Elizabeth H. Blackburn, PhD, Salk Institute for Biological Studies,...

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;





Observed Longer

telomeres





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



Observed Longer

telomeres



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



Observed Longer

telomeres

For cancers, it isn’t just longer telomeres that matter

– it’s WHAT made them longer that matters



Observed Longer

telomeres

Non-genetic

telomere-

lengthening

influences

Lower risk of

CAD, CHD, AD

GREATER

RISKS

(specific

cancers)



Role for non-genetic influences causing longer mean telomere

length in white blood cells in reducing all-cancers mortality



Observed Longer

telomeres

Non-genetic

telomere-

lengthening

influences

Lower risk of

CAD, CHD, AD

GREATER

RISKS

(specific

cancers)



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


Lifestyle

• Exercise activities

• Tobacco use

• Alcohol use

• Dietary factors


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……



Bladder Cancer Survival: Leukocyte Telomere Length

(weakly) Independently Predicts All-cause Mortality

Bladder cancer patient

mortality

Increasing

telomere

shortness

Depression

Bladder cancer patient

mortality


Bladder Cancer Survival: Interaction of leukocyte short

telomeres with depression


Depression (long telomeres)

or

Short telomeres (not depression)

or

Neither

or

BOTH

At bladder cancer diagnosis:


Bladder Cancer Survival: Interaction of leukocyte short

telomeres with depression


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……


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

Elizabeth H. Blackburn, PhD, Salk Institute for Biological Studies,...

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