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.
Individuals with constitutively long telomeres and/or variant genes associated with long telomeres exhibit increased risk of major cancers. However, almost all cancers have short telomeres.
Telomeres are shorter in somatic tissues of older than younger persons, yet older persons are at a higher risk of many cancers.
Incidence of cancer declines after the eight decade.
Multistage models of mutation-driven carcinogenesis have not attempted to reconcile the above conflicting findings in regards to telomeres.
A model based on the premise that mutations acquired at the stem cell level are largely independent of TL, while those acquired during clonal expansion are TL dependent, provides a solution for these conflicting findings and a new perspective on the role of telomere biology in carcinogenesis.