Heritable Defects in Mitotic and Telomere Function Confer Sarcoma Risk

Genetic variation in epithelial cancers has been well studied, but similar evaluations in sarcomas have not been as common, especially at the population level. To identify pathways and penetrant genes that are specific to mesenchymal cancers and are associated with sarcoma risk, Ballinger, Pattnaik, and colleagues conducted a comprehensive case–control study using whole-genome sequencing (WGS) of 1,644 sporadic cases and 3,205 matched healthy elderly controls. Results indicated a strong genetic basis for apparently sporadic sarcomas, with 37,830 rare single-nucleotide variants and insertions or deletions being identified, of which 1,033 were known or likely pathogenic, 10,702 were loss of function or protein truncating, and 26,085 were possibly pathogenic. Additional analyses using an extreme phenotype case–control design revealed interrelated gene clusters, with the largest being centered on TP53, a known sarcoma risk gene, and the next largest clusters involving RNA processing/M phase of the cell cycle and antigen processing, ubiquitination, and neddylation. Further enrichment to determine the most important pathways indicated three ontological groups: the first comprising the shelterin complex including the genes POT1, TERF1, and TINF2, the second comprising the mitotic spindle and centrosomal genes including CEP63, HAUS4, and HAUS5, and the third comprising EXT1 and EXT2, which are linked to hereditary exostoses and bone sarcomas. Comparison of sarcomas to epithelial cancers revealed sarcoma-specific enrichment of the shelterin and centrosome gene sets, while malignant peripheral nerve sheath tumors (MPNST) and gastrointestinal stromal tumors (GIST) showed even further enrichment in the centrosome set. Evaluation of susceptibility indicated that heritable defects in centrosome pathways conferred increased risk of MPNST or GIST, while shelterin complex/telomere function was associated with a predisposition to sarcoma, melanoma, and thyroid cancers. In conclusion, the results of this study provide insight into the biological mechanisms that underlie sarcoma risk and suggest that heritable defects in telomere and mitotic function are linked to increased sarcoma susceptibility.

Ballinger ML, Pattnaik S, Mundra PA, Zaheed M, Rath E, Priestley P, et al. Heritable defects in telomere and mitotic function selectively predispose to sarcomas. Science 2023;379:253–60.

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