Mutations in CIC and FUBP1 contribute to human oligodendroglioma

Abstract

Oligodendrogliomas are the second most common malignant brain tumor in adults and exhibit characteristic losses of chromosomes 1p and 19q. To identify the molecular genetic basis for this alteration, we performed exomic sequencing of seven tumors. Among other changes, we found that the CIC gene (homolog of the Drosophila gene capicua) on chromosome 19q was somatically mutated in six cases and that the FUBP1 gene [encoding far-upstream element (FUSE) binding protein] on chromosome 1p was somatically mutated in two tumors. 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.

Fig. 1

Loss of heterozygosity (LOH) maps of two representative tumors. (A) In tumor OLID 13, the estimated LOH on chromosome 1 extends from base 901,779 to base 148,526,024 and the estimated LOH on chromosome 19 extends from base 18,116,940 to base 62,357,562. (B) In tumor OLID 09, the estimated LOH on chromosome 1 extends from base 1,844,406 to base 110,751,800, the estimated LOH on chromosome 9 extends from base 108,032 to base 20,875,240 and the estimated LOH on chromosome 19 extends from base 18,545,563 to base 62,923,619. The “minor allele” of each SNP represents the allele that was less common in the tumor. If both alleles of the SNP were represented by an equal number of tags, the minor allele fraction would be represented as 100% on the y-axis. The remaining signals in the regions exhibiting LOH represent contaminating non-neoplastic cells in the samples. Partial allelic skewing (e.g., on chromosome 2 in OLID 13) reflects losses of the relevant region in a subfraction of the neoplastic cells within the tumor.

Fig. 2

Mutations in CIC (A) Sanger sequencing chromatograms showing representative CIC mutations in the indicated tumors. T, DNA from tumor; N, DNA from matched normal tissue. The mutated bases are overlined with a red bar. (B) Mutation distribution of CIC mutations. Red arrows represent missense mutations substitutions, black arrows represent insertions or deletions, and green arrows represent splice site alterations. See tables S3 and S4 for details. The black boxes denote exons, Pro-rich denotes the proline-rich domains, HMG denotes the high mobility group domain, and the start and stop codons are indicated.