Chordoma, Susceptibility To

A number sign (#) is used with this entry because evidence suggests that susceptibility to the development of chordomas is conferred by duplication in the gene encoding brachyury (T; 601397).

Chordomas are rare, clinically malignant tumors derived from notochordal remnants. They occur along the length of the spinal axis, predominantly in the sphenooccipital, vertebral, and sacrococcygeal regions. They are characterized by slow growth, local destruction of bone, extension into adjacent soft tissues, and, rarely, distant metastatic spread (Stepanek et al., 1998). The incidence of chordoma is age-dependent, with fewer than 5% occurring in children and adolescents (summary by McMaster et al., 2011).

Foote et al. (1958) described middle-aged brother and sister with sacrococcygeal chordoma. Recurrence and metastases occurred in both.

Stepanek et al. (1998) described chordoma in 4 members of a family in a pattern they considered most consistent with autosomal dominant inheritance with reduced penetrance. Two females and 2 males were affected. The index case was in a 20-year-old woman who had a chordoma in the region of the pituitary gland. A paternal aunt of this woman presented at 39 years with persistent nasal stuffiness and was found to have a chordoma abutting the posterior aspect of the nasal septum. A brother of that woman was found, at the age of 28 years, to have a sacral chordoma. A first cousin of that brother and sister had a chordoma of the nasopharynx.

There is a modest overall male predominance of chordomas (1.7:1), which is more striking (approximately 3:1) among patients with sacral chordomas. The age distribution at diagnosis is unimodal, with a median of 59 years. Treatment is predominantly surgical, followed by radiotherapy. Survival rates to 5 and 10 years are 68% and 40%, respectively (McMaster et al., 2001).

In a retrospective review, McMaster et al. (2011) identified 65 cases of pediatric chordoma, with onset between ages 0 and 18 years (median age at diagnosis was 12 years). Molecular studies were not performed. Most (64.1%) were intracranial, 26.6% were spinal, and 9.4% were sacral. Chordomas were exclusively skull-based in the youngest age tertile, while sacral chordomas were confined to patients in the oldest tertile. Survival was 68.2% at 5 years and 53.1% at 20 years. These figures were compared with and differentiated from 10 cases of chordoma associated with tuberous sclerosis complex (TSC1; 191100 and TSC2; 613254). The median age at onset in TSC-associated chordoma was much earlier, at 6.2 months (range 0 to 16 years), with only 1 patient diagnosed with chordoma after age 5. Chordomas were skull-based in 50% and sacral-based in 40%; the 16-year-old had a spinal-based tumor. The 5-year survival was 83%. Thus, clinical features can distinguish between the 2 disorders, although the findings also suggested an association between pediatric chordoma and TSC.

Kelley et al. (2001) performed a genomewide analysis for linkage in the family reported by Stepanek et al. (1998) with 10 individuals affected by chordoma. The maximum 2-point lod score based on only the affected individuals was 2.21, at recombination fraction 0.0, at marker D7S2195 on chromosome 7q. Combined analysis of additional members of this family (11 affected individuals) and of 2 unrelated families (1 with 2 affected individuals and the other with 3 affected individuals), with 20 markers on 7q, showed a maximum 2-point lod score of 4.05 at marker D7S500. Haplotype analysis of the 3 families showed a minimal disease gene region from D7S512 to D7S684, a distance of 11.1 cM and approximately 7.1 Mb on chromosome 7q33.

Yang et al. (2009) reported an additional affected patient in the large family reported by Kelley et al. (2001) that showed linkage to 7q33. However, the patient did not inherit the 7q33 haplotype from her affected father. Yang et al. (2009) thus performed a genomewide linkage study on this family and found significant linkage to an 11-Mb region on chromosome 6q25-q27 between D6S972 and D6S503 (lod score of 3.04). Analysis of the remaining 2 families reported by Kelley et al. (2001) showed that 1 shared the 6q25-q27 haplotype, but the other did not. Affected members of another family also shared the disease haplotype. In total, linkage to 6q25-q27 was observed in 3 families.

In 7 affected individuals from 4 unrelated families with chordomas, Yang et al. (2009) identified duplicated regions on chromosome 6q27 ranging from 52 to 489 kb. The results were obtained from a genomewide search for copy number variations (CNVs) using array CGH. Duplications were not detected in 16 individuals from families with melanoma, in 100 controls, or in individuals with chordoma from 3 additional families, suggesting genetic heterogeneity. The duplicated regions in all 4 families contained only the T gene (601397), and there were no previously reported CNVs in that gene. Sequence analysis did not identify any pathogenic mutations in the T gene. Quantitative PCR analyses of the T gene confirmed the duplications in all affected subjects and obligate carriers in all 4 families, with 1.42 to 2.22-fold increased changes. In addition, genomic DNA from 7 affected individuals showed clear duplications of the T gene. Bioinformatics analysis revealed that the breakpoints or breakpoint region were located at or near repetitive short and long interspersed repeat (SINE and LINE) elements or involved Alu-mediated nonallelic homologous recombination. Yang et al. (2009) concluded that duplication of the T gene results in increased susceptibility to the development of chordomas.

Pillay et al. (2012) conducted an association study of 40 individuals with chordoma and 358 ancestry-matched controls, with replication in an independent cohort. Whole-exome and Sanger sequencing of T exons showed a strong association of the common nonsynonymous single-nucleotide polymorphism (SNP) rs2305089 with chordoma risk (allelic odds ratio = 6.1, 95% confidence interval = 3.1-12.1; p = 4.4 x 10(-9)), a finding that is substantial in cancers with a nonmendelian mode of inheritance.

Somatic Mutations

Lee-Jones et al. (2004) identified 3 reports of chordomas found in patients with tuberous sclerosis complex (TSC; see 191100), an autosomal dominant syndrome characterized by hamartomas in multiple organs, epilepsy, mental retardation, and behavioral problems. TSC1 is caused by germline mutation in the TSC1 gene (605284) on chromosome 9q34 and TSC2 (613254) by mutation in the TSC2 gene (191092) on chromosome 16p13. These genes behave like tumor suppressor genes, as inactivation of the wildtype allele has been demonstrated in hamartomas, consistent with the Knudson 2-hit hypothesis. In 2 cases of sacrococcygeal chordomas in individuals with TSC, 1 with a germline TSC2 mutation and the other with a germline TSC1 mutation, Lee-Jones et al. (2004) confirmed somatic inactivation of the corresponding wildtype allele by loss of heterozygosity analysis and immunohistochemistry. These data provided the first molecular evidence for a pathogenic role of TSC genes in sacrococcygeal chordomas.