Genetic alterations in isocitrate dehydrogenase and other genes in malignant glioma

Patent metadata

Field	Value
Publication number	US-10894987-B2
Application number	US-201615353002-A
Country	US
Kind code	B2
Filing date	Nov 16, 2016
Priority date	Sep 3, 2008
Publication date	Jan 19, 2021
Grant date	Jan 19, 2021

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 glioblastomas 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 detecting an isocitrate dehydrogenase 1 (IDH1) mutation or an isocitrate dehydrogenase 2 (IDH2) mutation in a nucleic acid present in a tumor sample obtained from a human subject, wherein the tumor is a glioblastoma multiforme (GBM), comprising:
sequencing the nucleic acid wherein the nucleic acid comprises the IDH1 mutation or the IDH2 mutation, wherein the IDH1 mutation is present in a codon that encodes amino acid 132 in the wild type IDH1 polypeptide of SEQ ID NO: 130; or
wherein the IDH2 mutation is present in a codon that encodes amino acid 172 in the wild type IDH2 polypeptide of SEQ ID NO: 131; and wherein when the mutation is present, administering to the subject a treatment selected from the group consisting of: chemotherapy, radiation resection of the tumor, and combinations thereof.

2. The method of claim 1 , wherein the IDH1 mutation is present in a codon that encodes a histidine substitution at amino acid position 132 of IDH1.

3. The method of claim 1 , wherein the IDH2 mutation is present in a codon that encodes a lysine substitution at amino acid position 172 of IDH2.

4. The method of claim 1 , wherein the sample is selected from the group consisting of: tumor, blood, plasma, serum, cerebrospinal fluid, urine, saliva, and lymph.

5. The method of claim 1 , wherein prior to the step of performing a sequencing reaction, the nucleic acid is amplified, wherein the nucleic acid comprises at least a portion of:
the IDH1 gene or cDNA of the IDH1 mRNA, said portion comprising a codon that encodes an amino acid at position 132 in the wild type IDH1 polypeptide of SEQ ID NO: 130; or
the IDH2 gene or cDNA of the IDH2 mRNA, said portion comprising a codon that encodes an amino acid at position 172 in the wild type IDH2 polypeptide of SEQ ID NO: 131.

6. The method of claim 1 , wherein the step of performing a sequencing reaction utilizes sequencing-by-synthesis.

7. The method of claim 1 , wherein the IDH1 mutation is present in a codon that encodes a histidine substitution, a serine substitution, a cysteine substitution, a leucine substitution, or a glycine substitution at amino acid position 132 of IDH1.

8. The method of claim 1 , wherein the IDH2 mutation is present in a codon that encodes a lysine substitution, a glycine substitution, or a methionine substitution at amino acid position 172 of IDH2.

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 D
• 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

• C12Q1/6886 Primary

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

• C12Q2600/156

  Polymorphic or mutational markers · CPC title

• C12Q2600/112

  Disease subtyping, staging or classification · CPC title