CHAPTER 5 Genetic Risk Factors - ONS...Gene Figure 5-1 Chromosome and Gene Structure. Courtesy of the National Human Genome Research Institute, Bethesda, MD. C G A T G C A T Figure5-2

CHAPTER 5

Genetic Risk FactorsKathleen A. Calzone and Julia A. Eggert

OVERVIEWI. Organization and function of genetic material

A. Chromosomes are threadlike structures that containgenetic information.1. The 46 chromosomes in the human body are

made up of 23 chromosome pairs, one copy fromeach parent.a. The small arm of the chromosome is identified

as the “petite” or “p” arm of the chromosome.b. The large arm is labeled the “q” arm, because

“q” follows “p” (Figure 5-1).2. Autosomes represent the 22 chromosome pairs,

numbered 1 to 22, which do not determine sex.3. Sex chromosomes are the X and Y chromosomes,

which determine an individual’s sex.a. Women have two X chromosomes.b. Men have one X chromosome and one Y

chromosome.B. Nucleic acids consist of bases and a sugar and

phosphate group. Two types of nucleic acids exist.1. Deoxyribonucleic acid (DNA) comprises two

nucleotide chains, running in opposite directionsand held together by hydrogen bonds, which arecoiled around one another to form a double helix(Figure 5-2).a. In DNA, two types of bases are present:

purines and pyrimidines.(1) Two types of purines: adenine (A) and

guanine (G)(2) Two types of pyrimidines: thymine (T)

and cytosine (C)b. DNA base pairs are complementary on the

double strand; A attaches to T, and G attachesto C.

2. Ribonucleic acid (RNA) consists of a singlenucleotide chain, which represents acomplimentary copy of a strand of DNA.a. In RNA, the bases are the same as DNA except

the base uracil (U) replaces thymine (T).b. Transcription refers to the process of making

RNA from DNA.

c. Translation refers to the process of makingproteins from RNA.

d. Proteins consist of chains of amino acids.Sequences of the amino acids determine thefunction of the protein.

e. Primary types of RNA (Figure 5-3)(1) Messenger RNA (mRNA) contains

information about the order of the aminoacids in a protein.(a) A codon is a chain of three mRNA

nucleotides that specifies theproduction of one of 20 differentamino acids.

(b) More than one codon will code for aspecific amino acid.

(c) An mRNA nucleotide change in thethird place of the codon rarely causesan amino acid change. A change in thefirst place of the codon usually willcause a different amino acid to beproduced and an error in building theprotein. These changes are the directcause of polymorphisms andmutations.

(d) Three “stop” codons and theassociated RNAs stop the growth ofthe amino acid chain.(i) Transfer RNA (tRNA) brings the

amino acids to the site of proteinsynthesis.

(ii) Ribosomal RNA (rRNA)provides the structural supportfor the protein in addition toother functions.

(iii) Small silencing RNAs haveimportant roles in generegulation. These includemicroRNA (miRNA), Piwi-interacting RNA (piRNA) andsmall interfering RNA (siRNA)(Ghildiyal & Zamore, 2009).

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C. As seen in Figure 5-1, genes are individual units ofhereditary information, which are located at aspecific position on the chromosome.1. Genes consist of a sequence of DNA that codes for

a specific protein (see Figure 5-1).2. Genes consist primarily of exons and introns.

a. Exons are protein-coding segments of a gene.b. Introns are non–protein-coding segments or

the sequence-interrupting piece of a gene.II. Basic mechanisms of carcinogenesis, mutations, and

heredityA. Cancer has a multifactorial etiology with several

genetic, environmental, and personal factorsinteracting to produce a malignancy.

B. Genetic mutations and genetic instability are at thevery core of cancer development. Most cancers arenot the result of inherited mutations.1. Most cancers are associated with genetic

mutations that occur in single cells some timeduring the life of an individual.

2. A malignant tumor arises after a series of geneticmutations have accumulated.

B. Genetic mutations that are acquired are associatedwith exogenous (environmental) or indigenousfactors (biologic). For example, carcinogens areexogenous factors thought to operate by causinggenetic mutations.

C. Mutations are disease-causing variations in thesequence of DNA.1. Genetic mutations are usually acquired over a

lifetime. These are designated as somatic and areacquired genetic mutations in body cells thatoccur after conception.

2. In a person with a genetic predisposition tocancer, a mutation has been inherited in thegermline reproductive cells.

3. Types of mutationsa. Frameshift mutations occur when one or

more bases are added or deleted from thenormal sequence, resulting in an altered formof the protein.

b. Missense mutations are single–base pairchanges that result in the substitution of oneamino acid for another in the protein beingconstructed. Some of the substituted aminoacids may be critical to the function of theprotein.

c. Nonsense mutations change an amino acidsignal into a signal to stop adding amino acidsto a growing protein. Nonsense mutationsresult in a truncated, presumablynonfunctional, protein.

d. RNA-negative mutations result in the absenceof RNA transcribed from a gene copy.

Telomere

Centromerep arm

q armTelomere

Chromosome

Gene

Figure 5-1 Chromosome and Gene Structure. Courtesy of the National Human GenomeResearch Institute, Bethesda, MD.

CG

AT

GC

AT

Figure 5-2 Deoxyribonucleic Acid (DNA) Structure. FromCoed, J. & Dunstall, M. (2006). Anatomy and physiology formidwives (2nd ed.). New York: Churchill Livingstone.

CHAPTER 5 • Genetic Risk Factors 45

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e. Splicing mutations occur when DNA thatshould be removed from the coding sequenceis retained or when DNA that should not beadded is spliced in, resulting in frameshiftmutations.

f. Polymorphisms are changes in the DNAsequence of a gene that often are not diseaserelated, occur at variable frequency, and areassociated with individualization in thegeneral population. A single nucleotidepolymorphism (SNP, pronounced “snip”) is aDNA change in one nucleotide.

4. Chromosomal abnormalitiesa. Translocations refer to segments of one

chromosome that break off and attachthemselves to other chromosomes, resultingin altered protein production.

b. Aneuploidy is an abnormal number ofchromosomes.

c. Loss of heterozygosity refers to the loss of asegment of both copies of a chromosome.

d. Microsatellite instability (MSI) segments arerepetitive pieces of DNA scatteredthroughout the genome in the noncoding

Cytoplasm

RNA transcript splicedto produce mRNA

RNA transcribedfrom DNA

RNApolymerase

DNA

Nucleus

Completedprotein

Loaded tRNA binds toribosome, amino acidsare assembled in the orderdirected by the mRNA

Amino acids

tRNA

tRNA bindsamino acid

ATPADPGrowing peptide chain

Introns Exons

Primarytranscript

mRNA

mRNA

Ribosomalsubunit

Ribosomalsubunit

Nuclearpore

Figure 5-3 Three Types of Ribonucleic Acid (RNA). Adkinson, N., Yunginger, J., Busse, W.,Bochner, B., Holgate, S., & Simons, E. Middleton’s allergy principles and practice online (6th ed.).St. Louis, MO: Elsevier.

46 PART 2 • Scientific Basis for Practice

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regions (introns). MSI is a marker of germlineabnormality in mismatch repair genes incolorectal cancer, also known as Lynchsyndrome. If MSI is identified in sporadiccases, it is referred to as genehypermethylation.

D. A malignant tumor is derived from geneticinstability and genetic mutations in genes thatcontrol cell growth and proliferation.1. Types of regulatory genes

a. Proto-oncogenes are normal genes essentialfor normal cell growth and regulation.Mutations occurring in proto-oncogenesconvert to oncogene activation, which mayresult in uncontrolled cell division.

b. Tumor suppressor genes function asregulators of cell growth. Some tumorsuppressor genes appear to play a role in cellcycle regulation, whereas others have a role inDNA repair. Cells with mutation of a tumorsuppressor gene may develop uncontrolledcell growth.

c. DNA repair genes(1) Mismatch repair (MMR) genes are a type

of DNA repair genes responsible forkeeping the DNA free of “changes”during DNA synthesis. MMR genes areassociated with microsatellite instabilityin Lynch syndrome.

(2) Mutations in DNA repair genes may beinherited from a parent or acquired overtime because of aging or carcinogens fromthe environment.

2. Mutator phenotypea. The mutator gene phenotype allows an

increased mutation of genes because of poorproofreading or insertion of incorrectnucleotides left unrepaired. They seem to beefficient at acquiring mutations with bothclonal and random mutations, allowingthousands of mutations versus lower ratesseen with normal cells (Loeb, 2011).

b. DNA damage that is overlooked by repairmechanisms may lead to incorrect messagesin the DNA sequences, offering increasedchance of oncogene mutations. If this occurs,“driver” mutations offer a growth advantage.

c. “Passenger” mutations are those nucleotidechanges that do not provide a growthadvantage.

3. Control of cell growth and proliferationa. Apoptosis refers to the activation of a program

that leads to normal, programmed cell deathand often occurs in response to DNA damage.Malfunction results in uncontrolled cellproliferation of damaged and malignant cells.

b. Telomerase plays a role in cellular agingthrough the telomeres, which are the ends ofthe chromosome.(1) As cells age, telomerase is normally

repressed, and the telomeres areprogressively lost.

(2) In cancer, telomerase is reactivated,which keeps the telomeres intact,facilitating cell immortalization.

4. Cancer theoriesa. Knudson’s two-hit damage hypothesis refers

to the inactivation of both copies of a givenregulatory gene. Because all individuals areborn with two copies of almost every gene,Knudson originally theorized that bothfunctioning copies of the gene must beinactivated for cancer to occur. Now, on thebasis of molecular-level research, it is knownthat that one hit may exist, as seen withchronic myeloid leukemia (CML), that twohits cause retinoblastoma, and that many hitsover time cause cancers, such as colorectalcancer (Knudson, 2001).

b. Viral (retrovirus) infections copy a piece ofRNA genome into the human DNA by usingviral reverse transcriptase. Once the viralDNA or RNA (viral oncogene) is integratedinto the human genome, it is transcribed byhost RNA polymerase, causing mRNA to betranslated into a nonfunctioning protein andresulting in cell proliferation (Rickinson &Kieff, 2001).

c. The inflammation theory of cancerdevelopment notes that a variety of infectiousagents and their relationships withinflammatory cells are the primary causes ofcancer, proliferation, survival, and migrationof cancer cells. From the innate immunesystem, selectins, chemokines (e.g., nuclearfactor κΒ [NFκΒ]) and their receptorsencourage invasion, migration, andmetastasis(Coussens & Werb, 2002; Kawanishi, Hiraku,Pinlaor, & Ma, 2006).

E. Mendelian inheritance1. Autosomal dominant inheritance requires only

one altered copy of a gene to result in diseaseexpression (Figure 5-4).

2. Autosomal recessive inheritance requires twoaltered copies of a gene, one from each parent, toresult in disease expression (Figure 5-5).

3. X-linked inheritance is associated with theinheritance of genes located on the Xchromosome. Men carry one X and one Ychromosome, and genes on their X chromosomeare hemizygous (having only one copy of achromosome pair), so a mutation in a gene on an


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X chromosome in a man may result in diseaseexpression.

III. Key technical characteristics of predisposition genetictesting and tumor profilingA. Techniques for identifying mutations

1. Direct sequencinga. Determines the sequence of the gene being

tested and detects sequence changes in theregions being analyzed

b. Detects sequence changes in the regionsbeing analyzed but may miss mutationsoutside the coding region or mutations thatare large genomic rearrangements or largedeletions

2. Allele-specific oligonucleotide (ASO)a. Detects one single specific mutation that

involves a short sequence of DNA3. Genome-wide association studies (GWAS)

a. Survey the entire genome for smallnucleotide alterations and do the following:(1) Detect SNPs or small mutations to

determine association with disease (NCIDictionary of Genetic Terms, n.d.)

(2) Review for changes with specific disease(cancer type) versus people without thedisease

(3) Design high-throughput genomesequencing techniques to offer faster andcheaper ways to obtain genetic data, withpotential impact on personalized profilingfor diagnosis, pharmacogenomics, anddisease monitoring (Soon, Hariharan &Snyder, 2013)

4. Single-strand confirmation polymorphismanalysis (SSCP)a. A sequence change of DNA alters the size

and shape of a DNA fragment, which isdetected by SSCP on a gel.

b. An altered gene produces a gel band differentfrom that produced by a normal gene.

c. SSCP easily detects insertions or deletions offour or more bases of DNA; however,mutations exchanging one base for anotherwithout altering the length of the DNAfragment are difficult to detect. In thistechnique, gel electrophoresis separatesdifferent conformations of the strands priorto sequencing.

5. Large genomic rearrangements (LGRs)a. Detect large rearrangements, deletions, and

duplications (like pages or paragraphsmissing or rearranged in a mystery novel)

b. Found in BRCA1 family mutations:(1) At least two persons younger than

50 years diagnosed with breast cancer(2) Family history of breast and ovarian

cancers(3) Only ovarian cancer, with at least two

members diagnosed with ovarian cancer(4) A single breast cancer case prior to the

age of 36 years(5) None identified in only one breast cancer

case prior to age 51 (Engert et al., 2008)6. Microarray

a. Technique attaches large numbers (hundredsto thousands) of DNA, RNA, protein, ortissue segments to slides specific locations onthe slide, followed by application of afluorescent label. The biosample is processedso that the genetic material of the sample

Figure 5-4 Autosomal Dominant Inheritance.

Figure 5-5 Autosomal Recessive Inheritance.


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binds to the genetic material on the slide. Theslide is scanned to measure the brightness ofeach fluorescent dot. The brighter the dot,the greater is the fluorescent activity(Figure 5-6).

b. Microarray is used for mutation detection aswell as gene expression.

7. Next-generation DNA sequencing (second-generation sequencing)a. New, lower-cost, higher-efficiency

techniques to target the whole genome,whole exome, and whole transcriptome

b. Detect somatic cancer genome alterationsof the nucleotide (substitutions, smallinsertions, deletions, variations in copynumber)

8. Whole-exome sequencing (WES) or targetedexome capturea. Low-cost alternative technique to sequence

exon (gene to protein-coding regions)pieces of the genome

b. Identifies area of protein function change inmendelian and common diseases

9. Transcriptome sequencinga. Analyzes coding RNA molecules and non-

coding RNA sequences in one or specificpopulations of cells (Meyerson, Gabriel, &Getz, 2010)

10. Sequential analysis of gene expression (SAGE)a. Provides a picture of the mRNA population

in a cancer sample11. Protein truncation assay

a. Refers to an analysis of codingDNA, directlytranslated in the laboratory into protein

b. Shortened proteins detected on a gel, basedon mobility differences between larger andsmaller proteins

c. Sensitive for detection of mutations inwhich the sequence change results in ashortened form of the protein but does notdetect other types of mutations

B. Techniques to identify chemical modification orpackaging of DNA1. Review methylation across entire genome

(methylome)a. Addition of methyl groups to GC-rich region

of DNAb. Hypomethylation with removal of methyl

groups causing inactivation of a gene2. Methylation pattern of genes by tissue type

C. Considerations in genetic testing laboratoryselection1. Laboratories where genetic testing is performed

should meet the following criteria:a. Clinical Laboratory Improvement Act

(CLIA)–approved laboratoryb. Does not evaluate proficiency of DNA

testingc. Laboratory director certified by the

American Board of Medical Genetics2. Research in which genetic research is performed

in institutional laboratories with oversight toensure meeting biosafety standards such as theNIH Guidelines for Research InvolvingRecombinant DNA Molecules (http://oba.od.nih.gov/oba/rac/Guidelines/NIH_Guidelines.htm)

IV. Use of genetic markers for diagnosisA. Cytogenetics focuses on the structure, function,

and abnormalities of chromosomes (Jorde, 2009).It is commonly used to diagnose both solid andhematologic malignancies.1. Karyotype offers a view of the number and

structural appearance of chromosomalstructures in the cell nucleus (Lobo, 2008)(Figure 5-7).a. Balanced structural change in chromosomes

with evenly exchanged genetic material;for example, Philadelphia chromosometranslocation of 9;22, which yields anabnormal chromosome but genetic materialamount remains constant althoughreshuffled (Figure 5-8)(1) Chromosomal rearrangement example:

CML with the hybrid bcr-abl gene(2) Some thyroid cancers associated with

rearrangements in the RET geneb. Nonreciprocal change of chromosomes with

unequal genetic material to be lost or gained(1) Deletions or inactivation of a gene on a

chromosome begin the process ofaccumulation of genetic variation, whichthen initiates cancer development.Tumor suppressor genes are an exampleof this type of nonreciprocal change.

(2) Increases in the gene copy numbercontribute to cancer transformation.

Figure 5-6 Microarray. Courtesy of the National HumanGenome Research Institute, Bethesda, MD.


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In sarcomas, the chromosome 12q13-14region is commonly amplified.

(3) Extra copies of the ERBB2 (HER2/neu)gene cause overexpression of theepidermal growth factor protein, which isassociated with aggressive breast cancer.

2. Nomenclature common to cytogenetic reportsincludes the modal number of chromosomes,the sex chromosome designation (XX or XY oraberrations of these chromosomes), theabnormality abbreviation, with the firstchromosome separated with a semicolon fromthe second chromosome t(14;16), and then thearm and band number (q32; q23) (Table 5-1).

B. Gene expression (tumor) profiling uses multipletechniques (e.g., gene sequencing) to identify theexpression (proteins) of tens to thousands of genesconcurrently. It uses a personalized approach to

cancer to diagnose, predict outcomes, or suggestthe best treatment regimen for a person’s cancer.Techniques such as a DNA microarray or serialanalysis of gene expression (SAGE) are also used.1. Colon cancer profiling examples include

OncotypeDX and ColoPrint.2. Breast cancer gene profiling examples include

Mammaprint, Symphony, and OncotypeDX.3. Myeloma Prognostic Risk Signature (MyPRS)

measures the expression values (levels) of 70risk-related genes.

V. Potential therapeutic interventionsA. Pharmacogenomics and pharmacogenetics (Klotz,

2007)1. Pharmacogenetics identifies the genetic basis for

differences in the metabolism of an agent andassociated treatment response, which can beused to individualize therapy.

13p

q

p

q

14 15

1617

1819 20

21 22

X

Y

1

2 3

4 5

6 78 9 10

11

12

Figure 5-7 Karyotype of Normal Chromosomes with G-Banding. Courtesy of the NationalHuman Genome Research Institute, Bethesda, MD.


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a. A superfamily of enzymes, including thecytochrome P450 family, responsible foroxidation reactions for drug metabolism:(1) Root symbol: CYP(2) Arabic number for family(3) Letter for subfamily(4) Arabic numeral for specific gene(5) Number 1 followed by an asterisk (*1)

denotes the wild-type gene (mostcommon)

(6) Additional number with (*) signifies avariant (*5)

(7) The enzyme (protein or gene product)identified as CYP2C19 and gene italicized(CYP2C19)

(8) Variances in specific allele frequenciesamong different populations; forexample, the variant CYP2D6*4 occursfrequently in whites, whereas Asians havea higher frequency of CYP2D6*10

b. Pharmacodynamics—study of thebiochemical and physiologic effects of drugson the body

c. Pharmacokinetics—description of how thebody absorbs, distributes, metabolizes, andexcretes a drug

d. Genetic variation—affects differences inefficacy, toxicity, pharmacodynamics, andpharmacokinetics(1) The DPD protein of the DYPD gene

is involved in the metabolism of5-fluorouracil (5-FU). DPD inactivates80% of active 5-FU. Persons with aDYPD*2A variant have a greater risk of agrade 3 to 4 toxicity, most commonlyneutropenia.

(2) The enzyme TPMT regulates6-mercaptopurine (6-MP) for acutelymphoblastic leukemia (ALL). Personswith low TPMT activity may have highconcentrations of 6-MP, leading totoxicities. Dosages are based on types ofvariants with TPMT*2, with TPMT*3Ahaving low or intermediate TPMTactivity. TPMT*1 (wild-type) has thehighest TPMT activity, heterozygotes(*1/*3) with intermediate and (*3/*3)with the lowest activity.

(3) Drug transporters are responsible forpumping drug molecules across cellmembranes. If these transporters areoveractive, interference with drugeffectiveness will occur. One of thetransporters, P-glycoprotein, is encodedby the ABCB1 gene. P-glycoproteindecreases intestinal absorption and brain

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Table 5-1

Common Cytogenetic Nomenclature

Nomenclature Meaning

‘ Separate of different elements of acytogenetic report

( ) Surround structurally alteredchromosomes

+ Gain of chromosome- Loss of chromosome; Separate rearranged chromosomes when

>1 involvedcd Cell or cluster of differentiation on surface

of cell membranedel Deletion of chromosomal materialdn New chromosomal abnormality; not

inherited from parentsdup Duplication of chromosomal materialins Insertioninv Inversionmar Unidentifiable piece of chromosome

(marker)t Translocation or move of genetic materialtri Trisomytrp Triplication of a chromosome pieceExample 46, XY, t(14;16)(q32;q23)¼normal

number of chromosomes, male,translocation of chromosome 4 and 16;specifically with position 32 on the longarm of chromosome 14 rearrangingwith position 23 on the long arm ofchromosome 16

Data from Basic nomenclature for cytogenetics. <http://www.slh.wisc.edu/cytogenetics/abnormalities/nomenclature.dot> Accessed 11 September 2014.

Normal

C D

A B

Translocation

Normal Gain

Normal Amplification

Normal Deletion

Figure 5-8 Types of Chromosomal Changes. FromGoldman, L. & Schafer, A. (2008). Cecil medicine (23rd ed.).Philadelphia: Saunders.


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uptake while increasing drug excretionvia the biliary intestinal and renalsystems. High activity of ABCB1 couldincrease removal of chemotherapy drugs,causing unsatisfactory treatmentoutcomes.

e. Phenotypic responses of genotype that affectresponse to active and prodrug responses(Table 5-2).

2. Pharmacogenomic testing (Table 5-3) includesthe following:

a. Genetic testing is required for some cancertherapies. See Table 5-4 for a list of some ofthese cancer treatment agents (Whirl-Carrilloet al., 2012).

b. Individualized treatment is based on thegenetic characteristics of the individual andthe tumor (see tumor profiling, section IV B,above) (Roses, 2000).

c. Testing for use of drugs is specifically aimed atindividualized genetic change and alteredprotein product of tumors.

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Table 5-2

Metabolizer Phenotypes and Anticipated Impacts on Active Drug and Prodrug

Genotype-PredictedPhenotype Patient’s Gene Pair

Anticipated Impact on ActiveDrug

Anticipated Impact onProdrug

Poor or slow metabolizer Homozygous for both variantswith absent ornonfunctioning protein

Decreased efficiency inconverting active drug toinactive metabolites

Increases risk for higher levels ofactive drug and clinicaltoxicity

Inability to convert inactiveprodrug to activemetabolites

If prodrug has no therepeuticproperties, then patient willexperience lack of efficacydespite drug dose increases

Intermediate metabolizer Heterozygousvariant of one gene results inabsent or nonfunctioningprotein variant of othermember of gene pair resultsin protein with reducedfunction-or-Pair of genes, each withvariant that results in proteinwith reduced function-or-One member of gene pairwith variant results in proteinreduced functionother allele has sequenceconsistent with fullfunctioning protein

Decreased efficiency inconverting active drug toinactive metabolites

Increases risk for higher levels ofactive drug and clinicaltoxicity

If drug is normally dosed lowand slowly titrated upward,effectiveness may be achievedsooner than in extensivemetabolizers

Decreased efficiency inconverting inactive prodrugto active metabolites

Decreased effectivenss atstandard maintenancedoses may be anticipated

Extensive metabolizer Homozygous with sequence forfull-functioning protein

Active drug given at standarddoses metabolized to inactivecomponents, achievingeffectiveness without or withminimal adverse drugreactions (ADRs)

Prodrug converted to activemetabolites achievingeffectiveness without orwith minimal ADRs

Ultra-rapid metabolizer Heterozygous with one locusconsistent with fullfunctioning protein, otherlocus has two or more copiesof gene sequence resulting infull functioning protein

Heterozygous with one memberof gene pair has sequenceconsistent with fullfunctioning protein and othermember of gene pair hasvariant that causes increasedamounts of full functioningprotein to be produced

Increased efficiency inconverting active drug toinactive metabolites

Risk for decreased effectivenessat standard doses

Increased efficiency inconverting prodrug toactive metabolites Increasedrisk for toxicity fromhigher-than-expected levelsof active metabolites


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B. Proteomics1. Analysis of the structure, composition, and

function of proteins2. Can aid in the diagnosis and enhance the

understanding of the biologic basis of cancerC. Somatic gene therapy

1. Introduction of a functioning gene intothe somatic cells to replace missing ordefective genes or to provide a new cellularfunction

2. Ongoing investigational trials using somaticgene therapy for a variety of cancers

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Table 5-3

Some Genetic Variants and Their Effects on Pharmacotherapy*

Gene† Molecular EffectPolymorphism (NucleotideTranslation) Drug Effect on Therapy

CytochromeP450family

Decreased enzyme activity Various polymorphism Various Interindividual variabilityin pharmacokinetics(PK)

TPMT2, 3A,3C

Decreased enzyme activity Various polymorphism 6-MP,thioguanine

Hematopoietic toxicity

UGT1A 28 Decreased enzyme activity TA repeats in 5’ promoter Iriniotecan Neutropenia toxicityMDR1 Low expression (C3435T) Various Drug resistanceTYMS Increased enzyme activity 3 tandem repeats 5-FU,

MethotrexateDrug resistance

DPYD Decreased enzyme activity IVS14+1G 5-FU,Methotrexate

Neutropenia toxicity

DHFR Increased enzyme activity T91C Methotrexate Drug resistanceMTHFR Decreased enzyme activity (C677T) (A1298C) 5-FU,

MethotrexateToxicity

c-KIT Constitutive signal activation D860 N567K Imatinib Desensitizes activity inGIST

K-RAS Inhibition of the tyrosinekinase domain-bindingdrug

G12x G13D CetuximabPanitumomab

Desensitizes activity incolon-rectum

B-RAF Inhibition of the tyrosinekinase domain-bindingdrug

V600E VemurafenibGefitinib

Good response inmelanomas

EGFR Inhibition of the tyrosinekinase domain-bindingdrug

L858R Erlotinib Good response in NSCLC

BCR/ABLfusiongene

Constitutive signal activation T(9;22) BCR/ABL ImatinibDasatinibNilotinib

Good response in CML

ABL Inhibition of the tyrosineKinase domain-bindingdrug

T315I; M351T Imatinib Drug resistance in CML

PML/RARαfusiongene

Block of myeloid lineage cells T(15;17) PML/RARα All-TransRetinoic acid(ATRA)

Good response in AML-M3 subtypes

ADRB1ADRB2

G-protein altered R389G Beta-bloccants Desensitizes activity

MHC class B1

HLA-B�5701 aplotype Several SNPs includingcodon K751Q

Abacavir Hypersensitivity r

VKORC1 Associated with a higher/lower warfarin dose

Many, VKORC1 haplotypesincluding codon G3673A

Warfarin Variable anticoagulanteffect

5-FU, 5-Fluorouracil; 6-MP, 6-mercaptopurine; ADRB, adrenergic beta-receptors; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; DHFR, dihydrofolatereductase; EGFR, epidermal growth factor receptor; GIST, gastrointestinal stromal tumor; MDR1, multidrug resistance 1; MTHFR, 5,10-methylene tetra hydrofolate reductase;NSCLC, non–small-cell lung cancer; PK, pharmacokinetics; TPMT, thiopurine methyl transferase; TYMS, thymidylate synthase; UGT1A1, UDP-glucuronosyl transferase 1A1;VKORC1, vitamin K epoxide reductase complex 1.

*The present list is not comprehensive.†Genes are available for genotyping test or under consideration for clinical diagnostics.

Adapted from Di Francia, R., Valente, D., Catapano, O., Rupolo, M., Tirelli, U., & Berretta, M. (2012). Knowledge and skills needs for health professions aboutpharmacogenomics testing field. European Review for Medical and Pharmacological Sciences, 16(6), 781–788.


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D. Germline gene therapy1. Introduction of a functioning gene into the

egg or sperm to prevent transmission of a geneticmutation

2. Germline gene therapy not available becauseit raises several ethical, legal, and social concerns

VI. Common hereditary cancer syndromes and cancersusceptibility genesA. The common hereditary cancer syndromes,

clinical manifestations, inheritance patterns, andgenes are outlined in Table 5-5.

B. Features of hereditary cancer (Lindor, McMaster,Lindor & Greene, 2008)

1. Family member with a known germlinedeleterious mutation in a cancersusceptibility gene

2. Early age of cancer onset3. Cancer of rare histology4. Cancer in two or more close biologically related

relatives5. Bilateral cancer in paired organs (e.g., breast

or ovary)6. Multiple primary cancers in a single

individual7. Constellation of cancers in the family part of a

known hereditary cancer syndrome

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Table 5-4

Necessity of Pharmacogenetic Testing for Some Approved Oncologic Agents*

PharmacogeneticBiomarker Cancer Target Oncologic Agent

Test Required Prior to TreatmentBRAF (cobas 4800 BRAF V600 Mutation

Test)Unresectable or metastatic melanoma Vemurafenib

EGFR expression Metastatic colon cancer,Head and neck (testing not required) cancer

CetuximabPanitumumab

Estrogen receptor (ER) and progesteronereceptor (PR)

Breast cancer ExemestaneFulvestrantLetrozole

K-ras Colon cancer CetuximabPanitumumabDasatinib

HER2/neu overexpression Breast cancer TrastuzumabLapatinib

Presence of Philadelphia chromosome (Ph+)

Chronic myeloid leukemia (CML) ImatinibImatinib

PDGFRα Gastrointestinal stromal tumors (GIST) Tyrosine kinase inhibitorsFIP1L1-PDGFRα Myelodysplastic//proliferative disorders Imatinib

Tests Recommended for Treatment DecisionEGFR NSCLC ErlotinibG6PD Tumor lysis syndrome RasburicasePh+ CML NilotinibTPMT variants Acute lymphocytic leukemia, acute

nonlymphocytic leukemiaMercaptopurine, thioguanine

UGT1A1 variants Colorectal cancer IrinotecanNilotinib

Tests for Information OnlyCD-30 Hodgkin lymphoma

Anaplastic large cell lymphomaBrentuximab vedotin

c-Kit expression Kit+gastrointestinal stromal tumors ImatinibDYPD deficiency Colorectal or breast cancers Capecitabine, 5-fluorouracilPhiladelphia chromosome deficiency (Ph-) CML BusulfanPML/RAR gene expression Promyelocytic leukemia Arsenic Trioxide

*This information changes frequently and should be checked for current accuracy.

Data fromU.S. Food and Drug Administration. (2013, June 19). Table of valid genomic biomarkers in drug labels. http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378. Accessed 11 September 2014.; PharmGKB. (2013). Genetic tests. http://www.pharmgkb.org/views/viewGeneticTests.action. Accessed. 11September 2014.


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Table 5-5

Common Hereditary Cancer Syndromes and Cancer Susceptibility Genes

Syndrome Clinical Manifestations GeneMode ofInheritance

Ataxia-telangectasia Cerebral ataxia, oculocutaneous telangectasias, radiationhypersensitivity, leukemia, lymphoma, breast cancer, andother solid tumors

ATM Autosomalrecessive

Basal cell nevussyndrome

Basal cell carcinoma, medulloblastoma, ovarian fibrosarcoma,odontogenic keratocyst, palmar or plantar pits, and ectopiccalcification

PTCH Autosomaldominant

Breast/ovariancancer syndrome

Breast, ovary, fallopian tube, prostate, pancreas, and possiblygastric as well as other sites

BRCA1 Autosomaldominant

Breast, ovary, fallopian tube, prostate, pancreas, melanoma,and possibly gastric as well as other sites

BRCA2 Autosomaldominant

Cowden syndrome Multiple mucocutaneous lesions, vitiligo, angiomas, benignproliferative disease of multiple organ systems,macrocephaly, breast cancer, thyroid (nonmedullary)cancer, endometrial cancer, and renal cancer, as well as otherpossible sites

PTEN Autosomaldominant

Familialadenomatouspolyposis

Colon polyposis (adenomas), desmoid tumors, osteomas,thyroid cancer, and hepatoblastoma

APC Autosomaldominant

Familial juvenilepolyposis

Hamartomatous polyps of the stomach, small intestine, colon,and rectum

Colon cancer as well as cancers of the stomach, duodenum, andpancreas

BRIP1ASMAD4

Autosomaldominant

Fanconi anemia Leukemia, hepatocellular carcinomas, squamous cellcarcinomas of the head and neck, esophagus, cervix, vulva,anus, hepatic adenoma, myelodysplastic syndrome, aplasticanemia

FANCAFANCB/FAAP95FANCCFANCD1?BRCA2FANCD2FANCEFANCFFANCG/XRCC(FANCI/KIAA1784FANCJ/BACH1/BRIP1FANCL/PHF9/FAAP43/POG

FANCM/FAAP250/HefFANCCN/PALB2

Autosomalrecessive

Gorlin syndrome Basal cell carcinoma, brain tumors, and ovarian cancer PTCH Autosomaldominant

Gastric cancer, lobular breast cancer, and signet ring coloncancer

CDH1 Autosomaldominant

Lynch syndrome(previouslyknown ashereditarynonpolyposiscolorectal cancer[HNPCC])

Cancers of the colon, rectum, stomach, small intestine, biliarytract, brain, endometrium and ovary, and transitional cellcarcinoma of the ureters and renal pelvis

MLH1MSH2MSH6MSH3PMS1PMS2

Autosomaldominant

Li-Fraumenisyndrome

Breast cancer, sarcoma, brain tumors, leukemia, andadrenocortical carcinoma, as well as other possible cancers

TP53 Autosomaldominant

Melanoma Melanoma, astrocytoma, pancreatic cancer, and ocularmelanoma, as well as possibly breast cancer

CDKN2ACDK4

Autosomaldominant

Muir-Torresyndrome

Gastrointestinal and genitourinary cancers, skin, breast cancer,and benign breast tumors

MSH2MLH1

Autosomaldominant

Multiple endocrineneoplasia type 1

Pancreatic and neuroendocrine tumors, gastrinomas,insulinomas, parathyroid disease, and carcinoids, as well asadrenal cortical tumors, malignant schwannomas, ovariantumors, pancreatic islet cell cancers, and gastrointestinalstromal tumors

MEN1 Autosomaldominant

Continued


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C. Indications for cancer predisposition testing1. Criteria for predisposition genetic testing

vary, depending on the suspected inheritedcancer syndrome and mutations in the gene orgenes associated with that syndromea. Universal criteria for predisposition genetic

testing include the following:

(1) Confirmed family history consistentwith the hereditary cancer syndrome

(2) A test that can be interpreted onceperformed

(3) The test that will be used to assist inmedical decision making or will assist indiagnosis of a condition

................................................................................................................................

Table 5-5

Common Hereditary Cancer Syndromes and Cancer Susceptibility Genes—cont'd

Syndrome Clinical Manifestations GeneMode ofInheritance

Multiple endocrineneoplasia type 2

Medullary thyroid cancer, pheochromocytoma, papillarythyroid cancer, and ganglioneuromas

RET Autosomaldominant

MYH-associatedpolyposis (MAP)

Colon cancer and duodenal cancer, as well as colon, duodenal,and gastric fundic gland polyps, osteomas, sebaceous glandadenomas, and pilomatricomas

MYH Autosomalrecessive

Neurofibromatosistype 1

Malignant peripheral neural sheath tumors, neurofibromas,benign pheochromocytomas, meningiomas,hamartomatous intestinal polyps, gastrointestinal stromaltumors, optic gliomas, café-au-lait macules, axillary oringuinal freckles, iris hamartomas, and sphenoid wingdysplasia or congenital bowing or thinning of long bones, aswell as other malignancies

NF1 Autosomaldominant

Neurofibromatosistype 2

Neurofibromas, gliomas, vestibular schwannoma,schwannomas of other cranial and peripheral nerves,meningioma, ependymonas, and astrocytoma

NF2 Autosomaldominant

Prostate cancer Prostate and other cancers not established BRCA1BRCA2HOXB13RNASELELAC2/HPC2MSR1EMSYAMACRKLM6NBS1CHEK2Mismatch repair genes(MLH1, MSH2,MSH6, PMS2)

Several other loci understudy

Varied:Autosomaldominant,

Autosomalrecessive,

X-Linked

Retinoblastoma Retinoblastoma, soft tissue sarcoma and osteosarcoma,melanoma, brain tumors, nasal cavity cancers, lung cancer,bladder cancer, retinomas, and lipomas

RB1 Autosomaldominant

Von Hippel-Lindau Renal cell cancer, hemangioblastoma of brain, spinal cord, andretina, renal cysts, pheochromocytomas, endolymphatic sactumors, and pancreatic islet cell tumors

VHL Autosomaldominant

Wilms tumor Wilm tumor and nephrogenic rests WT1 Autosomaldominant

Xerodermapigmentosum

Basal and squamous cell skin cancer, melanoma, and sarcoma,as well as brain, lung, breast, uterus, kidney, and testiclecancers, leukemia, conjunctival papillomas, actinic keratosis,lid epithiomas, keratoacanthomas, angiomas, fibromas

XPAERCC3XPCERCC2DDB2ERCC4ERCC5POLH

Autosomalrecessive

From Lindor, N.M., McMaster, M.L., Lindor, C.J., Greene, M.H. (2008). Concise handbook of familial cancer susceptibility syndromes (2nd ed.). Journal of the NationalCancer Institute Monographs, 38, 1–93.


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(4) Informed consent by the client tobe tested

(5) Testing done in the context of pre- andpost-test genetic counseling (AmericanSociety of Clinical Oncology, 2003;Robson, Storm, Weitzel, Wollins, &Offit, 2010).(a) The National Society of Genetic

Counselors defines geneticcounseling as “the process of helpingpeople understand and adapt to themedical, psychological, and familialimplications of genetic contributionsto disease (National Society ofGenetic Counselors' Definition TaskForce, 2006).

(b) Providers delivering geneticcounseling may be physicians,nurses, or genetics counselors withspecialized training in genetics.Table 5-6 summarizes someresources available for finding ahealth care provider trained ingenetics.

2. The American Society of Clinical Oncology(ASCO) also recommends a review of theevidence of clinical utility for any genetic test(including multiplex tests, tests for low ormoderate disease genes, and SNP tests) beconsidered when either ordering or makingmedical recommendations based on a test result(Robson et al., 2010).

3. Not every client is appropriate forpredisposition genetic testing for inheritedcancer susceptibility.a. Genetic tests, including those for cancer risk,

are also available directly to the consumer, inwhich case ASCO also recommends a reviewof the clinical utility of the result before

making medical recommendations (Robsonet al., 2010).

D. Outcomes for cancer predisposition testing1. The predictive value of a negative test result

varies, depending on whether a known geneticmutation exists in the family.a. A negative test result in the presence of a

known genetic mutation indicates that theclient is within the general population risk ofcancer associated with that branch of thefamily.(1) However, family history from the other

parent still influences the risk ofdeveloping cancer.

b. A negative result with no known familygenetic mutation may occur because of oneof the following:(1) Identifying a mutation in a cancer

susceptibility gene may not be possiblebecause of the limited sensitivity of thetechniques used.

(2) The function of the gene may beaffected by a mutation in a different gene.

(3) The cancer in the family may beassociated with a cancer susceptibilitygene other than the one tested.

(4) The cancer in the family is not the resultof a germline genetic mutation.

c. A mutation of uncertain clinical significanceis identified. This refers to mutations inwhich the association with cancer risk cannotbe established.

2. The predictive value of a positive test resultvaries, depending on the type of geneticmutation identified and the degree ofcertainty that the function of the gene has beenaffected.a. Penetrance refers to the proportion of

all individuals with a specific genotypethat express the specific trait such ascancer.

b. Expression refers to the degree to which asingle individual with a specific genotype willexhibit a specific trait (e.g., cancer).(1) Expression may be different for different

genetic mutations in the same cancersusceptibility gene.

(2) Expression may also be affected byother genetic variations as well as bythe environment and other personalfactors.

VII. Medical management issues associated with the careof individuals harboring a mutation in a cancersusceptibility geneA. The management of cancer risk falls into five basic

categories:

............................................................

Table 5-6

Resources for Finding a Genetic HealthCare Provider

Resource Website

American Society of HumanGenetics

http://www.ashg.org/

International Society of Nursesin Genetics

http://www.isong.org/

National Society of GeneticCounselors, Find a GeneticCounselor

http://www.nsgc.org/tabid/69/Default.aspx

National Cancer InstituteCancer Genetics ServicesDirectory

http://www.cancer.gov/cancertopics/genetics/directory


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1. Surveillance, which is monitoring to detectcancer as early as possible, when the chancesfor cure are greatest

2. Risk-reducing surgery (also called prophylacticsurgery), which is the removal of as much of thetissue at risk as possible to reduce the risk ofdeveloping a cancer

3. Chemoprevention, which involves taking amedicine, vitamin, or other substance to reducethe risk of cancer

4. Risk avoidance, which is the avoidance ofexposures that may increase the risk of certaincancers

5. Healthy behaviors, including diet andexercise

B. Cancer risk management strategies available toindividuals at high risk for cancer because of amutation in a cancer susceptibility gene varyaccording to the gene, specific gene mutationidentified, or both. Each strategy has varyingdegrees of risks, benefits, and limitations, as well asvarying levels of evidence supporting the specificintervention.1. The National Cancer Institute Physician Data

Query (PDQ) Cancer Information Summarieson Genetics at http://www.cancer.gov/cancertopics/pdq/genetics provide evidence-based reviews for many common cancergenetic syndromes and include a summary ofcancer risk management strategies associatedwith that particular syndrome, as well as theassociated levels of evidence.

VIII. Ethical, legal, and social issues associated with geneticinformation (Offit & Thom, 2007)A. Predisposition genetic testing may have

psychological consequences, some of which couldimpact subsequent health behaviors and familycommunication.1. Survivor guilt is often observed in persons

who have not inherited the geneticmutation that is present in other closefamily members.

2. Transmitter guilt is often observed whenfamily members pass on the genetic mutationto one of their offspring.

3. Heightened anxiety may result when clientslearn that they are at a substantially increasedrisk for developing cancer or anotherprimary lesion.

4. Depression and anger may occur regardless ofgenetic status.

5. Personal identity issues result because geneticinformation involves the very essence of anindividual.

6. Regret for previous decisions may be presentin clients who have made major decisionsbased on their perceived cancer risk, and

testing results are inconsistent with what theyhad previously thought.

7. Uncertainty occurs because predispositiongenetic testing does not provide informationabout if or when cancer develops. In manyinstances, no proven risk-reducing strategyexists.

8. Intrafamilial issues arise becausepredisposition genetic testing affects allfamily members. These issues include, butare not limited to, the following:a. Coercion regarding testing, disclosure of

testing results to family members, andcancer risk management approaches

b. Effect of the genetic information on thepartner, who is not at risk physically butwhose children may be impacted

9. Stigmatization both within the family andwithin the individual’s social network.

10. Identification of an incidental finding ifmultiplex testing or some form of wholegenome analysis (e.g., whole exomesequencing, whole genome sequencing) isperformed

B. Predisposition genetic testing also has socialimplications.1. Financial considerations

a. Predisposition genetic testing may be veryexpensive. Some, but not all, insurers covertesting and counseling.

b. Insurers may be reluctant to coverenhanced surveillance programs unlessefficacy has been proven.

c. Insurers may not be willing to cover theexpense of prophylactic surgery unless ithas proven benefit.

2. Quality assurance of laboratory testing is notcertain because no regulation exists beyondapproval for molecular laboratories thatperform testing based on the CLIA.

3. Availability and quality assurance ofgenetic counseling are of concern, given thesmall number of trained providers in cancergenetics.

C. Legal issues for the client undergoingpredisposition testing may involve the following:1. Discrimination may occur for those harboring

an altered cancer susceptibility gene becausetheymay be considered as having a preexistingcondition or may be too high a risk to insureor employ (Offit & Thom, 2007).a. Health insuranceb. Life insurancec. Disability insuranced. Long-term care insurancee. Educationf. Employment


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2. State and federal legislative approacheshave already been proposed or enacted,depending on the issue and state (NationalCancer Institute PDQ Genetics EditorialBoard, 2013).a. The Health Insurance Portability and

Accountability Act (HIPAA), a federal lawenacted in 1996, states that geneticinformation cannot be used as a pre-existing condition or to determineeligibility for insurance.(1) This protection only applies to group

and self-funded plans.(2) This law does not protect against rate

hikes, access of insurers to anindividual’s genetic information, or theinsurer requiring genetic testing as acondition of insurance coverage.

b. The Genetic InformationNondiscrimination Act (GINA),federal legislation enacted in 2008, appliesto health insurance and employmentdiscrimination based on geneticinformation (Baruch & Hudson,2008; Hudson, Holohan, & Collins, 2008).(1) Health insurance protections include

protections against accessing anindividual’s genomic information,requirements for an individual toundergo a genetic or genomic test,and using genomic informationagainst a person during medicalunderwriting.

(2) Employment protections includeprohibiting employers from accessingan individual’s genetic information,use of genomic information to denyemployment, or collecting genomicinformation without consent.

(3) The GINA does not supersede statelegislation that provides for moreextensive protections.

(4) The GINA does not apply to activeduty military personnel, VeteransAdministration, or the Indian HealthService because the laws amended forGINA do not apply to these groups.

c. The U.S. Equal Employment OpportunityCommission released guidelines in March1995 on the definition of “disability” underthe Americans with Disabilities Act (ADA),which is now extended to includediscrimination based on geneticinformation. This set of guidelines is not lawbut simply is an interpretation of thelanguage of the ADA and may beoverturned in a court of law.

3. Self-insured employers may also be exemptfrom state laws and regulations on healthinsurance because of the EmployeeRetirement Income Security Act of 1974(ERISA), which governs employer pensionplans as well as other benefits.

D. Informed consent should precede genetictesting and include the following (Riley et al.,2012; Weitzel, Blazer, Macdonald, Culver, &Offit, 2011):1. Purpose of the genetic test2. Motivation for testing3. Risks of genetic testing4. Benefits of genetic testing5. Limitations of genetic testing6. Inheritance pattern of the gene(s)

being tested7. Risk of misidentified paternity, if applicable8. Accuracy and sensitivity of genetic testing

method9. Outcomes of genetic testing

10. Confidentiality of genetic testing results11. Possibility of discrimination12. Alternatives to genetic testing13. How testing will impact health care decision

making14. Cost of testing15. Right to refuse16. Testing in children (<18 years of age)

a. Performed when clinical utility for testingin children has been established

17. Management of incidental findingsE. Genetic technology raises legal liability issues for

the health care provider.1. Privacy and confidentiality

a. Genetic information of all types should behandled in a confidential manner toprevent unauthorized access.

2. Genetic testing should be preceded bygenetic counseling by a genetic health careprofessional, education, counseling, andinformed consent.

3. Health care providers may have a duty toinform clients regarding their potential forincreased cancer risk from an inheritedsusceptibility and the availability ofpredisposition genetic testing (Offit, Groeger,Turner, Wadsworth, & Weiser, 2004).

F. Table 5-7 summarizes some available genetic andgenomic resources.

NURSING IMPLICATIONSI. Interventions to assist the client and family to

understand cancer genetics and genetic testingA. Description of the organization and function of

genetic material and the role of genetics incarcinogenesis


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B. Assessment of the client’s beliefs about the cause ofcancer in the family and correct misconceptions

C. Description of the process for cancer risk evaluationand predisposition genetic testing

D. Discussion of the risks and benefits of predispositiongenetic testing

E. Discussion of the risks and benefits ofpharmacogenetic or genomic testing

F. Description of the rationale for the use of tumorprofiling

II. Interventions to decrease perceived and actual barriersto cancer risk managementA. Education and monitoring of the performance of

self-examination techniquesB. Education on the benefits of cancer risk

managementC. Facilitating reimbursement for cancer risk

management proceduresD. Encouragement of communication regarding fears

and concernsIII. Interventions to enhance coping and adaptation

A. Referral of the client, family, or both to communitysupport services.

B. Referral of the client, family, or both to professionalcounseling services, when indicated

C. Encouragement of the use of coping strategies thathave previously been effective

References

American Society of Clinical Oncology. (2003). American Societyof Clinical Oncology policy statement update: Genetic testingfor cancer susceptibility. Journal of Clinical Oncology, 21(12),2397–2406.

Baruch, S., & Hudson, K. (2008). Civilian and military genetics:Nondiscrimination policy in a post-GINA world. AmericanJournal of Human Genetics, 83(4), 435–444.

Coussens, L. M., & Werb, Z. (2002). Nature, 420(6917), 860–867.http://dx.doi.org/10.1038/nature01322.

Di Francia, R., Valente, D., Catapano, O., Rupolo, M., Tirelli, U., &Berretta, M. (2012). Knowledge and skills needs for health pro-fessions about pharmacogenomics testing field. European Reviewfor Medical and Pharmacological Sciences, 16(6), 781–788.

Engert, S., Wappenschmidt, B., Betz, B., Kast, K., Kutsche, M.,Hellebrand, H., et al. (2008). MLPA screening in the BRCA1gene from 1,507 German hereditary breast cancer cases: Noveldeletions, frequent involvement of exon 17, anad occurrence insingle early-onset cases. Human Mutation, 7(7), 948–958.http://dx.doi.org/10.1002/humu.20723.

Ghildiyal, M., & Zamore, P. (2009). Small silencing RNAs: Anexpanding universe. Nature Reviews Genetics, 10(2), 94–108.http://dx.doi.org/10.1038/nrg2504.

Hudson, K. L., Holohan, M. K., & Collins, F. S. (2008). Keepingpace with the times–The Genetic Information Nondiscrimina-tion Act of 2008. New England Journal of Medicine, 358(25),2661–2663.

Jorde, L. B. (2009). Clinical cytogenetics: The chromosomalbasis of human disease. In L. B. Jorde, & J. C. Carey (Eds.),Medical genetics (pp. 100–127): Mosby, Inc., an affiliate ofElsevier Inc.

Kawanishi, S., Hiraku, Y., Pinlaor, S., & Ma, N. (2006). Oxidativeand nitrative DNA damage in animals and patients withinflammatory diseases in relation to inflammation-related car-cinogenesis. The Journal of Biological Chemistry, 387, 365–372.http://dx.doi.org/10.1515/BC.

Klotz, U. (2007). The role of pharmacogenetics in the metabolismof antiepileptic drugs: Pharmacokinetic and therapeutic impli-cations. Clinical Pharmacokinetics, 46(4), 271.

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Table 5-7

Genomic Health Care Resources

Resource Website

Essential Genetic andGenomic Competenciesfor Nurses withGraduate Degrees

http://nursingworld.org/MainMenuCategories/EthicsStandards/Genetics-1/Essential-Genetic-and-Genomic-Competencies-for-Nurses-With-Graduate-Degrees.pdf

Genetic and GenomicNursing:Competencies,Curricula Guidelinesand OutcomeIndicators, 2nd edition

http://www.genome.gov/Pages/Careers/HealthProfessionalEducation/geneticscompetency.pdf

Genetics/GenomicsCompetency Centerfor Education (G2C2)

http://www.g-2-c-2.org

Genetic Home Reference http://ghr.nlm.nih.gov/Genetic Testing Registry http://www.ncbi.nlm.nih.gov/gtr/Global Genetics and

Genomics Community(G3C)

http://www.g-3-c.org

National Cancer InstitutePhysician Data Query(PDQ) CancerInformationSummaries: Genetics

http://www.cancer.gov/cancertopics/pdq/genetics

Online MendelianInheritance in Man

http://www.omim.org/

Telling Stories:Understanding RealLife Genetics

http://www.tellingstories.nhs.uk/about_us.asp

Oncology NursingSociety. (2012).Oncology nursing: Theapplication of cancergenetics and genomicsthroughout theoncology carecontinuum

http://www.ons.org/Publications/Positions/HealthCarePolicy

PharmacogenomicsEducation Program(PharmGenEd)

https://pharmacogenomics.ucsd.edu/

U.S. Surgeon General’sFamily HistoryInitiative

http://www.hhs.gov/familyhistory/


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Knudson, A. G. (2001). Two genetic hits (more or less). Cancer, 1(2), 157–162.

Lindor, N. M., McMaster, M. L., Lindor, C. J., & Greene, M. H.(2008). Concise handbook of familial cancer susceptibility syn-dromes - second edition. Journal of the National Cancer Insti-tute Monographs, 38, 1–93.

Lobo, I. (2008). Chromosome abnormalities and cancer cytoge-netics. Nature Education, 1(1). Retrieved from, http://www.nature.com/scitable/topicpage/chromosome-abnormalities-and-cancer-cytogenetics-879.

Loeb, L. A. (2011). Human cncers express mutator phenotypes:Origin, consequences and targeting. Nature Reviews: Cancer,11, 450–457.

Meyerson, M., Gabriel, S., & Getz, G. (2010). Advances in under-standing cancer genomes through second-generation sequenc-ing. Nature Reviews Genetics, 11, 685–696. http://dx.doi.org/10.1038/nrg2841.

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National Society of Genetic Counselors' Definition Task Force,Resta, R., Biesecker, B. B., Bennett, R. L., Blum, S., Hahn, S.E., Strecker, M. N., et al. (2006). A new definition of geneticcounseling: National Society of Genetic Counselors' Task Forcereport. Journal of Genetic Counseling, 15(2), 77–83.

NCI Dictionary of Genetic Terms. (n.d.). Genome wide associa-tion study (GWAS). Retrieved from http://www.cancer.gov/geneticsdictionary?cdrid¼636780.

Offit, K., Groeger, E., Turner, S., Wadsworth, E. A., & Weiser, M.A. (2004). The “Duty to Warn” a patient’s family membersabout hereditary disease risks. Journal of the American MedicalAssociation, 292, 1469–1473.

Offit, K., & Thom, P. (2007). Ethical and legal aspects of cancergenetic testing. Seminars in Oncology, 34, 435–443.

PharmGKB. (2013). Genetic tests. Retrieved from, http://www.pharmgkb.org/views/viewGeneticTests.action.

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Riley, B. D., Culver, J. O., Skrzynia, C., Senter, L. A., Peters, J. A.,Costalas, J. W., et al. (2012). Essential elements of genetic can-cer risk assessment, counseling, and testing: Updated recom-mendations of the National Society of Genetic Counselors.Journal of Genetic Counseling, 21(2), 151–161. http://dx.doi.org/10.1007/s10897-011-9462-x.

Robson, M. E., Storm, C. D., Weitzel, J., Wollins, D. S., & Offit, K.(2010). American Society of Clinical Oncology policy state-ment update: Genetic and genomic testing for cancer suscep-tibility. Journal of Clinical Oncology, 28(5), 893–901.

Roses, A. D. (2000). Pharmacogenetics and the practice of medi-cine. Nature, 405(6788), 857–865. http://dx.doi.org/10.1038/35015728 DOI:10.1038%2F35015728.

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Documents

CHAPTER 5 Genetic Risk Factors - ONS...Gene Figure 5-1 Chromosome and Gene Structure. Courtesy of the National Human Genome Research Institute, Bethesda, MD. C G A T G C A T Figure5-2