Mutations, Cancer and the Telomere Length Paradox

Abstract

Individuals with short telomeres should be at increased risk for cancer, since short telomeres lead to genomic instability - a hallmark of cancer. However, individuals with long telomeres also display an increased risk for major cancers, thus creating a cancer-telomere length (TL) paradox. The two-stage clonal expansion model we propose is based on the thesis that a series of mutational hits (1st Hit) at the stem-cell level generates a clone with replicative advantage. A series of additional mutational hits (2nd Hit) transforms the expanding clone into cancer. By proposing that the 1st Hit is largely telomere length-independent, while the 2nd Hit is largely TL-dependent, we resolve the paradox, highlighting a regulatory role of telomeres in cancer.

Keywords: cancer; clones; evolution; mutation; stem cells; telomeres.

Fig. 1, Key Figure. Mutation accumulation in the two-stage telomere model of carcinogenesis

The dotted horizontal line partitions the first—stage series of mutational hits (1^st Hit) from the second-stage series of mutational hits (2^nd Hit). The 1^st Hit occurs during replication of stem cells; it primes non-cancerous clones to acquire replicative advantage. The 2^nd Hit takes place in the clones, causing further selection, which might ultimately lead to malignant transformation. Telomere length differentially affects the 1^st Hit and the 2^nd Hit. The 1^st Hit is independent of telomere length. The chance of a clone having the 2^nd Hit and undergoing malignant transformation scales with the maximal clone size, which depends on telomere length. Thus, the chance for malignant transformation increases in the following order: scenario c > scenario b > scenario a.