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February 3-5, 2016 | Lansdowne Resort, Leesburg, VA
Elizabeth H. Blackburn, PhD,
Salk Institute for Biological Studies,
Cancer Prevention
Future Medicine: Prevent, Preempt and Intercept Diseases. Why Now?
Preempt Treat
Pre-disease Advanced
Advances in
• Understanding disease etiology
• Understanding disease biology
• Clinical treatment options
are giving us the ability to think about preventing and
intercepting more cancers, and earlier.
Future Medicine: Prevent, Preempt and Intercept Diseases. Why Now?
Kensler et al (2016). Cancer Prevention Res. Special report.
NON-GENETIC GENETICEnvironmental Life events/behavior
First, a framework……
Aging-related diseasesoften go hand-in-hand (co-morbidity):
Poor immune function Diabetes Cardiovascular disease CancersMental/cognitive disorders/depression
Immune system Cancer Cells
Developing Cancers
Cancers
Pre-malignancies
Genome instabilities, mutationsInflammation, checkpoints
PREVENTING CANCER FROM DEVELOPING
Eliminate Tobacco Use
Maintain a Healthy Weight, Eat a Healthy Diet
Stay Active
Protect Skin From Ultraviolet Exposure
Prevent Infection With Cancer-causing Pathogens
• Helicobacter pylori, HPV, Hepatitis B/C virus (HBV and HCV), EBV
Limit Exposure to Other Risk Factors
• reproductive factors, occupational cancer-causing agents, and
environmental pollutants
AACR Cancer Report 2015
To Optimize These Actions: Understanding the science -
An Example originating from basic science research:
Chromosome End Maintenance Helps Protect from Diseases of
Human Aging – including Cancers
Telomeres
cap ends of
chromosomes
Telomeres Cap and Protect the Ends of Chromosomes
3’5’
3’ 5’
Telomere Shortening:
from DNA end replication problem,
replication stress,
oxidative and other damage
Min length needed to prevent fusions
= ~3.8 Kb
(human white blood cells) ...Baird et al 2015
Disrupts -cellular functions
-mitochondrial functions
-cell renewal capability
Causes -secretion of pro-inflamm. and pro-tumorigenic factors
Can lead to genomic instability
Persistent DNA
damage
signalling!
Telomere too short
mitochondria
TelomereUncapped Telomere!
Telomere damage:
A Vicious CycleSecreted
Inflammatory
factors
DNA
cell
div
isio
ns
Cells keep dividing
Most human cancers
With sufficient
telomerase action:
Addition and shortening stay
balanced
Multiple regulatory
mechanisms
Death
Te
lom
ere
le
ng
th
0 8030 Chronological age
Human telomere length and age in years
Copenhagen study: Odds of all-causes mortality
Mean follow-up time after leukocyte telomere measure = 7 yrs.
Telomere length
was measured at this time
(N= 64,637)
Who had died
~ 7 years (mean time) after
telomere length measure
(N= ~ 7,604)
Compare to
Mean Baseline Telomere Length
Year 0 = baseline
time
Rode et al, 2015
Copenhagen study: Numbers of Deaths by Telomere Length
Decile (unadjusted)
y = 360.82e0.1238x
R² = 0.9777
0
200
400
600
800
1000
1200
1400
0 1 2 3 4 5 6 7 8 9 10
All-cause mortality
All-causemortality
Expon. (All-cause mortality)
Rode et al, 2015
Raw
Number of
Deaths
(unadjusted)
Telomere Length decile 1 = longest 10 = shortest
Decile 10 =
Shortest
telomeres
Copenhagen study: Numbers of Deaths by Telomere Length
Decile (unadjusted) Rode et al, 2015
Raw
Number of
Deaths
(unadjusted)
Telomere Length decile 1 = longest 10 = shortest
Decile 10 =
Shortest
telomeres
0
200
400
600
800
1000
1200
1400
0 1 2 3 4 5 6 7 8 9 10
Any cancer
All-causemortality
Expon. (All-causemortality)
Copenhagen study: Leukocyte Telomere Length
Independently Predicts All-cause Mortality
0.8
0.9
1
1.1
1.2
1.3
1.4
1.5
1 2 3 4 5 6 7 8 9 10
Multivariate-Adjusted All-cause Mortality Hazard Ratios vs. Baseline Leukocyte Telomere Length
HR…
N = 64,637
7,604 deaths
Mean Follow-Up
time = 7 years
Mortality
Hazard
Ratio
Multivariate
Adjusted
Decile 10 =
Shortest
telomeres
Willeit et al 2012Rode et al, 2015;Lapham et al, 2015;
In general populations, reduced mortality correlates with longer
mean telomere length in white blood cells
REDUCED mortality risks:
all causes / cardiovascular / all-cancers
Observed Longer
telomeres
Telomere shortness in white blood cells Predicts Incident Cancer
and Cancer Mortality, Fifteen-Years ALL CANCERS
Longest
Mid
Telomere Length at
Baseline by Tertiles
Shortest
Longest
Mid
Shortest
Willeit, P. et al. JAMA 2011;306:42-44
Cancer incidence Cancer mortality
Telomere length measured at time
0
Shortened Telomere Length Is Associated with Increased Risk of
Cancer: A Meta-Analysis Ma H, Zhou Z, Wei S, Liu Z, et al. (2011). .
Longer Favors control
Shorter
Favors case
Odds ratios (ORs) and
95% confidence intervals
(CIs) for overall cancer
risk associated with
relative telomere length
(shorter vs. longer,
grouped by median of
telomere length).
Death
Te
lom
ere
le
ng
th
0 8030 Chronological age
Human telomere length and age in years:
mutations in known telomere maintenance genes
Short Telomeres: Inherited
Telomere Syndromes
Disease
impact
Rare genetic mutations that cause
telomere shortness cause diseases of aging Inherit a rare mutation causing half the
telomerase level / reduced telomere
maintenance
Early death
Cancers
Immune loss
Pulm. fibrosis
Cirrhosis
Diabetes
Neuropsych.
Cardiovasc.
Short Telomeres
GENETICS tells us:
Rare Human Mutations in
Telomerasea or Telomere proteinb
Genes with known telomere functionsa hTERC, hTERT, DKC1,NOP10, NHP2, WRAP53, b TINF2, RTEL1, POT1, CTC1, TPP1
Causality: Known Telomere Maintenance Gene Mendelian (Rare)
Mutations INCREASE RISKS for certain Cancer TYPES
Less
Telomerase;
SHORTER Telomere
(genetic)
WORSE
CANCER
RISKS
eg, Hematological,
squamous cell, gastrointestinal
3’5’
3’ 5’
G-rich
sequence
Chromosome end Gene Effect on LTL
equiv. age-rel loss
years base-prs
TERC 3.91 117
TERT 3.14 94
NAF1 2.99 90
OBFC1 2.76 83
RTEL1 2.47 74
ACYP2 2.23 67
ZNF208 1.92 58
Human leukocyte telomere length (LTL)
genome-wide association SNPs
known
telomere
functions
*
Additive allele effects on Coronary Artery Disease risk
Codd et al 2013
GWAS meta-analysis
COMMON Genetic variants of Known Telomere Maintenance
Genes Causing Shorter Telomeres Increase Risks of CDV
Willeit et al 2012Rode et al, 2015;Lapham et al, 2015;
In general populations, reduced mortality correlates with longer
mean telomere length in white blood cells
REDUCED mortality risks:
all causes / cardiovascular / all-cancers
Observed Longer
telomeres
In general populations, reduced mortality correlates with longer
mean telomere length in white blood cells
REDUCED mortality risks:
all causes / cardiovascular / all-cancers
Observed Longer
telomeresLower risk of
CAD, CHD, AD
Codd et al 2013
Zhan et al 2015 JAMA
Neurol.72:1202-1203
ALZHEIMERS: “shorter TL was causally associated with a higher risk for AD
(OR, 1.36 per SD decrease of TL; 95%CI, 1.12 to 1.67; P = .002).” Zhan et al 2015
Telomere-lengthening
common gene variants
BUT, Common variants of Telomere Maintenance Genes causing
LONGER telomeres also INCREASE RISKS for certain cancers
REDUCED mortality risks:
all causes / cardiovascular / all-cancers
Observed Longer
telomeres
Telomere-lengthening
common gene variants
Lower risk of
CAD, CHD, AD
GREATER
RISKS
(specific
cancers)
Lin J et al CEBP, 2014
Impacts of Telomere maintenance differences
VARY by Cancer TYPE
Less
Telomerase;
Telomere Shortness
(genetic and observed)
WORSE
CANCER
RISKS
Over-active
telomere
maintenance
(genetic)
eg, Hematological,
squamous cell, gastrointestinalmelanoma, lung
Willeit et al 2012Rode et al, 2015;
But recall, for cancers, OBSERVED LONGER telomeres in white
blood cells predict LESS all-cancers mortality
REDUCED mortality risks:
all causes / cardiovascular / all-cancers
Observed Longer
telomeres
For cancers, it isn’t just longer telomeres that matter
– it’s WHAT made them longer that matters
REDUCED mortality risks:
all causes / cardiovascular / all-cancers
Observed Longer
telomeres
Non-genetic
telomere-
lengthening
influences
Lower risk of
CAD, CHD, AD
GREATER
RISKS
(specific
cancers)
Telomere-lengthening
common gene variants
Role for non-genetic influences causing longer mean telomere
length in white blood cells in reducing all-cancers mortality
REDUCED mortality risks:
all causes / cardiovascular / all-cancers
Observed Longer
telomeres
Non-genetic
telomere-
lengthening
influences
Lower risk of
CAD, CHD, AD
GREATER
RISKS
(specific
cancers)
Telomere-lengthening
common gene variants
Factors Influencing mean telomere length in white blood cells
(Multiple observational studies)
CHRONIC stress
Depression
Low education
Prenatal stress
Childhood trauma
Abuse
Neighborhood disorder
Tobacco use
Poor diets
Obesity
Education.
Resiliency
factors:- Exercise
- Sleep
- Stress-
reduction
Omega-3.
Precision Prevention
Age
Gender
Family history/genetic predisposition to developing cancer
Obesity
Reproductive/medical factors
Socio-economic factors
Exposure to known carcinogens/ viruses/pathogens
AACR Cancer Report 2015
Lifestyle
• Exercise activities
• Tobacco use
• Alcohol use
• Dietary factors
AACR Cancer Report 2015
Precision Prevention (cont’d)
Obesity
Socio-economic factors
Exposure to known carcinogens/ viruses/pathogens
Lifestyle
• Exercise activities
• Tobacco use
• Alcohol use
• Dietary factors
Precision Prevention/Telomere maintenance factors
AACR Cancer Report 2015) x
Factors Influencing Telomere Maintenance in Humans
(Multiple observational studies)
CHRONIC stress
Depression
Low education
Prenatal stress
Childhood trauma
Abuse
Neighborhood
disorder
Tobacco use
Poor diets
Obesity
Education.
Resiliency
factors:- Exercise
- Sleep
- Stress-
reduction
Omega-3.
*
Controlled
intervention
study,
2015
*Need to determine the “right”
balance for telomere maintenance
Interactions with GENETIC FACTORS?
Increasing Precision Prediction of Cancer progression by
combining telomere measures with other risk factors
Prediction from combination of factors?
An example from cancer patients……
Lin J et al CEBP, 2014
Lin J et al CEBP, 2014
Bladder Cancer Survival: Leukocyte Telomere Length
(weakly) Independently Predicts All-cause Mortality
Bladder cancer patient
mortality
Increasing
telomere
shortness
Depression
Bladder cancer patient
mortality
Lin J et al CEBP, 2014
Bladder Cancer Survival: Interaction of leukocyte short
telomeres with depression
Lin J et al CEBP, 2014
Depression (long telomeres)
or
Short telomeres (not depression)
or
Neither
or
BOTH
At bladder cancer diagnosis:
Lin J et al CEBP, 2014
Bladder Cancer Survival: Interaction of leukocyte short
telomeres with depression
Lin J et al CEBP, 2014
Kaplan–Meier survival curves by cross-classification of
depression score CES-D (>16 vs. <16) and telomere length
(long vs. short) N = 441
Adjusted for age, gender, ethnicity,
smoking status, bladder cancer stage,
bladder cancer grade, and treatment
Bladder Cancer Survival: leukocyte short telomere interaction with depression
At bladder cancer diagnosis
Depression (long telomeres)
OR
Short telomeres (not depression)
OR
Neither
OR
BOTH
ONLY depression OR ONLY short telomeres OR neitherAfter 2 ½ years – Who had died
BOTH depression PLUS short telomeres
After 2 ½ years – Who had died
After 5 years – Who had diedONLY depression OR ONLY short telomeres OR neither
BOTH depression PLUS short telomeresAfter 5 years – Who had died
Increasing Precision Prediction of Cancer progression by
combining telomere measures with other risk factors
Prediction from combination of factors?
An example from cancer patients……
Lin J et al CEBP, 2014
PREVENTING CANCER FROM DEVELOPING AND
PROGRESSING
Continued greater understanding of mechanisms
Actively determine risk profiles
Screening and Early Detection
Vaccines
Socioeconomic improvements
AACR Cancer Report 2015) x
Can We Stem the Tide?
Approximately 44% of men and 38% of women will develop
cancer in their lifetimes
Cancer is the second most common cause of death from disease,
the first being cardiovascular disease
1,658,370 new cancer cases and 589,430 cancer deaths were
estimated for 2015 (1,620 per day)
Source: AACR
Can We Afford NOT to Stem the Tide?
If left unabated, 2,387,304 new cases are expected to be
diagnosed in the U.S. annually by 2035
The # of new U.S. cancer cases per year is predicted to rise from
1.5 million in 2010 to 1.9 million in 2020
Direct medical costs of US cancer care in 2010: $125 billion. By
2020: $156 billion
Source: AACR
THANK YOU
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