. The method of claim 15 , wherein the subject is identified as having an isocitrate dehydrogenase 1 (IDH1) mutation by a method that employs an amplification primer,
wherein the amplification primer comprises at least 10 but fewer than 600 contiguous nucleotide residues of a coding sequence of a IDH1 protein found in a tumor of the subject, or its complement, the at least 10 contiguous nucleic acid residues comprising:
a first nucleotide that is present at a position in a mutant codon that corresponds to a wild type codon that encodes amino acid 132 in the wild type IDH1 polypeptide of SEQ ID NO: 130, wherein the mutant codon comprising the first nucleotide encodes an amino acid selected from the group consisting of: histidine (H), cysteine (C), serine (S), leucine (L), and glycine (G), wherein the amplification primer is labeled with a detectable label; or
wherein the subject is identified as having an isocitrate dehydrogenase 1 (IDH1) mutation by a method that employs a hybridization probe,
wherein the hybridization probe comprises at least 10 but fewer than 600 contiguous nucleotide residues of a coding sequence of a IDH1 protein found in a tumor of the subject, or its complement, the at least 10 contiguous nucleic acid residues comprising:
a second nucleotide that is present at a position in a mutant codon that corresponds to a wild type codon that encodes amino acid 132 in the wild type IDH1 polypeptide of SEQ ID NO: 130, wherein the mutant codon comprising the second nucleotide encodes an amino acid selected from the group consisting of: histidine (H), cysteine (C), serine (S), leucine (L), and glycine (G), wherein the hybridization probe is labeled with a detectable label; or both.

Assignees

• Univ Johns Hopkins
• Univ Duke

Inventors

• Vogelstein Bert
• Kinzler Kenneth W
• Parsons D Williams
• Zhang Xiaosong
• Lin Jimmy Cheng-Ho
• Leary Rebecca J
• Angenendt Philipp
• Papadopoulos Nickolas
• Velculescu Victor
• Parmigiani Giovanni
• Karchin Rachel
• Jones Sian
• Yan Hai
• Bigner Darell
• Kuan Chien-Tsun
• Riggins Gregory J

Classifications

• G16B40/20

  Supervised data analysis · CPC title

• G16B20/20

  Allele or variant detection, e.g. single nucleotide polymorphism [SNP] detection · CPC title

• C12Q2600/112

  Disease subtyping, staging or classification · CPC title

• C12Q1/6886 Primary

  for cancer (immunoassay for cancer G01N33/575) · CPC title

• C12Q2600/156

  Polymorphic or mutational markers · CPC title