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 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 telomere length-dependent, we resolve the paradox, highlighting a regulatory role of telomeres in cancer.

Telomere length, telomerase reverse transcriptase promoter mutations, and melanoma risk

“…Telomere length independent first mutational hit in stem cells likely precedes the second hit where telomere length hypothetically acts as a deterministic factor in cancer development. 32 Our data from the melanoma family with the -57A>C germline TERT promoter mutation exemplifies a severe case for the role of long constitutive telomeres in cancer disposition that would be in consonant with the two hit model of telomere length paradox. 16 The germline mutation predisposes the carriers to an early onset set of melanoma with rapid progression to metastasis through an increased TERT expression.…”

“…32 Instinctively, the vulnerability to genomic instability, a basic hallmark of most cancers, would be pronounced with short telomeres, which are considered causal in initiating a cascade that leads to events like chromothripsis at telomere crisis. 32 Instinctively, the vulnerability to genomic instability, a basic hallmark of most cancers, would be pronounced with short telomeres, which are considered causal in initiating a cascade that leads to events like chromothripsis at telomere crisis.…”

“…32 Instinctively, the vulnerability to genomic instability, a basic hallmark of most cancers, would be pronounced with short telomeres, which are considered causal in initiating a cascade that leads to events like chromothripsis at telomere crisis. 32 Our data from the melanoma family with the -57A>C germline TERT promoter mutation exemplifies a severe case for the role of long constitutive telomeres in cancer disposition that would be in consonant with the two hit model of telomere length paradox. Telomere length independent first mutational hit in stem cells likely precedes the second hit where telomere length hypothetically acts as a deterministic factor in cancer development.…”

“…Increased risk of cancers due to long constitutive telomeres has been termed as a paradox. 32 Instinctively, the vulnerability to genomic instability, a basic hallmark of most cancers, would be pronounced with short telomeres, which are considered causal in initiating a cascade that leads to events like chromothripsis at telomere crisis. [33][34][35] In view of strong epidemiological evidence to the contrary, a two stage clonal expansion model proposed to explain telomere length cancer paradox centers around two hits.…”

Environmental Exposures, Telomere Length at Birth, and Disease Susceptibility in Later Life

“…4 Furthermore, the ticking biological clock concept is inconsistent with recent research showing that a longer LTL is associated with increased risk for development of major cancers. 5, 6 The association of LTL, which reflects TL in somatic cells other than hematopoietic cells, 7 with both cancer and cardiovascular disease might best be understood as an evolutionary trade-off between cancer due to increased proliferative potential (longer telomeres) and cardiovascular disease due to diminished proliferative potential and poor repair capacity (short telomeres). 8 From this perspective, TL at birth and thereafter is hardly an aging biomarker, but it might represent susceptibility to different disease categories later in life.…”