Longevity, telomere biology and melanoma riskEduardo Nagore

Department of Dermatology

Instituto Valenciano de Oncología

Valencia (Spain)

Eduardo Nagore

Longevity, telomere biology and melanoma risk

I do not have any relevant relationships with industry related to this presentation.

Disclosure of conflict of interest & relationships with industry

Ageing

• Accumulation of changes in human beings over time:• Physical

• Psychological

• Social

• It is among the greatest known risk factors for most human diseases(including cancer).

• With age, the number of cell replications increases, which in turnincreases the chance of having somatic mutations and it eventuallycan lead to uncontrolled growth.

Acta Derm Venereol 2018; 98: 624–629

Cancer incidence rises exponentially withincreasing age

Telomeres

• TTAGGG repeats of 10-15 kb length at the end of the chromosome

• Functions:• End replication

• End protection (‘capping’):

against modification of genetic material

during celular replication.

- Recombination

- End-end fusion

- Degradation

Acta Derm Venereol 2018; 98: 624–629Mutation Res 2017; 771: 15-31

Telomeres

• DNA replication machinery cannot copy the very end of the

linear DNA

• Telomeres shorten by 30-150 nucleotides in every cell division:

telomere length shortens with age

• After 40-60 population doublings cells stop dividing, “Hayflick

limit” (telomere length threshold of 5 kb: high risk of imminent

death through celular senescence).

• The rate of biological ageing in human varies greatly and can be

estimated, in part, by assessing telomere shrinkage with age.

Aging 2017;9:1130

Telomeres

• Telomeres can be enlarged by telomerase

• Telomerase activity is absent in most of

adult somatic cells. Exceptions: germline

cells, stem cells and progenitor cells of

renewable tissues and activated

lymphocytes.

• Tumors maintain telomeres by

• Activity of telomerase (90%)

• Alternate lengthening of telomeres (ALT

mechanism)

Aging 2017;9:1130Mutation Res 2017; 771: 15-31

Telomere lenght dynamics is defined by:• Length at birth• Age dependent attrition

Telomere lenght dynamics is defined by:• Length at birth• Age dependent attrition

Baseline telomere length:

• Heritability: 64% (95% CI: 39%-83%)

• Shared environmental factors: 22% (95% CI: 6%-49%)

Age-dependent telomere length atrition rate

• Heritability: 28% (95% CI: 16%-44%)

• Environmental factors: 72% (95% CI: 56%-84%)

Factors influencing telomere length

• Sedentary lifestyle

• Mental stress

• Calorie intake (only in men)

• Total fats and saturated fatty acids

• Smoking (recent meta-analysis shows not increase of telomereattrition)

• ......

Telomere dysfunction

Shortening of the telomere:

• Disruption of the binding betweens proteins and telomeres

• Consequences:

• Limits cell renewal capability

• Can lead to genomic instability: subject to the very kinds of fusions

• Cells can become cancerous

Short telomeres are found in pre-neoplasticlesions• Short telomeres promote chromosomal fusions and cancer formation

• Dysfunctional telomeres promote genoma instability and cancer in the absence of p53 function: fusion promotes aneuploidy, amplificatios, deletions

• Once cancer is started then telomerase is reactivated promoting invasión (90% cancers have telomerase activation)

• Short telomeres are associated with an enhanced risk of fatal cancers

Inherited factors Environmental factors

• Inheritance of short telomeres• Mutations in telomere maintenance genes• Certain inherited cancer syndromes• Mutations in DNA repair pathways

• Carcinogens• ROS• Inflammation

Accelerated telomere shortening/dysfunction

Increased DNA damage

Genomic instability

Loss of p53function

Functionalp53

senescence

CancerStem cell exhaustion

ageing

Cancer incidence rises exponentially withincreasing age

Telomere length and cancer risk

• Senescence is secondary to telomeric attrition and senescence cellsaccumulate with aging.

• Disorders with mutations that compromise telomerase activity(premature ageing and short telomeres) have an increased incidenceof malignancies which occur at an early age of presentation (forexample, dyskeratosis congenita).

• BUT: the link between cancer susceptibility and telomere lenght haveshown conflicting results:• Short vs. Long

Med Hypoth 2016; 97: 7-10Pathology 2006; 38: 103-113

Short vs. Long telomeres

• Short: pronounced vulnerabilityto genomic instability

• Longer: increased cell survival and, therefore, at higher risk of acquiring driver mutations. Twohits model:• Stem cell (with active telomerase)

• Differentiated cell

1st quartile with the shortest telomeres vs. reference, 4th quartile, with the longesttelomeres

Relative telomere lenght:Ratio telomere repeat copy number/copynumber of a single copy gene (albumin)

Ho: people with multiple nevi look younger

Mendelian randomization

Mendelian randomization

Mendelian randomization

Pooled estimate OR: 2.66 (95% CI: 2.07-3.25)

Longer Telomeres (by MR study) increase risk of:- Lung cancer- Endometrial cancer- Kidney cancer- Melanoma- Bladder cancer- Testicular cancer- Glioma cancerShorter telomeres increase risk of coronary heart disease

J Med Genet 2016

Black: High penetranceBlue: Medium penetranceRed: Low penetrance

J Med Genet 2016

Black: High penetranceBlue: Medium penetranceRed: Low penetrance

Tumor clone selection

Multivariate analysis

Multivariateanalysis

Human cell lines derived from metastatic melanoma

Telomere length and telomerase at somatic level:TERT promoter mutations (activation of telomerase)

• Presence of TERT promoter mutations increases TERT expression levels :

Somatic alterations in TERT promoterGermline polymorphism

Somatic alterations in TERT promoterGermline polymorphism

• Difference in TERT expression by mutation type:

N= 308 patientsMedian follow-up=72 mesesRelapses=75Deaths due to melanoma=34

IJC 2018

IJC 2018

IJC 2018

Conclusions

• Increased telomere length in peripheral blood leucocytes is associated with increased melanoma risk, probably because it afford ample time for continued cell division until telomerase rejuvenation and telomere stabilization. Short telomeres, on the contrary, are associated with poor prognosis. Immune response alteration is a plausible explanation but not proven yet.

• In contrast, once a patient has developed the disease, it is the shorter telomeres in tumors that would presumably lead to rapid chromosomal fusions and aneuploidy resulting in poor outcome.

• TERT promoter mutations increase telomerase activity facilitating the survival of very proliferative tumors (mainly driven by MAPK activating mutations) which in the end associate poor survival.

• The effect varies according to the mutation type.

Acknowledegments

Prof. Rajiv KumarDivision of Molecular EpidemiologyGerman Cancer Research CenterHeidelbergGermany