Genetic Variability and Cancer Germline polymorphisms are frequent: 1 SNP every 400-1500 bp (> 1 per gene) Cancer has acquired mutations (some tumor “mutations”

Genetic Variability and Cancer

• Germline polymorphisms are frequent: 1 SNP every 400-1500 bp (> 1 per gene)

• Cancer has acquired mutations (some tumor “mutations” common: e.g. most CML has t(9;22); Rb has LOH relative to germline)

The Intl SNP Map Working Group Nature 2001

Relling & Dervieux 2001;1:99-108

Host and tumorgenomesaffect variabilityin anticancertherapy

Given Similar Schedule and Regimen, Pharmacogenetics should Have Similar

Implications for Children and Adults

• Host– developmental

changes expressed in somatic tissues contribute to child vs adult PK, PD differences

– germline poly-morphisms affect host similarly in children and adults

• Tumor– tumors different

children vs adults– germline

polymorphisms affect tumor response/invasive-ness similarly in children vs adults

Pharmacogenetics and Cancer

Polymorphisms in:• host metabolism• host distribution &

transport• host receptors &

targets• tumor receptors &

targets• pathogens

May affect:• cancer risk• host toxicity• tumor response• infectious

complications

GST Status affects Risk of Toxicity and Chance for Cure

anticancerdrug

free-radicalsor

electrophiles

more:less:less:

less:more:more:

inactivationtoxicityanticancer effect

inactivationtoxicityanticancer effect

mutant GST

wild-type GST

+

glutathione

H C CH2 CH2 C NH C NH CH2

NH2 CH2 COOH

SH

COOH HO

Glutathione S-Transferase Polymorphisms and Outcome ofChemotherapy in Childhood Acute Myeloid LeukemiaBy Stella M. Davies, Leslie L. Robison, Jonathan D. Buckley, Tom Tjoa, William G. Woods, Gretchen A. Radloff,Julie A. Ross, and John P. Perentesis J Clin Oncol 19:1279-1287.

N = 306Dex, VP, AraC, TG, dauno: standard vs intensive timing

GSTT1 genotype did not affect outcome with Standard timing, but did affect outcome with

Intensive timing5 yr Std

timingGST1+

StdtimingGST1-

InttimingGST1+

InttimingGST1-

Survival 41 35 59 43

DFS 47 53 64 47

Death inremission

28 26 12 33

(P < 0.05)

JCO 19:1279, 2001

greater anticancer drug effectin breast cancer..... but .....higher risk of toxic death

in AML

Examples: Mutant GST associated with:

1.0

0.8

0.6

0.4

0.2

00 1 2 3 4 5 6 7 8

wild type

heterozygote

mutant

Years from Diagnosis

GST-P1

Cancer Res 60:5621-4, 2000

1.00

0.75

0.50

0.25

00 1 2 3 4 5 6 7 8

Time (years)

GST-T1

JCO 19:1279-87, 2001

(+)

(–)

Among women with breast cancer, GSTP1 mutation associated with improved survival

greater anticancer drug effectin breast cancer..... but .....higher risk of toxic death

in AML

Examples: Mutant GST associated with:

1.0

0.8

0.6

0.4

0.2

00 1 2 3 4 5 6 7 8

wild type

heterozygote

mutant

Years from Diagnosis

GST-P1

Cancer Res 60:5621-4, 2000

1.00

0.75

0.50

0.25

00 1 2 3 4 5 6 7 8

Time (years)

GST-T1

JCO 19:1279-87, 2001

(+)

(–)

• The effect of each polymorphism must be evaluated in the context of the disease and its therapy (e.g. intensifying therapy in GST wild-type pts may be correct in children with AML but not adults with breast cancer)

Tumor

2 tandemrepeats

TS

Good antitumorresponse to 5FU

TS activity

3 tandemrepeats

Poor antitumorresponse to 5FU

TS activity

28bp repeats5FUMP(active)

5FU Dihydro 5-FU (inactive)

enhancer region

Normal DPD ;Normal 5FU

TOLERABILIITY

exon13 exon15 exon13 exon14 exon15

exon13 exon14 exon15

AG GT AG GT AG GT

MUT:A Wt:G

mRNA

Non-functional protein functional protein

~97% wt~3% het

JCI 98:610-15, 1998JCO 19:1779-86, 2001

Low DPD ;High 5FUTOXICITY

DPD

Thymidylate synthase ( TS )

DPD - dihydropyrimidine dehydrogenase

5FU toxicity andantitumor responseare affected bygenetic polymorphismsin DPD and TS

Gonzalez et al; Diasio et al

Relling & Dervieux Nature Ca Rev 2001;1:99-108

Tumor

2 tandemrepeats

TS


TS activity

3 tandemrepeats


TS activity



enhancer region


TOLERABILIITY



AG GT AG GT AG GT

MUT:A Wt:G

mRNA


~97% wt~3% het

JCI 98:610-15, 1998JCO 19:1779-86, 2001


DPD




Tumor

2 tandemrepeats

TS


TS activity

3 tandemrepeats


TS activity



enhancer region


TOLERABILIITY



AG GT AG GT AG GT

MUT:A Wt:G

mRNA


~97% wt~3% het

JCI 98:610-15, 1998JCO 19:1779-86, 2001


DPD




Relling & Dervieux Nature Ca Rev 2001;1:99-108

• > 1 polymorphism affects drug efficacy

• Germline polymorphisms also affect tumor responsiveness

DHF

THF

DHFR

TS

MTXglu

MTXglu

GARtf AICARtf

PRPPde novopurinesynthesis

GGH

MTXglu5

gluglu

n=7

MTXglu

RFC

diffusion

MTXgluMRP

THF5,10-CH2

MTHFR5-CH3THF

Homocysteine

Methionine

Polymorphisms in Gene Products for MTXMetabolism and Targets may Affect PK/PD

Greater oral mucositisindex (OMI) after MTX among BMT patients with mutant MTHFR C677Tgenotypes than amongpatients with C677Cgenotypes

Ulrich et al Blood 98:231-4, 2001

But MTHFR did not Affect Toxicity after HDMTX (with LV)

• The effect of each polymorphism may be dependent upon dose and schedule of the anticancer agent

Relling & Dervieux 2001;1:99-108

UGT1A1 Polymorphism affects risk of Irinotecan Toxicity

Thiopurine Methyltransferase(TPMT) Polymorphism affects6MP Pharmacodynamics

10

8

6

4

2

00 5 10 15 20 25 30

TPMT Activity

2000

1000

0Mut/Mut Wt/Mut Wt/Wt

HPRT

TGNs DNAincorporation

MP MeMPTPMT

toxicityrisk of relapse

myelosuppressionrisk secondary cancer

wt/wt

wt/m

m/m

Leukemia 14:567-72, 2000Relling & Dervieux Nature Ca Rev 2001;1:99-108

Cumulative Incidence of 6mp Dose Alterationsto Prevent Toxicity

During Continuation Therapy of Total XII

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 0.5 1 1.5 2 2.5

Years

CI

Homozygous Wild Types Heterozygotes Mutants

Relling et al JNCI, 1999

0

2

4

6

8

10

12

14

0 1 2 3 4 5

Antimetabolite Intensity Index*

Cum

ulat

ive

inci

denc

e (%

) br

ain

tum

or

XIX-RTSC

X-High

XII

Antimetabolite Intensity (during irradiation) vs Cumulative Risk of Brain Tumor

* Score = 1 for ITs during rads, -1 for LV during rads, 2 for systemic MTX during rads, 2 for full dose 6MP during rads

Lancet 1999

Www.pharmacogenetics.org

Drug Metabolizing Enzyme Polymorphisms

Drugs

secondarybrain tumor

thrombosis

arrhythmia Non-DrugInfluences

glucuronosyltransferase

polym orphism

cytochrom eP450

m utation

thiopurinem ethyl-

transferasemutation

cranialirradiation

pneumonia

folatedeficiencyasparaginase

macrolideantibiotics

thiopurine

potassiumchannel

polym orphismprothrombin

m utationtransporter

Polymorphisms in Drug Receptors, Targets, and Transporters

• Elucidating the clinical implications of each polymorphism may take a long time (AKA drugs have unintended consequences)

Incorporate Pharmacogenetics into all Clinical Trials

• Clinical trials are expensive

• freezing a tube of blood is cheap

• genotyping will get cheaper in the future

• obtain proper consent for future pharmacogenetic studies

• let’s not pretend we currently understand what to look at in the future

Polymorphisms Affecting Supportive Care Impact on Patient

Outcome

• Antimicrobials (K+ channels)

• cardiovascular agents (ACE, beta receptors)

• antithrombotics (CYP2C9, MTHFR, Factor V Leiden, prothrombin)

“Emphasis should not be focused on population averages, but rather on providing prescribers with the tools to determine the most effective and safest drug dosage for individual patients with a minimum of trial and error.”– Gerhard Levy, Clin Pharmacokin 34:323-

33, 1998

Documents

Genetic Variability and Cancer Germline polymorphisms are frequent: 1 SNP every 400-1500 bp (> 1 per gene) Cancer has acquired mutations (some tumor “mutations”