Genetics of Colorectal Cancer
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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.

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Cancer is a disease of the cell cycle l.jpg
Cancer is a Disease of the Cell Cycle

“Carcinoma is a genetic disease, it is not necessarily inherited”



Types of genes which may mutate to cause cancer l.jpg
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 l.jpg
Adenoma-Carcinoma SequenceAccumulation of MutationsDCC, MCC, p53, K-ras, APC, MSH2, MLH1, etc.




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Prevalence of Adenomas and Incidence of Colon Cancer of CRC, 1992-1996

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 l.jpg
Risk Factors for Colorectal Cancer (CRC) of CRC, 1992-1996

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 l.jpg
Risk of Colorectal Cancer (CRC) of CRC, 1992-1996

5%

General Population

Personal History of

Colorectal Neoplasia

15-20%

15-40%

Inflammatory Bowel Disease

70-80%

HNPCC Mutation

>95%

Familial Adenomatous Polyposis

(FAP)

Lifetime Risk (%)


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Colorectal Cancer of CRC, 1992-1996Statistics 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



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Outline of CRC, 1992-1996

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


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Colorectal Cancer of CRC, 1992-1996

~5-8% of all cases of CRC are hereditary

~15-20% are “familial”/multifactorial

~75% of cases are sporadic


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Characteristics of Average Risk of CRC, 1992-1996

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


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Characteristics of “Familial” CRC of CRC, 1992-1996

“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


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Characteristics of Hereditary CRC of CRC, 1992-1996

Multiple relatives with colorectal cancer

One or more diagnosed at an early age (<50)

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


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Hereditary CRC Syndromes of CRC, 1992-1996

Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

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 (MAP)

Peutz-Jeghers syndrome (PJS)

Familial Juvenile Polyposis (FJP)


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HNPCC: AKA “Lynch Syndrome” of CRC, 1992-1996

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 l.jpg
HNPCC of CRC, 1992-1996

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%


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HNPCC: of CRC, 1992-1996Clinical 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


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HNPCC of CRC, 1992-1996

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


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MSI/IHC Screening of CRC, 1992-1996

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


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FAP of CRC, 1992-1996

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


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FAP - Surveillance of CRC, 1992-1996

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 l.jpg
Attenuated FAP of CRC, 1992-1996

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


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Genetic Testing: FAP/AFAP of CRC, 1992-1996

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


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APC gene mutation in of CRC, 1992-1996Ashkenazi 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


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MAP syndrome/MYH gene of CRC, 1992-1996

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 l.jpg
Peutz-Jeghers Syndrome of CRC, 1992-1996

<1% of all CRC cases

Hamartomatous polyps of GI tract as early as 1st decade

Mucocutaneous hyper pigmentation

lips, mouth, buccal mucosa, fingers

Usually seen in children < 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 l.jpg
Familial Juvenile Polyposis of CRC, 1992-1996

<1% 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 30’s

Increased risk gastric, GI, pancreatic CA

~50% of cases have mutations in eitherthe MADH4 or BMPR1A genes


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Family Health History of CRC, 1992-1996

“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


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Goal: Classification of CRC, 1992-1996

Assessment

Risk Classification

Intervention

Standard prevention recommendations

Average

Family History

Moderate

(“Familial”)

Personalized prevention recommendations

Referral for genetic evaluation with personalized prevention recommendations

High/Genetic


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Consider Genetics Referral for: of CRC, 1992-1996

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

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


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Consider Genetics Referral for: of CRC, 1992-1996

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


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CRC Risk Management of CRC, 1992-1996

Average Risk

No family history CRCOR

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

Age to Begin

50 years


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CRC Risk Management of CRC, 1992-1996

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


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CRC Risk Management of CRC, 1992-1996

Age toBegin

HNPCC or suspected HNPCC20-25 years

1. Colonoscopy every 1-2 yrs

2. Genetic counseling; consider genetic testing

FAP or suspected FAP10-12 years

1. Flex sig or colonoscopy every1-2 yrs

2. Genetic counseling; consider genetic testing


Case 1 joan l.jpg
Case 1: Joan of CRC, 1992-1996

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 Caucasian


Pedigree case 1 l.jpg
Pedigree: Case 1 of CRC, 1992-1996

French, Irish, Scottish

German, English

88 yr

Dx 50

61 yr

63 yr

CRC Dx 48

4 polyps

50 yrs

38 yr

KEY:

35 yr

Dx 38

Endometrial CA

Colorectal CA

Adenomatous Polyps

10 yr

8 yr


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Case 1: Assessment of CRC, 1992-1996

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 l.jpg
Case 2: Ted of CRC, 1992-1996

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:

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 & 34

Maternal grandmother: breast cancer age 85


Pedigree case 2 l.jpg
Pedigree: Case 2 of CRC, 1992-1996

Italian

Irish

German

CRC 79 d.82

BrCa 85 yrs d.87

d. 58 MI

84

55

58

60

56

Cervical CA 30 yrs

Cervical CA 32 yrs

Colon CA 54 yrs

KEY:

CRC

Breast CA

Cervical CA

34 yrs

30 yrs


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Case 2: Ted of CRC, 1992-1996

Verify Diagnoses! Obtain and review pathology reports on all reported cancers, whenever possible

If diagnoses are correct: Ted has no family history indicative of a known colon cancer syndrome (HNPCC, FAP, other)

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


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Chemo Prevention of CRC, 1992-1996

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


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