Oligodendroglioma drive genes
Oligodendrogliomas are the second most common malignant brain tumor in adults. These tumors often contain a chromosomal abnormality involving a pericentromeric fusion of chromosomes 1 and 19, resulting in losses of the entire short arm of the former and the long arm of the latter. To identify the molecular genetic basis for this alteration, we performed exomic sequencing of seven anaplastic oligodendrogliomas with chromosome 1p and 19q losses. Among other changes, we found that that CIC (homolog of the Drosophila gene capicua) on chromosome 19q was somatically mutated in six of the seven cases and that FUBP1 (far upstream element (FUSE) binding protein) on chromosome 1p was somatically mutated in two of the seven cases. Examination of 27 additional oligodendrogliomas revealed 12 and 3 more tumors with mutations of CIC and FUBP1, respectively, 58% of which were predicted to result in truncations of the encoded proteins. These results suggest a critical role for these genes in the biology and pathology of oligodendrocytes.
1. A method of identifying and treating an oligodendroglioma in a subject, comprising:
detecting in a sample obtained from the subject a mutation in CIC, FUBP1, or both CIC and FUBP1, wherein the mutation is selected from the group consisting of: CIC (R201W), CIC (R213P), CIC (R215Q), CIC (QK1517RD), CIC (A253T), CIC (P1485L), CIC (A306T), CIC (R215W), FUBP1 (E445X), FUBP1 (E411X), and combinations thereof,
wherein the sample comprises a brain tissue suspected of being a brain tumor, or in cells or nucleic acids shed from the brain tumor,
identifying the subject having the mutation as having the oligodendroglioma, and
administering an anti-tumor agent to the subject identified as having the oligodendroglioma.
2. A method of stratifying and treating a subject with a brain tumor, comprising:
detecting in a sample obtained from the subject a mutation of CIC, wherein the mutation is selected from the group consisting of: CIC (R201W), CIC (R213P), CIC (R215Q), CIC (QK1517RD), CIC (A253T), CIC (P1485L), CIC (A306T), CIC (R215W), and combinations thereof,
wherein the sample comprises brain tumor tissue, or cells or nucleic acids shed from the brain tumor tissue,
stratifying the subject having the mutation by assigning the subject to a group having an oligodendroglioma that is refractory to EGFR inhibitors, and
administering an anti-tumor agent to the stratified subject having the oligodendroglioma that is refractory to EGFR inhibitors,
wherein the agent is not an EGFR inhibitor.
3. The method of claim 2 further comprising:
assigning the subject stratified as having the oligodendroglioma that is refractory to EGFR inhibitors with the to a clinical trial group, wherein the clinical trial group consists of subjects whose brain tumors have the mutation.
4. The method of claim 1 , wherein detecting in a sample is performed by sequencing a nucleic acid in the sample.
5. The method of claim 2 , wherein detecting in a sample is performed by sequencing a nucleic acid in the sample.
6. The method of claim 1 , wherein the mutation is in CIC, and the anti-tumor agent is not an EGFR inhibitor.