Genetics of Colorectal Genetics of Colorectal CancerCancer
Peter Lee MDPeter Lee MDCentral Ohio Colon & Rectal CenterCentral Ohio Colon & Rectal Center
OverviewOverview
Molecular biology of cancerMolecular biology of cancer Epidemiology of colorectal cancerEpidemiology of colorectal cancer Inherited colorectal cancersInherited colorectal cancers Screening implications of colorectal cancerScreening implications of colorectal cancer SummarySummary
Cancer is a disease of the cell cycleCancer is a disease of the cell cycle
“Carcinoma is a genetic disease but it is not necessarily inherited”
Knudsen’s “two hit” hypothesisKnudsen’s “two hit” hypothesis
Types of genes which may mutate to cause cancer:Types of genes which may mutate to cause cancer:
OncogenesOncogenes Tumor suppressor genesTumor suppressor genes DNA repair genesDNA repair genes p53p53
OncogenesOncogenes
Cellular oncogene c-oncCellular oncogene c-onc Viral oncogene v-oncViral oncogene v-onc Proto-oncogene, activated by mutation to Proto-oncogene, activated by mutation to
c-oncc-onc
Proto-oncogene activationProto-oncogene activation
Tumour suppressor genesTumour suppressor genes
The gene’s normal function is to regulate cell The gene’s normal function is to regulate cell division. Both alleles need to be mutated or removed division. Both alleles need to be mutated or removed in order to lose the gene activity.in order to lose the gene activity.
The first mutation may be inherited or somatic.The first mutation may be inherited or somatic. The second mutation will often be a gross event The second mutation will often be a gross event
leading to loss of heterozygosity in the surrounding leading to loss of heterozygosity in the surrounding area.area.
Types of proto-oncogeneTypes of proto-oncogene Growth factorGrowth factor
e.g. SIS oncogene (PDGF)e.g. SIS oncogene (PDGF) G proteinsG proteins
e.g. rase.g. ras Nuclear transcription factorsNuclear transcription factors
e.g. MYCe.g. MYC
p53p53 Suppress progression through the cell cycle in Suppress progression through the cell cycle in
response to DNA damageresponse to DNA damage Initiate apoptosis if the damage to the cell is severe Initiate apoptosis if the damage to the cell is severe Is a transcription factor and once activated, it Is a transcription factor and once activated, it
represses transcription of one set of genes (several represses transcription of one set of genes (several of which are involved in stimulating cell growth) of which are involved in stimulating cell growth) while stimulating expression of other genes involved while stimulating expression of other genes involved in cell cycle controlin cell cycle control
Transformation is a Transformation is a multistep processmultistep process
Transformation is a multistep processTransformation is a multistep process
DNA MismatchesDNA Mismatches
Damage to nucleotides in ds-DNADamage to nucleotides in ds-DNA Misincorporation of nucleotideMisincorporation of nucleotide Missed or added nucleotidesMissed or added nucleotides
Acquired DNA DamageAcquired DNA Damage
-C-A- -T-A-
-G-T- -G-T-
M
Demethylation
Nucleotide MisincorporationNucleotide Misincorporation
-C-A-G-C-T-
-G-T-C-C-A-
-C-A-G-C-T-
-G-T-C-C-A-
-C-A-G-C-T-
-G-T-T-C-A-
-C-A-G-C-T-
-G-T-C-C-A-correctly copied
CT substitution
Added NucleotidesAdded Nucleotides
-C-A-G-C-T-
-G-T-C-C-A-
-C-A-G-C-T-
-G-T-C-C-A-
-C-A-G-C-T-
-G-T-C C-A-
-C-A-G-C-T-
-G-T-C-C-A-
A
correctly copied
nucleotide added
Human Mismatch Repair GenesHuman Mismatch Repair Genes
MLH1 MLH1 (3p21)(3p21) PMS1 PMS1 (2q31-33)(2q31-33) PMS2 PMS2 (7p22)(7p22) MSH2 MSH2 (2p16)(2p16) MSH3 MSH3 (5q3)(5q3) MSH6 MSH6 (2p16) (=GT Binding Protein)(2p16) (=GT Binding Protein)
Mismatch Repair GenesMismatch Repair Genes
Recognition and repair of mismatchesRecognition and repair of mismatches Other functionsOther functions
Repair of branched DNA structuresRepair of branched DNA structures Prevent recombination of divergent sequencesPrevent recombination of divergent sequences Direct non-MMR proteins in nucleotide excision Direct non-MMR proteins in nucleotide excision
and other forms of DNA repairand other forms of DNA repair
Other MMR ProteinsOther MMR Proteins
DNA ligaseDNA ligase Replication protein AReplication protein A Replication factor CReplication factor C Proliferating Cell Nuclear AntigenProliferating Cell Nuclear Antigen ExonucleasesExonucleases DNA polymerase DNA polymerase
Defective Mismatch RepairDefective Mismatch Repair
Defects in MMR Genes and FunctionDefects in MMR Genes and Function Microsatellite InstabilityMicrosatellite Instability Cancer developmentCancer development
90% of HNPCC colorectal cancers90% of HNPCC colorectal cancers 20% of sporadic colorectal cancers20% of sporadic colorectal cancers 30% of sporadic uterine cancers30% of sporadic uterine cancers
Cancer DevelopmentCancer Development
Activation of OncogenesActivation of Oncogenes Inactivation of Tumour Suppressor GenesInactivation of Tumour Suppressor Genes Defects in DNA mismatch repairDefects in DNA mismatch repair Susceptible to mutationSusceptible to mutation
Genetics of Colorectal Genetics of Colorectal CancerCancer
Colorectal CancerColorectal Cancer
11% of cancer-11% of cancer-related deathsrelated deaths
Tumor Tumor progression may progression may take 10-35 yearstake 10-35 years
Adenomatous Adenomatous polyp develops polyp develops into carcinomainto carcinoma
Chromosome changes in colorectal cancerChromosome changes in colorectal cancer
Cancer karyotype Stable karyotype
Worldwide Statistics for Colorectal Worldwide Statistics for Colorectal Cancer (CRC)Cancer (CRC)
875,000 cases in 1996875,000 cases in 1996 8.5% of all new cases of cancer8.5% of all new cases of cancer
556,000 deaths556,000 deaths Incidence rates vary (Up to 20 fold)Incidence rates vary (Up to 20 fold)
Highest in North America, Western Europe, Highest in North America, Western Europe, Australia, New Zealand, JapanAustralia, New Zealand, Japan
Lowest in India, Northern AfricaLowest in India, Northern Africa
Estimated New Cancer Cases of 10 Estimated New Cancer Cases of 10 Leading Sites by Gender for the US 2000Leading Sites by Gender for the US 2000
Colorectal Cancer Statistics in the Colorectal Cancer Statistics in the USUS
• Second overall leading cause of cancer-related Second overall leading cause of cancer-related deaths in the USdeaths in the US
• Estimated 130,000 new cases and 56,300 Estimated 130,000 new cases and 56,300 deaths in the year 2000deaths in the year 2000
• Declining trends between 1990 and 1996Declining trends between 1990 and 1996 Incidence rate: 2.1% per yearIncidence rate: 2.1% per year Mortality rates: 1.7% per yearMortality rates: 1.7% per year
Average Annual Age-Specific US Incidence Average Annual Age-Specific US Incidence and Mortality Rates of CRC, 1992-1996and Mortality Rates of CRC, 1992-1996
Prevalence of adenomasPrevalence of adenomas
Age ≥ 50 with any adenomas: 25-40%Age ≥ 50 with any adenomas: 25-40% Lifetime risk of cancer at age 50Lifetime risk of cancer at age 50
5% for females5% for females 6% for males6% for males Advanced adenomas at highest riskAdvanced adenomas at highest risk
Risk Factors for Colorectal Cancer Risk Factors for Colorectal Cancer (CRC)(CRC)
AgingAging Personal history of CRC or adenomasPersonal history of CRC or adenomas High-fat, low-fiber dietHigh-fat, low-fiber diet Inflammatory bowel diseaseInflammatory bowel disease Family history of CRCFamily history of CRC Hereditary colon cancer syndromesHereditary colon cancer syndromes
Risk of Colorectal Cancer (CRC)Risk of Colorectal Cancer (CRC)
0 20 40 60 80 100
General populationGeneral population
Personal history of Personal history of colorectal neoplasiacolorectal neoplasia
Inflammatory Inflammatory bowel diseasebowel disease
HNPCC mutationHNPCC mutation
FAPFAP
5%5%
15%–20%15%–20%
15%–40%15%–40%
70%–80%70%–80%
>95%>95%
Lifetime risk (%)Lifetime risk (%)
Familial Risk for CRCFamilial Risk for CRC
Lifetime Lifetime CRC risk CRC risk
(%)(%)
0
20
40
60
80
100
NoneNone One 1°One 1° One 1° One 1° and two and two
2°2°
One 1° One 1° age age <45<45
Two 1°Two 1° HNPCC HNPCC mutationmutation
2%2% 6%6% 8%8% 10%10%17%17%
70%70%
AarnioAarnio M et al. M et al. Int J CancerInt J Cancer 64:430, 1995 64:430, 1995 HoulstonHoulston RS et al. RS et al. Br Med JBr Med J 301:366, 1990 301:366, 1990 St John DJ et al. St John DJ et al. Ann Intern Med Ann Intern Med 118:785, 1993 118:785, 1993
Inherited Colorectal Inherited Colorectal CancersCancers
Heredity of Colorectal Cancer Heredity of Colorectal Cancer
5-8% of all cases of CRC are hereditary5-8% of all cases of CRC are hereditary
15-20% are “familial” / multifactorial15-20% are “familial” / multifactorial
75% of cases are sporadic75% of cases are sporadic
Feuer EJ: DEVCAN: National CA Inst. 1999
Causes of Hereditary Causes of Hereditary Susceptibility to CRCSusceptibility to CRC
Adapted from Burt RW et al. Adapted from Burt RW et al. Prevention and Early Detection of CRCPrevention and Early Detection of CRC, 1996, 1996
Sporadic Sporadic (65(65%–%–85%)85%)
Familial Familial (10(10%–%–30%)30%)
Hereditary Hereditary nonpolyposis colorectal nonpolyposis colorectal
cancer (HNPCC) (5%)cancer (HNPCC) (5%)Familial adenomatous Familial adenomatous polyposis (FAP) (1%)polyposis (FAP) (1%)
Rare CRC Rare CRC syndromes syndromes
(<0.1%)(<0.1%)
Features of Familial CRCFeatures of Familial CRC
Family history of CRC Family history of CRC with no clear with no clear inheritance pattern inheritance pattern
Age at onset typical of Age at onset typical of sporadic CRCsporadic CRC
Multiple causesMultiple causes Few or no adenomas Few or no adenomas
SporadicSporadic
Familial CRCFamilial CRCFAPFAP
Rare CRC Rare CRC syndromessyndromes
HNPCCHNPCC
Progression of Colorectal CancerProgression of Colorectal Cancer
Normal Normal epitheliumepithelium
Hyper-Hyper-proliferativeproliferativeepitheliumepithelium
EarlyEarlyadenomaadenoma
Inter-Inter-mediatemediate
adenomaadenoma
LateLateadenomaadenoma CarcinomaCarcinoma MetastasisMetastasis
Loss ofLoss ofAPCAPC
ActivationActivationof of K-rasK-ras
Deletion Deletion of 18qof 18q
Loss ofLoss ofTP53TP53
Other Other alterationsalterations
Adapted from Fearon ER. Adapted from Fearon ER. CellCell 61:759, 1990 61:759, 1990
Adenomatous polypAdenomatous polyp
Adenomatous polypAdenomatous polyp Can take 5-10 years for polyp to developCan take 5-10 years for polyp to develop Up to 10% of polyps develop into cancerUp to 10% of polyps develop into cancer Size and histology are risk factors for polyp to Size and histology are risk factors for polyp to
cancer progressioncancer progression
Characteristics of Average RiskCharacteristics of Average Risk
No well-defined threshold between sporadic No well-defined threshold between sporadic and familial CRC at this timeand familial CRC at this time
Probably safe to include individuals with:Probably safe to include individuals with: No personal risk factors or family history of CRCNo personal risk factors or family history of CRC One 2nd or 3rd degree relative with CRC >60 years One 2nd or 3rd degree relative with CRC >60 years
with no other family history of CRCwith no other family history of CRC
CCharacteristics of Familial CRCharacteristics of Familial CRC
““Clustering” of colon cancer cases in the family Clustering” of colon cancer cases in the family (age> 50 at diagnosis) without clear dominant (age> 50 at diagnosis) without clear dominant patternpattern
One close relative with CRC <60 yrs & family One close relative with CRC <60 yrs & family history does not meet criteria for known history does not meet criteria for known hereditary CRC syndromeshereditary CRC syndromes
Likely to be multiple low penetrant genes plus Likely to be multiple low penetrant genes plus environmental factorsenvironmental factors
Family members warrant earlier CRC screeningFamily members warrant earlier CRC screening Starting at 40 years or 5-10 yrs earlier than age of Starting at 40 years or 5-10 yrs earlier than age of
diagnosis of the youngest affected relativediagnosis of the youngest affected relative
Winawer et al., Gastroenterology 2003:124:544-560
Characteristics of Hereditary CRCCharacteristics of Hereditary CRC
Multiple relatives with colorectal cancerMultiple relatives with colorectal cancer One or more diagnosed at an early age (<50)One or more diagnosed at an early age (<50)
Sequential generations affectedSequential generations affected Except in autosomal recessive syndromesExcept in autosomal recessive syndromes
Other cancers in the family known to be Other cancers in the family known to be associated with CRC (uterine, ovarian, GI)associated with CRC (uterine, ovarian, GI)
Multiple primary tumors or polypsMultiple primary tumors or polyps
Hereditary CRC syndromesHereditary CRC syndromes
Hereditary Non-Polyposis Colorectal Cancer (HNPCC)Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Variants: Muir-Torre, TurcotVariants: Muir-Torre, Turcot
Familial Adenomatous Polyposis (FAP)Familial Adenomatous Polyposis (FAP) Variants: Gardner, TurcotVariants: Gardner, Turcot Attenuated FAP Attenuated FAP APC mutation in Ashkenazi JewsAPC mutation in Ashkenazi Jews
Others: Others: Multiple adenomatous polyposis syndrome/MYH gene (MAP)Multiple adenomatous polyposis syndrome/MYH gene (MAP) Peutz-Jeghers syndrome (PJS)Peutz-Jeghers syndrome (PJS) Familial Juvenile Polyposis (FJP)Familial Juvenile Polyposis (FJP)
HNPCC: HNPCC: AKA “Lynch syndrome”AKA “Lynch syndrome”
2-3% of all colorectal cancer cases Autosomal dominant; high penetrance Typical age of CA onset is 40-50 yrs Multiple affected generations 60-70% right-sided/proximal CRC tumors Polyps may be present, multiple primaries common. Can
overlap with AFAP High lifetime risk of CRC and other cancers beginning age 20
Cancer Risks in HNPCCCancer Risks in HNPCC
Aarnio M et al. Aarnio M et al. Int J CancerInt J Cancer 64:430, 1995 64:430, 1995
% with % with cancercancer
100100
8080
6060
4040
2020
002020 4040 6060 808000
Age (years)Age (years)
Colorectal Colorectal 78%78%
Endometrial Endometrial 43% 43%
Stomach Stomach 19%19%Biliary tract Biliary tract 18%18%Urinary tract Urinary tract 10%10%Ovarian Ovarian 9%9%
Lifetime cancer risks: HNPCC
Colorectal 80% Endometrial 20-60% Gastric 13-19% Ovarian 9-12% Biliary tract 2% Urinary tract 4% Small bowel 1-4% Brain/CNS 1-3%
Contribution of Gene Mutations Contribution of Gene Mutations to HNPCC Familiesto HNPCC Families
MSH2 MSH2 30%30%
MLH1MLH130%30%
PMS1 PMS1 (rare)(rare)
PMS2PMS2 (rare) (rare)
MSH6 MSH6 (rare)(rare)
Unknown 30%Unknown 30%SporadicSporadic FamilialFamilial
HNPCCHNPCC
FAPFAP
Rare CRC Rare CRC syndromessyndromes
Liu B et al. Liu B et al. Nat MedNat Med 2:169, 1996 2:169, 1996
Amsterdam Criteria (HNPCC)Amsterdam Criteria (HNPCC)
33 or more relatives with an HNPCC-related or more relatives with an HNPCC-related cancer, one of whom is a 1cancer, one of whom is a 1stst degree relative of degree relative of the other twothe other two
22 or more successive generations affected or more successive generations affected 11 or more cancers diagnosed before age 50 or more cancers diagnosed before age 50 Failure to meet these criteria Failure to meet these criteria
does does notnot exclude HNPCC exclude HNPCC
Mutations in HNPCC Mutations in HNPCC
Caused by mutations or deletions in mismatch repair (MMR) Caused by mutations or deletions in mismatch repair (MMR) genes genes
MSH2, MLH1, MSH6, (PMS2)MSH2, MLH1, MSH6, (PMS2) 90% of detectable mutations in MSH2 and MLH190% of detectable mutations in MSH2 and MLH1
50% of families meeting Amsterdam II Criteria have 50% of families meeting Amsterdam II Criteria have detectable mutationsdetectable mutations
Testing/screening options: Testing/screening options: Direct genetic testing of MMR genes (in select families)Direct genetic testing of MMR genes (in select families) Initial screening of the tumor tissue by MSI/IHC Initial screening of the tumor tissue by MSI/IHC
When to perform genetic testingWhen to perform genetic testing
Family history fulfills Amsterdam II criteria Family history fulfills Amsterdam II criteria oror Patient has two HNPCC related cancers Patient has two HNPCC related cancers oror Patient has CRC and a 1Patient has CRC and a 1stst degree relative with degree relative with
HNPCC-related cancer, with at least one HNPCC-related cancer, with at least one cancer diagnosed <50 years of agecancer diagnosed <50 years of age
Always test an affected family member firstAlways test an affected family member first!!
Cancer in MSH2 mutation familyCancer in MSH2 mutation family
Oesophagus59 yrs
Ovary37 yrs
Ovary29 yrs
Colon39 yrs
Rectum42 yrs
Synchronous44 yrs
StomachSynchronous47 years
Synchronous41 yrs
SarcomaMediastinum
27 yrs
Endometrial Cancer Colorectal/Upper GI Cancer
Ovarian Cancer Other Cancer
MSI/IHC screeningMSI/IHC screening
Microsatellite InstabilityMicrosatellite Instability (MSI) on tumor tissue (MSI) on tumor tissue can be used to screen for HNPCC in select cases can be used to screen for HNPCC in select cases
Immunohistochemistry Immunohistochemistry (IHC) on tumor tissue(IHC) on tumor tissue can be used to detect the presence or absence of the mismatch repair can be used to detect the presence or absence of the mismatch repair
proteins (MSH2, MLH1, etc.) proteins (MSH2, MLH1, etc.) ““Screen positiveScreen positive” individuals can be offered cancer genetic ” individuals can be offered cancer genetic
counseling/assessment and targeted genetic testingcounseling/assessment and targeted genetic testing
Microsatellite Instability (MSI)Microsatellite Instability (MSI) 10%–15% of sporadic tumors have MSI10%–15% of sporadic tumors have MSI 95% of HNPCC tumors have MSI at multiple loci95% of HNPCC tumors have MSI at multiple loci
Electrophoresis gelElectrophoresis gel
NormalNormal MSI tumorMSI tumor
Umar A et al: J Natl Cancer Inst, 2004; 96(4):261-268
Criteria for MSI/IHC screeningCriteria for MSI/IHC screening CRC or endometrial CA <50 yrsCRC or endometrial CA <50 yrs 2 HNPCC cancers in same person2 HNPCC cancers in same person CRC with “MSI-H histology” diagnosed <60 yrsCRC with “MSI-H histology” diagnosed <60 yrs
Infiltrating lymphocytes, Crohn’s-like lymphocytic Infiltrating lymphocytes, Crohn’s-like lymphocytic reaction, mucinous/signet ring differentiation, reaction, mucinous/signet ring differentiation, medullary growth patternmedullary growth pattern
CRC and one or more 1CRC and one or more 1stst degree relative with an degree relative with an HNPCC-related cancer, one diagnosed <50 yrsHNPCC-related cancer, one diagnosed <50 yrs
CRC and two or more 1CRC and two or more 1stst or 2 or 2ndnd degree relatives degree relatives with HNPCC-related cancers, any agewith HNPCC-related cancers, any age
Genetic Testing for Genetic Testing for HNPCC SusceptibilityHNPCC Susceptibility
Begin genetic testing with affected family member
Negative result
Continued risk of unidentified familial
mutation
Offer testing to at-risk family
members
Positive result
HNPCC SurveillanceHNPCC Surveillance
Gene carriers or at-risk relatives:Gene carriers or at-risk relatives: CRC: colonoscopy age 20-25, repeat 1-2 yrsCRC: colonoscopy age 20-25, repeat 1-2 yrs Women: gyn exam, endometrial aspiration, TV Women: gyn exam, endometrial aspiration, TV
U/S, CA-125 (?) age 25-35, repeat 1-2 yrsU/S, CA-125 (?) age 25-35, repeat 1-2 yrs If one HNPCC family member affected w/the If one HNPCC family member affected w/the
following:following: Stomach CA: EGD age 3-35, repeat 1-2 yrsStomach CA: EGD age 3-35, repeat 1-2 yrs Urinary tract CA: urine cytology age 30-35, repeat Urinary tract CA: urine cytology age 30-35, repeat
1-2 yrs1-2 yrs
NCCN practice guidelines in oncology – v.1.2003
•
Diagnostic & Screening Criteria
Amsterdam Criteria:– Exclude FAP
– 3 relatives with CRC• 1 FDR to other two
– 2 affected generations– 1 CRC diagnosed <50
Bethesda Criteria:– Individual with 2 or
more HNPCC cancers– CRC or endometrial
cancer dx. < 45– Adenomas dx. < 40
Diagnostic Screening
FAPFAP
Prevalence 0.01%Prevalence 0.01% 100’s to 1000’s of colonic adenomas by teens100’s to 1000’s of colonic adenomas by teens
Cancer risk: colon, gastric, duodenum (periampulla), Cancer risk: colon, gastric, duodenum (periampulla), small bowel, pancreas, papillary thyroid, childhood small bowel, pancreas, papillary thyroid, childhood hepatoblastomahepatoblastoma
7% risk of CRC by 21 yrs; 93% by 50 yrs7% risk of CRC by 21 yrs; 93% by 50 yrs Variants: Gardner, TurcotVariants: Gardner, Turcot
Clinical Features of FAPClinical Features of FAP Estimated penetrance Estimated penetrance
for adenomas >90%for adenomas >90%
CHRPE may be presentCHRPE may be present congenital hypertrophy congenital hypertrophy
of the retinal pigment of the retinal pigment epitheliumepithelium
Untreated polyposis Untreated polyposis leads to 100% risk of leads to 100% risk of cancer cancer
Genetics of FAPGenetics of FAP Autosomal dominant inheritance Autosomal dominant inheritance Caused by mutations in Caused by mutations in APCAPC tumor suppressor gene tumor suppressor gene
on chromosome 5q on chromosome 5q Up to 30% of patients have Up to 30% of patients have de novo de novo germline germline
mutationsmutations Most families have unique mutationsMost families have unique mutations
Most mutations are protein truncating Most mutations are protein truncating
Genotype/phenotype relationships emergingGenotype/phenotype relationships emerging
The The APCAPC Tumor Suppressor Gene Tumor Suppressor Gene MutationsMutations
3'3'5'5'
Codon 1309Codon 1309
1 2 3 4 5 6 7 8 9 1011121314 15
FAP – surveillanceFAP – surveillance
ColonColon Annual sigmoidoscopy, age 10-12 yrsAnnual sigmoidoscopy, age 10-12 yrs Prophylactic colectomy following polyp detection Prophylactic colectomy following polyp detection
w/continued surveillance of rectum, ileal pouchw/continued surveillance of rectum, ileal pouchDuodenal/gastricDuodenal/gastric
EGD age 25, repeat 1-3 yrsEGD age 25, repeat 1-3 yrs
Gastroenterology 2001; 121: 195. AGA Statement
Genetic Testing: FAP/AFAPGenetic Testing: FAP/AFAP Test an affected family member first!Test an affected family member first!
After genetic counseling and informed consentAfter genetic counseling and informed consent APC gene testing can confirm a suspected APC gene testing can confirm a suspected
diagnosisdiagnosis Family members of a person with a known APC Family members of a person with a known APC
mutation can have mutation-specific testing mutation can have mutation-specific testing Genetic testing for children at risk for FAP can be Genetic testing for children at risk for FAP can be
considered before beginning colon screening considered before beginning colon screening
Attenuated FAPAttenuated FAP
20 to 100 polyps, usually more proximal20 to 100 polyps, usually more proximal Onset later than FAP, average age of onset = 50Onset later than FAP, average age of onset = 50 Lifetime risk of CRC = 80%Lifetime risk of CRC = 80% Extracolonic tumors occur at same rate as FAPExtracolonic tumors occur at same rate as FAP
Not associated with CHRPENot associated with CHRPE Variant of FAP, mutations in same APC geneVariant of FAP, mutations in same APC gene
Surveillance: Surveillance: annual annual colonoscopycolonoscopy starting late teens or early 20’s starting late teens or early 20’s Option of subtotal colectomy Option of subtotal colectomy
APC gene mutation in APC gene mutation in Ashkenazi JewsAshkenazi Jews
Missense mutation (I1307K) associated with increased risk of Missense mutation (I1307K) associated with increased risk of CRC and adenomas in Ashkenazi Jews (AJ)CRC and adenomas in Ashkenazi Jews (AJ)
Found in 6% of the general AJ populationFound in 6% of the general AJ population 12% of AJs with CRC 12% of AJs with CRC 29% of AJs with CRC and a positive family history 29% of AJs with CRC and a positive family history
Lifetime risk of CRC in mutation carrier is 10-20% Lifetime risk of CRC in mutation carrier is 10-20%
Screening: colonscopy every 2-5 yrs starting at 35 yrsScreening: colonscopy every 2-5 yrs starting at 35 yrs
MAP syndrome/MYH geneMAP syndrome/MYH gene
Multiple adenomatous polyposis (MAP) syndromeMultiple adenomatous polyposis (MAP) syndrome Autosomal recessive; mutations in the MYH geneAutosomal recessive; mutations in the MYH gene Median number of polyps = 55 Median number of polyps = 55 Mean age of polyp diagnosis = 30-50 yearsMean age of polyp diagnosis = 30-50 years Small, mildly dysplastic tubular adenomasSmall, mildly dysplastic tubular adenomas Some tubulovillous, hyperplastic, serrated adenomas, Some tubulovillous, hyperplastic, serrated adenomas,
microadenomas microadenomas 30% of individuals with 15-100 polyps have 30% of individuals with 15-100 polyps have
homozygous mutations in the MYH genehomozygous mutations in the MYH gene Genetic testing should be offered if >15 polyps (and Genetic testing should be offered if >15 polyps (and
APC gene testing negative)APC gene testing negative)
Peutz-Jeghers syndromePeutz-Jeghers syndrome
<1% of all CRC cases<1% of all CRC casesHamartomatous polyps of GI tract as early as 1Hamartomatous polyps of GI tract as early as 1stst
decadedecadeMucocutaneous hyperpigmentation Mucocutaneous hyperpigmentation
lips, mouth, buccal mucosa, fingers lips, mouth, buccal mucosa, fingers Usually seen in children < 5 yrsUsually seen in children < 5 yrs
Cancer risk: Cancer risk: colon, small intestine, stomach, pancreas, breast, colon, small intestine, stomach, pancreas, breast,
ovaries, uterus, testes, lungs, kidneysovaries, uterus, testes, lungs, kidneys
Mutations in STK11 gene Mutations in STK11 gene found in 70% of familial cases and 30-70% of found in 70% of familial cases and 30-70% of
sporadic casessporadic cases
Familial Juvenile PolyposisFamilial Juvenile Polyposis
<1% of all CRC cases<1% of all CRC cases
Autosomal dominantAutosomal dominant
5 or more juvenile polyps in colon or GI tract 5 or more juvenile polyps in colon or GI tract Appear in 1Appear in 1stst or 2 or 2ndnd decade decade 50% lifetime risk of CRC; AOO in 30’s50% lifetime risk of CRC; AOO in 30’s Increased risk gastric, GI, pancreatic CAIncreased risk gastric, GI, pancreatic CA
~50% of cases have mutations in either~50% of cases have mutations in either the the MADH4 or BMPR1A genesMADH4 or BMPR1A genes
Consider Genetics Referral for:Consider Genetics Referral for:
Two or more family members with CRC* at least one <50Two or more family members with CRC* at least one <50
Three or more family members w/CRC*; any ageThree or more family members w/CRC*; any age
Patient with colon cancer before 40 yrsPatient with colon cancer before 40 yrs
Endometrial cancer and family history of CRC <50Endometrial cancer and family history of CRC <50
Persons with more than one primary CRC <50 yrs or with both Persons with more than one primary CRC <50 yrs or with both endometrial CA and CRC endometrial CA and CRC
Family or personal history of CRC and one or more 1Family or personal history of CRC and one or more 1stst degree degree relative with an HNPCC-related cancer, one diagnosed <50 yrs. relative with an HNPCC-related cancer, one diagnosed <50 yrs.
**Same side of familySame side of family
Consider Genetics Referral for: Consider Genetics Referral for:
MSI and/or IHC tumor results suspicious for HNPCCMSI and/or IHC tumor results suspicious for HNPCC
Autosomal dominant pattern of cancers in the familyAutosomal dominant pattern of cancers in the family
Persons with 15 or more adenomatous colorectal polypsPersons with 15 or more adenomatous colorectal polyps
Persons with multiple hamartomatous or juvenile GI polypsPersons with multiple hamartomatous or juvenile GI polyps
Persons with a family history of a known hereditary cancer Persons with a family history of a known hereditary cancer syndromesyndrome
Screening Implications of Screening Implications of Inherited Colorectal Inherited Colorectal
CancersCancers
Risk of inherited CRCRisk of inherited CRC
Risk for CRC based on family history increases with:Risk for CRC based on family history increases with: Closer degree of relationship and # of affected membersCloser degree of relationship and # of affected members
Younger age of onsetYounger age of onset
Presence of extracolonic tumors, multiple primariesPresence of extracolonic tumors, multiple primaries
Family History: Empiric RisksFamily History: Empiric Risks
Lifetime Risk CRCLifetime Risk CRC
General population in USGeneral population in US 2 to 6%2 to 6%
One 1One 1stst degree relative w/CRC degree relative w/CRC 2-3 fold2-3 fold
Two 1Two 1stst degree relatives w/CRC degree relatives w/CRC 3-4 fold3-4 fold
11stst degree relative w/CRC <50 degree relative w/CRC <50 3-4 fold3-4 fold
One 2One 2ndnd or 3 or 3rdrd degree relative w/CRC degree relative w/CRC 1.5-fold1.5-fold
Two 2Two 2ndnd degree relatives w/CRC degree relatives w/CRC 2-3 fold2-3 fold
Goal: ClassificationGoal: Classification
Family Hx
Assessment
Personalized prevention recommendations
Referral for genetic evaluationwith personalized preventionrecommendations
Standard preventionrecommendations
Intervention
Average
Moderate(“Familial”)
High/Genetic
Risk Classification
CRC Risk ManagementCRC Risk Management
Age to BeginAge to Begin Average RiskAverage Risk 50 yrs50 yrs
1.1. No family history CRC No family history CRC OR OR
2.2. One 2One 2ndnd or 3 or 3rdrd degree relative with CRC degree relative with CRC
FOBT annually + Flex sig every 5 yrs; ORColonoscopy every 10 yrs; OR
DCBE every 5 yrs
CRCCRC Risk ManagementRisk Management
Moderate/Family historyModerate/Family history Age to beginAge to begin1. Two 11. Two 1stst degree relatives with CRC any age degree relatives with CRC any age 40 years*40 years* or one 1or one 1stst degree relative with CRC < 60 degree relative with CRC < 60
2. One 12. One 1stst degree relative with CRC >60 or degree relative with CRC >60 or 40 years40 years two 2two 2ndnd degree relatives with CRC any age degree relatives with CRC any age
* Or 5-10 yrs earlier than earliest case in family* Or 5-10 yrs earlier than earliest case in family
Gastroenterology: 2003;124:544-560
Colonoscopy every 5 yrs
Average risk screening
Adenoma-Carcinoma SequenceAccumulation of Mutations
DCC, MCC, p53, K-ras, APC, MSH2, MLH1, etc.
CRC Risk ManagementCRC Risk Management
Age to BeginAge to Begin
HNPCC or suspected HNPCCHNPCC or suspected HNPCC 20-25 yrs 20-25 yrs
FAP or suspected FAPFAP or suspected FAP 10-12 yrs 10-12 yrs
1. Colonoscopy every 1-2 yrs2. Genetic counseling; consider genetic testing
1. Flex sig or colonoscopy every1-2 yrs2. Genetic counseling; consider genetic testing
Chemoprevention
Evidence that ASA, NSAIDs, Calcium, and COX-2 inhibitors may reduce incidence of CRC by reducing # of adenomas
40-50% risk reduction for developing CRC regardless of location in colon, age, gender, and race
Generally performed by RCT’s in patients with prior CRC followed for recurrence of adenomas
Diet, fiber, and antioxidant vitamins have not been shown by RCT’s to decrease risk of recurrent adenomas
COX-2i’s and Sulindac have been shown to reduce the number of adenomas found in FAP alone
Not effective for sporadic colon CA Actually can cause regression of adenomas
SummarySummary
SummarySummary
Risk factors for colon cancer Risk factors for colon cancer Inherited Inherited Acquired (sporadic)-adenomatous polyp, IBDAcquired (sporadic)-adenomatous polyp, IBD
Genetic basis for colon cancer Genetic basis for colon cancer Inherited (FAP, HNPCC, to be defined) Inherited (FAP, HNPCC, to be defined) Sporadic polyp-different pathways Sporadic polyp-different pathways
SummarySummary
Genetic counseling and testingGenetic counseling and testing HNPCCHNPCC FAPFAP
Implications for screening/surveillanceImplications for screening/surveillance Family membersFamily members Other malignanciesOther malignancies
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