Tumor Suppressor Genes with Segmental Duplications Are Prone to Somatic Deletions and Structural Variations

Segmental duplications (SD) are blocks of genomic DNA with high sequence homology that are hotspots for chromosomal rearrangements, coinciding with copy-number and single-nucleotide variations in the population. SDs could represent unstable genomic regions that are susceptible to somatic alterations in human cancers. In this study, we aimed to elucidate the genomic locations of SDs in relation to cancer-related genes and their propensity for somatic alterations in cancer. The analysis showed that tumor suppressor genes (TSG) were less associated with SDs compared with noncancer genes in nearly all mammalian species. TSGs with SDs were larger in size in humans but only modestly conserved among mammals. In humans, the proportion of noncancer genes with SDs decreased as the gene age increased. However, for TSGs, a loss of association with SDs was apparent among young genes. Pan-cancer analysis revealed that TSGs with SDs were more prone to deletions and structural variations independently of gene size. Reanalysis of publicly available experimental data further revealed that genes with SDs tended to replicate late and were more likely to undergo the error-prone mitotic DNA synthesis upon replication stress. In conclusion, the loss of SDs from TSGs during mammalian evolution protects against tumor formation by reducing somatic alterations.

Tumor suppressor genes with segmental duplications have an increased risk for somatic alterations, including deletions and structural variations, in human cancers, identifying them as a genetic Achilles' heel in tumor suppression.