Familial chordoma, a tumor of notochordal remnants, is linked to chromosome 7q33

Abstract

Chordoma is a rare tumor originating from notochordal remnants that is usually diagnosed during midlife. We performed a genomewide analysis for linkage in a family with 10 individuals affected by chordoma. The maximum two-point LOD score based on only the affected individuals was 2.21, at recombination fraction 0, at marker D7S2195 on chromosome 7q. Combined analysis of additional members of this family (11 affected individuals) and of two unrelated families (one with 2 affected individuals and the other with 3 affected individuals), with 20 markers on 7q, showed a maximum two-point LOD score of 4.05 at marker D7S500. Multipoint analysis based on only the affected individuals gave a maximum LOD score of 4.78, with an approximate 2-LOD support interval from marker D7S512 to marker D7S684. Haplotype analysis of the three families showed a minimal disease-gene region from D7S512 to D7S684, a distance of 11.1 cM and approximately 7.1 Mb. No loss of heterozygosity was found at markers D7S1804, D7S1824, and D7S2195 in four tumor samples from affected family members. These results map a locus for familial chordoma to 7q33. Further analysis of this region, to identify this gene, is ongoing.

Figures

Figure 1

Pedigree of family 1. The four index cases are indicated by arrows. All affected individuals had clival chordoma, except for individual III-3, who had a sacral chordoma. Deceased individuals (indicated by a diagonal line through the symbol) and individual III-6 were not genotyped. An asterisk (*) denotes that a DNA sample was obtained.

Figure 2

Pedigrees of families 2 (A) and 3 (B). Symbols are as described in the legend to table 1.

Figure 3

Multipoint LOD-score plot of the region, in chromosome 7, of the gene for familial chordoma, in family 1 alone (A) and in the three families combined (B), under an affecteds-only analysis using GENEHUNTER (Kruglyak et al. 1996).