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Genetics of Colorectal Cancer


Genetics of Colorectal Cancer ... Consider Genetics Referral for: CRC Risk Management CRC Risk Management CRC Risk Management Case 1: Joan Pedigree: ... – PowerPoint PPT presentation

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Title: Genetics of Colorectal Cancer

Genetics of Colorectal Cancer
Cancer is a Disease of the Cell Cycle
Carcinoma is a genetic disease, it is not
necessarily inherited
Knudsens two hit hypothesis
Types of genes which may mutate to cause cancer
  • Oncogenes
  • Suppressor genes
  • DNA repair genes
  • p53

Adenoma-Carcinoma Sequence Accumulation of
Mutations DCC, MCC, p53, K-ras, APC, MSH2, MLH1,
Estimated New Cancer Cases of 10 Leading Sites by
Gender for the US 2000
Male Male
Prostate 29
Lung and bronchus 14
Colon and rectum 10
Urinary bladder 6
Non-Hodgkins Lymphoma 5
Melanoma of skin 4
Oral cavity and pharynx 3
Kidney and renal pelvis 3
Leukemia 2
Pancreas 2
All other sites 19
Female Female
Prostate 30
Lung and bronchus 12
Colon and rectum 11
Urinary bladder 6
Non-Hodgkins Lymphoma 4
Melanoma of skin 4
Oral cavity and pharynx 3
Kidney and renal pelvis 2
Leukemia 2
Pancreas 2
All other sites 22
Average Annual Age-Specific US Incidence and
Mortality Rates of CRC, 1992-1996
Prevalence of Adenomas and Incidence of Colon
  • Age gt50 years with any adenomas 25-40
  • Lifetime risk of cancer at age 50 years
  • 5 for females
  • 6 for males
  • Persons with advanced adenomas are at greatest

Risk Factors for Colorectal Cancer (CRC)
  • Aging
  • Personal history of CRC or adenomas
  • High-fat, low-fiber diet
  • Inflammatory bowel disease
  • Family history of CRC
  • Hereditary colon cancer syndromes

Risk of Colorectal Cancer (CRC)
General Population
Personal History of Colorectal Neoplasia
Inflammatory Bowel Disease
HNPCC Mutation
Familial Adenomatous Polyposis (FAP)
Lifetime Risk ()
Colorectal Cancer Statistics in the US
  • Second overall leading cause of cancer-related
    deaths in the U.S.
  • Estimated 149,000 new cases and 50,000 deaths in
    the year 2008
  • Declining trends between 1990 and 1996
  • Incidence rate 2.1 per year
  • Mortality rates 1.7 per year

Family History Empiric Risks
Lifetime Risk CRC Lifetime Risk CRC
General population in U.S 2 to 6
One 1st degree relative with CRC 2-3 fold
Two 1st degree relatives with CRC 3-4 fold
1st degree relative with CRC lt50 3-4 fold
One 2nd or 3rd degree relative with CRC 1.5 fold
Two 2nd degree relatives with CRC 2-3 fold
  • Hereditary colorectal cancer syndromes
  • Cancer family history a primary tool
  • Evaluating your patients for familial CRC risk
  • Genetic counseling and testing for hereditary
    colorectal cancer
  • How, when, where to refer patients for genetic

Colorectal Cancer
  • 5-8 of all cases of CRC are hereditary
  • 15-20 are familial/multifactorial
  • 75 of cases are sporadic

Characteristics of Average Risk
  • No well-defined threshold between sporadic and
    familial CRC at this time
  • Probably safe to include individuals with
  • No personal risk factors or family history of CRC
  • One 2nd or 3rd degree relative with CRC gt60 years
    with no other family history of CRC

Characteristics of Familial CRC
  • Clustering of colon cancer cases in the family
    (gt50 at diagnosis) without clear dominant
    pattern, or
  • One close relative with CRC lt60 years and family
    history does not meet criteria for known
    hereditary CRC syndromes
  • Likely to be multiple low penetrant genes plus
    environmental factors at play
  • Family members warrant earlier CRC screening
  • Starting at 40 years or 5-10 years earlier than
    age of diagnosis of the youngest affected relative

Characteristics of Hereditary CRC
  • Multiple relatives with colorectal cancer
  • One or more diagnosed at an early age (lt50)
  • Sequential generations affected
  • Except in autosomal recessive syndromes
  • Other cancers in the family known to be
    associated with CRC (uterine, ovarian, GI)
  • Multiple primary tumors or polyps

Hereditary CRC Syndromes
  • Hereditary Non-Polyposis Colorectal Cancer
  • Variants Muir-Torre, Turcot
  • Familial Adenomatous Polyposis (FAP)
  • Variants Gardner, Turcot
  • Attenuated FAP
  • APC mutation in Ashkenazi Jews
  • Others
  • Multiple adenomatous polyposis syndrome/MYH gene
  • Peutz-Jeghers syndrome (PJS)
  • Familial Juvenile Polyposis (FJP)

HNPCC AKA Lynch Syndrome
  • 2-3 of all colorectal cancer cases
  • Autosomal dominant high penetrance
  • Typical age of CA onset is 40-50 years
  • Multiple affected generations
  • 60-70 right-sided/proximal CRC tumors
  • Polyps may be present, multiple primaries common.
    Can overlap with AFAP.

  • Lifetime cancer risks
  • 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

HNPCC Clinical Diagnostic Criteria
  • Amsterdam II Criteria (3-2-1)
  • 3 or more relatives with an HNPCC-related cancer,
    one of whom is a 1st degree relative of the other
  • 2 or more successive generations affected
  • 1 or more cancers diagnosed before age 50

  • Caused by mutations or deletions in mismatched
    repair (MMR) genes
  • MSH2, MLH1, MSH6, (PMS2)
  • 50 of families meeting Amsterdam II Criteria
    have detectable mutations
  • Testing/Screening options
  • Direct genetic testing of MMR genes (in select
  • Initial screening of the tumor tissue by MSI/IHC

MSI/IHC Screening
  • Microsatellite Instability (MSI) on tumor tissue
  • can be used to screen for HNPCC in select cases
  • Immunohistochemistry (IHC) on tumor tissue
  • can be used to detect the presence or absence of
    the mismatch repair proteins (MSH2, MLH1, etc.)
  • Screen positive individuals can be offered
    cancer genetic counseling/assessment and targeted
    genetic testing

  • 1 in 10,000 incidence
  • 100s to 1000s of colonic adenomas by teens
  • Cancer risk colon, gastric, duodenum
    (periampulla), small bowel, pancreas, papillary
    thyroid, childhood hepatoblastoma
  • 7 risk of CRC by 21 yrs 93 by 50 yrs
  • Autosomal dominant APC gene mutations
  • Variants Gardner, Turcot

FAP - Surveillance
  • Colon
  • Annual sigmoidoscopy, age 10-12 yrs
  • Prophylactic colectomy following polyp detection
    with continued surveillance of rectum, ileal
  • Duodenal/gastric
  • EGD age 25, repeat 1-3 yrs
  • Thyroid
  • Annual PE, age 10
  • Hepatoblastoma
  • Annual screen by abd U/S AFP from birth to 5

Attenuated FAP
  • 20 to 100 polyps, usually more proximal
  • Onset later than FAP, average AOO 50
  • Lifetime risk of CRC 80
  • Extracolonic tumors occur at same rate as FAP
  • Variant of FAP, mutations in same APC gene
  • Surveillance
  • annual colonoscopy starting late teens or early
  • Option of subtotal colectomy

Genetic Testing FAP/AFAP
  • Test an affected family member first!
  • After genetic counseling and informed consent
  • APC gene testing can confirm a suspected
  • Family members of a person with a known APC
    mutation can have mutation-specific testing
  • Genetic testing for children at risk for FAP can
    be considered before beginning colon screening

APC gene mutation in Ashkenazi Jews
  • Missense mutation (I1307K) associated with
    increased risk of CRC and adenomas in Ashkenazi
    Jews (AJ)
  • Found in 6 of the general AJ population
  • 12 of AJs with CRC
  • 29 of AJs with CRC and a positive family history
  • Lifetime risk of CRC in mutation carrier is
  • Screening colonoscopy every 2-5 yrs starting at
    35 yrs

MAP syndrome/MYH gene
  • Multiple adenomatous polyposis (MAP) syndrome
  • Autosomal recessive mutations in the MYH gene
  • Median number of polyps 55
  • Mean age of polyp diagnosis 30-50 years
  • Polyps mainly small, mildly dysplastic tubular
    adenomas. Some tubulovillous, hyperplastic,
    serrated adenomas, microadenomas
  • 30 of individuals with 15-100 polyps have
    homozygous mutations in the MYH gene
  • Genetic testing should be offered if gt15 polyps
    (and APC gene testing negative)

Peutz-Jeghers Syndrome
  • lt1 of all CRC cases
  • Hamartomatous polyps of GI tract as early as 1st
  • Mucocutaneous hyper pigmentation
  • lips, mouth, buccal mucosa, fingers
  • Usually seen in children lt 5 yrs
  • Cancer risk
  • colon, small intestine, stomach, pancreas,
    breast, ovaries, uterus, testes, lungs, kidneys
  • Mutations in STK11 gene
  • found in 70 of familial cases and 30-70 of
    sporadic cases

Familial Juvenile Polyposis
  • lt1 of all CRC cases
  • Autosomal dominant
  • 5 or more juvenile polyps in colon or GI tract
  • Appear in 1st or 2nd decade
  • 50 lifetime risk of CRC AOO in 30s
  • Increased risk gastric, GI, pancreatic CA
  • 50 of cases have mutations in either the MADH4
    or BMPR1A genes

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Family Health History
  • The family tree has become the most important
    genetic test of all. The more you know, the more
    tools you have to practice preventive medicine
  • Donna Russo, Certified Genetic Counselor, NY
    Presbyterian-Columbia Hospital

Goal Classification
Risk Classification
Standard prevention recommendations
Family History
Moderate (Familial)
Personalized prevention recommendations
Referral for genetic evaluation with personalized
prevention recommendations
Consider Genetics Referral for
  • Two or more family members with CRC at least one
  • Three or more family members w/CRC any age
  • Patient with colon cancer before 40 yrs
  • Endometrial cancer and family history of CRC lt50
  • Persons with more than one primary CRC lt50 yrs or
    with both endometrial CA and CRC
  • Family or personal history of CRC and one or more
    1st degree relative with an HNPCC-related cancer,
    one diagnosed lt50 yrs.
  • Same side of family

Consider Genetics Referral for
  • MSI and/or IHC tumor results suspicious for HNPCC
  • Autosomal dominant pattern of cancers in the
  • Persons with 15 or more adenomatous colorectal
  • Persons with multiple hamartomatous or juvenile
    GI polyps
  • Persons with a family history of a known
    hereditary cancer syndrome

CRC Risk Management
Age to Begin 50 years
  • Average Risk
  • No family history CRC OR
  • One 2nd or 3rd degree relative with CRC
  • FOBT annually flex sig every 5 years OR
  • Colonoscopy every 10 years OR
  • DCBE every 5 years

CRC Risk Management
  • Moderate/Family history
  • Two 1st degree relatives with CRC any age
  • or one 1st degree relative with CRC lt 60
  • - Colonoscopy every 5 yrs
  • One 1st degree relative with CRC gt60 or
  • two 2nd degree relatives with CRC any age
  • - Average risk screening
  • Or 5-10 yrs earlier than earliest case in family

Age to begin
40 years
40 years
CRC Risk Management
  • Age to Begin
  • HNPCC or suspected HNPCC 20-25 years
  • 1. Colonoscopy every 1-2 yrs
  • 2. Genetic counseling consider genetic
  • FAP or suspected FAP 10-12 years
  • 1. Flex sig or colonoscopy every1-2 yrs
  • 2. Genetic counseling consider genetic

Case 1 Joan
  • Joan, age 38, was recently diagnosed with
    endometrial cancer. Family history reveals
  • Paternal grandmother endometrial cancer, age 50
  • Paternal uncle colon cancer, age 48
  • Father colonoscopy at age 50 four adenomatous
    polyps removed
  • No other significant history
  • Both sides of the family are Northern European

Pedigree Case 1
French, Irish, Scottish
German, English
88 yr
Dx 50
61 yr
63 yr
4 polyps 50 yrs
CRC Dx 48
38 yr
35 yr
Dx 38
Endometrial CA Colorectal CA Adenomatous Polyps
8 yr
10 yr
Case 1 Assessment
  • Joan meets Amsterdam II Criteria and is at risk
    for HNPCC
  • Refer to genetics for cancer genetic counseling
    and discussion of genetic testing for HNPCC
  • Testing options
  • Direct gene testing of MLH1 and MSH2 OR
  • MSI/IHC screening of tumor tissue with gene
    sequencing if MSI positive

Case 2 Ted
  • Ted is 30 and wants a colonoscopy because his
    mother was just diagnosed with colon cancer after
    routine screening at age 54. Family history
  • Paternal grandfather died of CRC at age 79.
  • No hx of endometrial, ovarian, small bowel or
    ureter/kidney cancer on either side of family.
  • Two maternal aunts cervical cancer at ages 30
  • Maternal grandmother breast cancer age 85

Pedigree Case 2
CRC 79 d.82
BrCa 85 yrs d.87
d. 58 MI
Cervical CA 30 yrs
Cervical CA 32 yrs
Colon CA 54 yrs
CRC Breast CA Cervical CA
34 yrs
30 yrs
Case 2 Ted
  • Verify Diagnoses! Obtain and review pathology
    reports on all reported cancers, whenever
  • If diagnoses are correct Ted has no family
    history indicative of a known colon cancer
    syndrome (HNPCC, FAP, other)
  • Teds lifetime risk of colorectal CA is increased
    2 to 3 fold due to one affected first degree
    relative (gt50)
  • Moderate/familial risk Screening by colonoscopy
    starting at age 40, or 10 yrs earlier than
    earliest case in family, is reasonable

Chemo Prevention
  • Evidence that ASA, NSAIDs, Calcium, and COX-2
  • inhibitors may reduce incidence of CA by
    reducing of
  • adenomas
  • ?? 40-50 risk reduction for developing
    colorectal CA regardless of
  • location in colon, age, gender, and race
  • Generally performed by RCTs in patients with
  • colorectal CA followed for recurrence of
  • Diet, fiber, and antioxidant vitamins have not
  • shown by RCTs to decrease risk of recurrent
  • COX-2is and Sulindac have been shown to reduce
  • number of adenomas found in FAP alone
  • ?? Not effective for sporadic colon CA
  • ?? Actually can cause regression of adenomas