MTCC repression

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					 Elias Ghandour,MD FACP FACG
• Clinical Associate Professor Texas Tech
• Follow American College of Physician
• Follow American College of
• Member American Association for
  theStudy of Liver Diseases
                 Colon cancer
•   Incidence.
•   Mortality
•   Gentic
•   Risk modification
•   Prevention
    – American College of Gastroenterology Guidelines
      for Colorectal Cancer Screening 2008, published
      march 2009
Cancer statistics, 2008. Cancer J Clin. 2008 Mar-Apr;58(2):71-96. Epub 2008 Feb 20.
9% Colon
• Death rates have declined progressively
  – detection of disease at an earlier stage
  – more effective treatments, particular adjuvant therapy.

• The United States has one of the lowest
  mortality rates from CRC, despite having a
  higher incidence than most countries.
  – 61 percent of all patients treated for colorectal cancer
    (all stages and sites combined) survive five years.
The adenoma to colon cancer
                         The early stages

                                          Enhance expression of c-Myc
                                          and other proteins that promote
APC Gene

                                          cellular division

                                          β-catenin may play a role in cell
                                          adhesion processes

           •repression of β-catenin reduces the tendency for abnormal tissue expansion
APC Gene


                             Cell migrate from base
                              of crypts toward the
β-catenin                    epithelial surface prior
                                  to apoptosis

            Normal cells
APC Gene

              abrogation of APC binding releases
           β-catenin from the suppressive effects of
            Both APC alleles are probably mutated
              in most tumors, consistent with the
            hypothesis that lack of functional APC
            releases suppression of β-catenin and
                 leads to adenomatous growth.

    Ademoatous cells
  APC Gene

               The occasional tumors that lack APC
                mutations frequently have β-catenin
              mutations that resist repression by APC.
               β-catenin resistance requires that only
              one allele mutate to escape suppression
                              by APC.

Ademoatous cells/ no APC Mutation
The adenoma to colon cancer
  Growth Beyond Small Adenomas

• Among early adenomas less than 1cm, fewer than 10
  percent had mutations to either K-RAS or N-RAS.
• Whereas more than 50 percent of adenomas greater
  than 1cm and carcinomas had a mutation to one of these
• The RAS family acts oncogenically, with a mutation to a
  single allele sufficient to cause progression.
  Development of Late Adenomas
As adenomas continue to grow, they tend to
lose parts of 18q, the long arm of
chromosome 18
  about 50 percent of late adenomas and 75
  percent of carcinomas have 18q loss.
Limited evidence genes DCC, SMAD4, and
SMAD2 in 18q21 in carcinogenesis.
          Transition to Cancer
• Loss of functional p53 by damage to both alleles
  drives progression to carcinomas
• p53 suppresses cell division or induces apoptosis in
  response to stress or damage.
• p53 is on the short arm of chromosome 17, region
• Allelic losses on 17p occur in 75 percent in cancers.
        Microsatellite Instability
• Approximately 15 percent of colorectal tumors do not have
  widespread chromosomal abnormalities.
• Instead, these tumors usually have mutations in their
  mismatch repair (MMR) system,
• Loss of MMR causes increased mutation in repeated DNA
  sequences, such as those in microsatellite regions.
• This failure to repair mismatches in repeats causes
  repetitive microsatellites to change their length at a much
  higher rate than normal during DNA replication.
• The observed fluctuations in microsatellite length lead to
  the name microsatellite instability (MSI) for defects in
  MMR. Genes with repetitive sequences seem to be at
  greater risk for mutation in MSI tumors.
• Most colorectal tumors have either MSI or CIN, but not
  both. Some form of accelerated mutation may be needed
  for progression to aggressive colorectal cancer.
           HNPCC Pathway
• Individuals who inherit defects in MMR
  develop hereditary nonpolyposis colorectal
  cancer (HNPCC) as well as other cancers
  that together make up Lynch's syndrome.
• Typically, individuals inherit one defective
  allele at a locus involved in MMR.
  Heterozygous cells are usually normal for
• A somatic mutation to the second allele at
  the affected locus leads to loss of function in
  a component of the MMR system.
               HNPCC Pathway

The morphological sequence in HNPCC follows the classical
In the classical pathway, the adenoma to carcinoma ratio is
about 30:1.
By contrast, HNPCC patients have an adenoma to carcinoma
ratio of about 1:1
This suggests much faster progression from adenoma to
carcinoma in HNPCC, probably driven by the high somatic
mutation rate in MSI cells.
• Some colorectal cancers accumulate changes in gene
  expression by hypermethylation of promoter regions,
  which can suppress transcription.
• Commonly hypermethylated genes in colorectal cancers
  include p14, p16, hMLH1, MGMPT, and HPP1.
             RISK FACTORS
• Familial adenomatous
  polyposis .
• Hereditary nonpolyposis
  colorectal cancer, Lynch
  syndrome (HNPCC)
• Personal or family history of
  sporadic cancers or
  adenomatous polyps
• Inflammatory bowel disease
              RISK FACTORS
• Diabetes mellitus and insulin resistance.
• Cholecystectomy
   – 278,460 patients followed for up to 33 years after
     surgery, slightly increased risk of right-sided colon
• Alcohol
• Obesity
• coronary heart disease, Cigarette smoking, Ureterocolic
  anastomoses, Prior pelvic irradiation, long-term
  consumption of red meat or processed meats, Prior
  treatment for Hodgkin lymphoma.
•   Diet — Many epidemiologic studies have shown an association between the
    intake of a diet high in fruits and vegetables and protection from colorectal
•   Fiber, Garlic
•   Folic acid
•   Vitamin B6 (pyridoxine)
•   Calcium /Magnesium
•   Physical activity
•   Aspirin and NSAIDs
•   Combination therapy with DFMO and sulindac — alpha-
    difluoromethylornithine (DFMO) is an enzyme-activated irreversible inhibitor
    of ornithine decarboxylase, Large trials evaluating efficacy and safety are
•   Hormone replacement therapy —
•   Statins — the data are conflicting.
•   Antioxidants — no convincing evidence
•   Omega 3 fatty acids in observational studies, Consumption of omega 3 fatty
    acids (mainly as fish oil) has been associated with a reduced incidence of
    colorectal cancer.
CRC screening recommendations
Preferred CRC screening recommendations
• Cancer prevention tests should be offered
   first. The preferred CRC prevention test is
   colonoscopy every 10 years, beginning at
   age 50. Screening should begin at age 45
   years in African Americans

Cancer detection test. This test should be
  offered to patients who decline colonoscopy
  or another cancer prevention test. The
  preferred cancer detection test is annual FIT
  for blood

Alternative CRC prevention tests
• Flexible sigmoidoscopy every 5 – 10 years
• CT colonography every 5 years

Alternative cancer detection tests
• Annual Hemoccult Sensa
• Fecal DNA testing every 3 years
CRC screening recommendations
Recommendations for screening when family history is positive but
evaluation for HNPCC considered not indicated

• Single first-degree relative with CRC or advanced adenoma
diagnosed at age ≥ 60 years.
Recommended screening: same as average risk.

• Single first-degree with CRC or advanced adenoma diagnosed
at age < 60 years or two first-degree relatives with CRC or
advanced adenomas.
Recommended screening: colonoscopy every 5 years beginning
at age 40 years or 10 years younger than age at diagnosis of the
youngest affected relative.
• Patients who meet the Bethesda criteria should undergo microsatellite
instability testing of their tumor or a family member’s tumor and/or
   tumor immunohistochemical staining for mismatch repair proteins

• Patients with positive tests can be offered genetic testing. Those
with positive genetic testing, or those at risk when genetic testing
is unsuccessful in an affected proband, should undergo
colonoscopy every 2 years beginning at age 20 – 25 years, until
age 40 years, then annually thereafter

       •   Bethesda criteria
       •   CRC diagnosed in individual under age 50 years.
       •   Presence of synchronous, metachronous colorectal, or other HNPCC-associated tumors,
           regardless of age.
       •   CRC with the MSI-H histology (presence of tumor-infiltrating lymphocytes, Crohn’s-like
           lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern), in
           patient 60 years of age.
       •   CRC in 1 or more first-degree relatives with an HNPCC-related tumor, with 1 of the
           cancers being diagnosed under age 50 years.
       •   CRC diagnosed in 2 or more first- or second-degree relatives with HNPCC- related
           tumors, regardless of age.
• Patients with classic FAP (>100 adenomas) should be advised to pursue genetic
   counseling and genetic testing, if they have siblings or children who could
   potentially benefit from this testing

• Patients with known FAP or who are at risk of FAP based on family history (and
   genetic testing has not been performed)
should undergo annual flexible sigmoidoscopy or colonoscopy, as appropriate,
   until such time as colectomy is deemed by physician and patient as the best

• Patients with retained rectum after subtotal colectomy should
undergo flexible sigmoidoscopy every 6 – 12 months.
• Patients with classic FAP, in whom genetic testing is negative, should
undergo genetic testing for bi-allelic MYH mutations.

Patients with10 – 100 adenomas can be considered for genetic testing for
   attenuated FAP and if negative, MYH associated polyposis
Changes in this guideline from the 2000 ACG
     recommendations for screening
 Changes in this guideline from the 2000 ACG
      recommendations for screening
1. Screening tests are divided into cancer prevention and cancer
    detection tests. Cancer prevention tests are preferred over detection
2. Screening is recommended in African Americans beginning at age 45
3. CT colonography every 5 years replaces double contrast barium
    enema as the radiographic screening alternative, when patients
    decline colonoscopy.
4. FIT (fecal immunochemical test) replaces older guaiac-based fecal
    occult blood testing. FIT is the preferred cancer detection test.
5. Annual Hemoccult Sensa and fecal DNA testing every 3 years are
alternative cancer detection tests.
6. A family history of only small tubular adenomas in fi rst-degree
relatives is not considered to increase the risk of CRC.
7. Individuals with a single fi rst-degree relative with CRC or advanced
adenomas diagnosed at age ≥60 years can be screened like
average-risk persons.
 Key measures for improving the quality and cost
 effectiveness of colonoscopy as a CRC screening test

• Bowel preparation should be given in split doses (half of the dose is
    given on the day of procedure).
• Cecal intubation should be documented by description of landmarks
    and photography.
• All colonoscopists should document adenoma detection rates.
• Withdrawal times should average at least 6 min in intact colons, in
    which no biopsies or polypectomies are performed; this has greatest
    relevance to colonoscopists with low adenoma detection rates.
• Polyps should be removed by effective techniques, including snaring
    (rather than forceps methods) for all polyps >5 mm in size.
• Piecemeal resection of large sessile lesions requires close follow-up.
• In patients with complete examinations and adequate preparation,
recommended screening and surveillance intervals should be followed.

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