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National Cancer InstituteSlide Show on Single Nucleotide

Polymorphisms [SNPS]

• http://nci.nih.gov/cancertopics/understandingcancer/geneticvariation

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Understanding Cancer and Related Topics

Understanding SNPs and Cancer

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Developed by:Susan Greenhut, M.S.Donna Kerrigan, M.S.Jeanne KellyBrian HollenExplains tiny variations in the human genome called Single Nucleotide Polymorphisms (SNPs) that can influence a person’s health. Shows how SNPs occur in both coding and noncoding regions and can cause silent, harmless, harmful, or latent effects. Shows how SNPs can be markers for cancer. Suggests that SNPs may also be involved in the different levels of individual cancer risk observed. Suggests that, in the future, SNPs databases may be used to improve cancer diagnosis and treatment planning.

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Cancer – Different Fates

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Cancer – A Complex Disease

Diabetic islet cell

Normal islet cellNormal lung cell

Lung cancer cell

Many years later

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SNPs A SNPs B

SNPs C SNPs D

SNPs May Be the Solution

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What Is the Human Genome?

Human Cell

Nucleus

Chromosomes

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DNA and Chromosome Structure

DNA molecule (chromosome)

Chemical bases

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T

G

C

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The Genome Contains Genes

Gene 2 Coding region Protein 2

Protein 1

Noncoding region

Noncoding region

Gene 1 Coding region

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Variation in the Human Genome

Person 1 Person 2

= Variations in DNA

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What Is Variation in the Genome?Common Sequence

Variations

Polymorphism

Deletions

Translocations

Insertions

Chromosome

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Variations Causing No Changes

= Variations in DNA that cause no changes

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Variations Causing Harmless Changes

= Variations in DNA that cause harmless changes

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Variations Causing Harmful Changes

= Variation in DNA that causes harmful change

No Disease

No Disease Hemophilia

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Variations Causing Latent Changes

Many years laterMany years later

= Variations in DNA that cause latent effects

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SNPs Are the Most CommonType of Variation

At least 1 percent of the populationMost of the population

Common sequence

G to C

SNP site

Variant sequence

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Why Are SNPs Significant?

Person 1 Person 2

= SNP variations in DNA

SNP marks Gene A

Gene BGene A

SNP may cause Gene B to make altered protein

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Amino Acids

Lysine side chain

20 Different Amino Acids

Basic Structure of an Amino Acid

Graphic Representation of an Amino Acid

Lysine

Carboxyl group

Amino group

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Amino Acid Side ChainsWater-Loving

Lysine

Water

Oil

Histidine Glutamic acid

Aspartic acid

Arginine

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Amino Acid Side ChainsOil-Loving

Alanine

Water

Oil

Methionine

Phenylalanine

Proline

Cysteine Tryptophan

LeucineGlycine Valine

Isoleucine

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Amino Acid Side ChainsAmbivalent

Water

Oil

Serine

Tyrosine

Asparagine Threonine

Glutamine

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ProteinsAmino group

Carboxyl group

Peptide bond

Amino group

Amino group

Carboxyl group

Carboxyl group

Peptide bond

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Genes to Proteins I

DNA

TACGCAATATGCATT

AUGCGUUAUACGUAA

mRNA

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Genes to Proteins II

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Genes to Proteins III

Ribosome

mRNA

tRNA

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Codons:AUG=Methionine=StartCGU=ArginineUAU=TyrosineACG=ThreonineUAA=Stop

Methionine

Arginine

Threonine

Tyrosine

U G C G U U A U A C U A AG

StopTyrosineMethionine

ThreonineArginine

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Protein Folding and Function

Amino acid chain grows

and folds

into a 3-D structure.

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SNPs in Coding Regions – No Changes in Protein

DNA SNP C to G

RNA CodonCUG to CUC

Protein Leucine to Leucine

No change in shape

Leucine Leucine

mRNA

G A C

C U G C U C

CUG CUC

G A G

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SNPs in Coding Regions – Subtle, Harmless Changes in Protein

DNA SNP A to C

RNA CodonGAU to GAG

Protein Aspartic acid

to Glutamic acid

Slight change in shape

Aspartic acid Glutamic acid

mRNA

C T A

G A U G A G

GAU GAG

C T C

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SNPs in Coding Regions – Harmful Changes in Protein – Mutations

DNA SNP T to A

RNA CodonGAU to GUU

Protein Aspartic acid

to Valine

Change in shape

Aspartic acid Valine

mRNA

C T

G A U G U U

GAU GUU

C AA A

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SNPs in Coding Regions – Subtle Changes in Proteins

That Only Switch on Under Certain ConditionsSmoking

Switched-on genes

Pattern AMany years later

= SNPs causing latent effects

Pattern BMany years later

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Smoking and Susceptibility toLung Cancer

Water-SolubleCarcinogenEliminator

Carcinogen

Activator Precarcinogen

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Smoking and Susceptibility to Lung Cancer –SNPs in Carcinogen-Making Proteins

Hyperactive Activator Lazy Activator

Carcinogen

Precarcinogen

Carcinogen

Precarcinogen

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Smoking and Susceptibility to Lung Cancer –SNPs in Detoxifying Proteins

Active Eliminator Lazy Eliminator

Carcinogen

Water-SolubleCarcinogen

Carcinogen

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Arylamines and Bladder CancerAcetylator Deaminator

Arylamines

PrecarcinogenNonreactive compound (safely removed from body)

Carcinogen

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SNPs and Bladder Cancer RiskLazy Acetylator Deaminator

Arylamines

PrecarcinogenNonreactive compound (safely removed from body)

Carcinogen

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Not the Whole Story

Bladder cancer patient

United States Population

Fast acetylators Slow acetylators

=10 people

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SNPs and Drug Interactions

Transporter

Drug

Absorption in the breast

Drug in breast tissue

Metabolism in the liver

Excretion in the kidney

Drug becomes inactive or toxicTransportation in

the blood

Drug in bloodstream

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SNPs in Noncoding Regions – Markers for Genes

Gene Y

SNP X

Gene Y

SNP X

Gene Y

SNP X

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SNP Maps

All SNPs are recorded

SNP locationAll chromosomes are sequenced

SNP Data

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SNP profile A

SNP profile B

SNP profile F

SNP profile E

SNP profile DSNP profile C

Individual SNP Profiles

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SNP Profiles and Response toDrug Therapy

Does Not Respond to Standard Drug Treatment

Breast Cancer Patients

Individual SNP Profiles Are Sorted

SNP profile A SNP profile B

SNP profile D

SNP profile E SNP profile C

Responds to Standard Drug Treatment

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SNP Profiles May Help to Identify Cancer Genes

CC gene 5

SNPs common in colon cancer patients are colon cancer gene markers

CC gene 1

CC gene 2

CC gene 3

CC gene 4

Chrom EChrom A

Chrom B Chrom C Chrom D

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SNPs and Cancer Risk

Kidney cancer patients

=10 people, SNP B

=10 people, SNP A

Normal population

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Summary – SNPs and Cancer Research

Better treatment for patients

Patient A

SNP profile

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