Download Genetics of Colorectal Cancer - Scioto County Medical Society

Genetics of
Colorectal
Cancer
Cancer is a Disease of the Cell Cycle
“Carcinoma is a genetic disease, it is not necessarily inherited”
Knudsen’s “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, etc.
Estimated New Cancer Cases of 10
Leading Sites by Gender for the US 2000
Male
Female
Prostate
29%
Prostate
30%
Lung and bronchus
14%
Lung and bronchus
12%
Colon and rectum
10%
Colon and rectum
11%
Urinary bladder
6%
Urinary bladder
6%
Non-Hodgkin’s Lymphoma
5%
Non-Hodgkin’s Lymphoma
4%
Melanoma of skin
4%
Melanoma of skin
4%
Oral cavity and pharynx
3%
Oral cavity and pharynx
3%
Kidney and renal pelvis
3%
Kidney and renal pelvis
2%
Leukemia
2%
Leukemia
2%
Pancreas
2%
Pancreas
2%
All other sites
19%
All other sites
22%
Average Annual Age-Specific US
Incidence and Mortality Rates of CRC,
1992-1996
Prevalence of Adenomas and
Incidence of Colon Cancer

Age >50 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
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)
5%
General Population
Personal History of
Colorectal Neoplasia
15-20%
15-40%
Inflammatory Bowel Disease
70-80%
HNPCC Mutation
>95%
Familial Adenomatous Polyposis
(FAP)
0
20
40
60
Lifetime Risk (%)
80
100
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
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 <50
3-4 fold
One 2nd or 3rd degree relative with
CRC
Two 2nd degree relatives with CRC
~1.5 fold
2-3 fold
Outline





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
services
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 >60 years with no
other family history of CRC
Characteristics of “Familial” CRC




“Clustering” of colon cancer cases in the family (>50
at diagnosis) without clear dominant pattern, or
One close relative with CRC <60 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


Sequential generations affected



One or more diagnosed at an early age (<50)
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 (HNPCC)


Familial Adenomatous Polyposis (FAP)




Variants: Muir-Torre, Turcot
Variants: Gardner, Turcot
Attenuated FAP
APC mutation in Ashkenazi Jews
Others:


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Multiple adenomatous polyposis syndrome/MYH gene (MAP)
Peutz-Jeghers syndrome (PJS)
Familial Juvenile Polyposis (FJP)
HNPCC: AKA “Lynch Syndrome”

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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.
HNPCC
• Lifetime cancer risks:
–
–
–
–
–
–
–
–
Colorectal
Endometrial
Gastric
Ovarian
Biliary Tract
Urinary Tract
Small Bowel
Brain/CNS
80%
20-60%
13-19%
9-12%
2%
4%
1-4%
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 two
2 or more successive generations affected
 1 or more cancers diagnosed before age 50

HNPCC

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 families)
Initial screening of the tumor tissue by MSI/IHC
MSI/IHC Screening

Microsatellite Instability (MSI) on tumor tissue


Immunohistochemistry (IHC) on tumor tissue


can be used to screen for HNPCC in select cases
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
FAP

1 in 10,000 incidence

100’s to 1000’s 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
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Colon
 Annual sigmoidoscopy, age 10-12 yrs
 Prophylactic colectomy following polyp detection with
continued surveillance of rectum, ileal pouch
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 yrs.
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 20’s

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 diagnosis

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 10-20%

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 >15 polyps (and APC gene
testing negative)
Peutz-Jeghers Syndrome
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<1% of all CRC cases
Hamartomatous polyps of GI tract as early as 1st decade
Mucocutaneous hyper pigmentation
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Cancer risk:
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lips, mouth, buccal mucosa, fingers
Usually seen in children < 5 yrs
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

<1% of all CRC cases

Autosomal dominant

5 or more juvenile polyps in colon or GI tract

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Appear in 1st or 2nd decade

50% lifetime risk of CRC; AOO in 30’s

Increased risk gastric, GI, pancreatic CA
~50% of cases have mutations in either the MADH4 or BMPR1A
genes
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
Assessment
Family
History
Risk Classification
Intervention
Average
Standard prevention
recommendations
Moderate
Personalized prevention
recommendations
(“Familial”)
High/Genetic
Referral for genetic
evaluation with personalized
prevention recommendations
Consider Genetics Referral for:

Two or more family members with CRC* at least one <50

Three or more family members w/CRC*; any age

Patient with colon cancer before 40 yrs
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Endometrial cancer and family history of CRC <50

Persons with more than one primary CRC <50 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 <50 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 family

Persons with 15 or more adenomatous colorectal polyps

Persons with multiple hamartomatous or juvenile GI polyps

Persons with a family history of a known hereditary cancer
syndrome
CRC Risk Management
Average Risk
Age to Begin
50 years
No family history CRC OR
One 2nd or 3rd degree relative with CRC
1.
2.

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 < 60
- Colonoscopy every 5 yrs
One 1st degree relative with CRC >60 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
HNPCC or suspected HNPCC
Age to Begin
20-25 years
1. Colonoscopy every 1-2 yrs
2. Genetic counseling; consider genetic testing
FAP or suspected FAP
1. Flex sig or colonoscopy every1-2 yrs
2. Genetic counseling; consider genetic testing
10-12 years
Case 1: Joan

Joan, age 38, was recently diagnosed with
endometrial cancer. Family history reveals:
1.
2.
3.
4.
5.
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
Caucasian
Pedigree: Case 1
French, Irish, Scottish
German, English
88 yr
Dx 50
61 yr
63 yr
CRC Dx 48
4 polyps
50 yrs
38 yr
KEY:
Dx 38
Endometrial CA
Colorectal CA
Adenomatous
Polyps
10 yr
8 yr
35 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:
1.
2.
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 reveals:
1.
Paternal grandfather: died of CRC at age 79.
2.
No hx of endometrial, ovarian, small bowel or
ureter/kidney cancer on either side of family.
3.
Two maternal aunts: cervical cancer at ages 30 & 34
4.
Maternal grandmother: breast cancer age 85
Pedigree: Case 2
Italian
Irish
CRC 79
d.82
German
BrCa 85 yrs
d.87
d. 58 MI
84
55
58
60
56
Colon CA
54 yrs
Cervical
CA 30 yrs
Cervical
CA 32 yrs
KEY:
CRC
Breast CA
34 yrs
30 yrs
Cervical CA
Case 2: Ted

Verify Diagnoses!

If diagnoses are correct: Ted has no family history indicative of a
known colon cancer syndrome (HNPCC, FAP, other)
Obtain and review pathology reports on all
reported cancers, whenever possible

Ted’s lifetime risk of colorectal CA is increased 2 to 3 fold due to one
affected first degree relative (>50)

Moderate/familial risk: Screening by colonoscopy starting at age 40, or
10 yrs earlier than earliest case in family, is reasonable
Chemo Prevention

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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 RCT’s in patients with prior
colorectal CA 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