Did you arrive here by via search engine?
Click here to view the original version of this article

Click to Print This Page
(This section will not print)

The Genetics of Colon Carcinoma

Course Authors

Maulik Shah, M.D., Ph.D. and Priya Gopalan, M.D., Ph.D.

Dr. Shah, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX. Dr Gopalan, Department of Obstetrics and Gynecology, Washington University, St. Louis, MO.

Drs. Shah and Gopalan report no commercial conflicts of interest.

Estimated course time: 1 hour(s).

Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

 
Learning Objectives

Upon completion of this Cyberounds®, you should be able to:

  • Discuss the molecular pathogenesis of sporadic vs. hereditary colorectal cancer

  • Describe the rare hereditary syndromes and the more common hereditary nonpolyposis colon cancer (HNPCC)

  • Diagnose HNPCC by Bethesda Criteria

  • List screening and management guidelines for HNPCC.

 

Background

  1. Colorectal cancer is the second most prevalent cancer in men and women.
  2. Colorectal cancer is the second leading cause of cancer death.
  3. The lifetime risk for developing colorectal cancer is 6%.
  4. There has been no change in the incidence rate over the last 40 years.

Risk Factors

  1. Approximately 50% of colorectal cancers are sporadic without any obvious familial predisposition.
  2. As many as 30% of patients with colorectal cancer have a family history of disease.
  3. Risk factors
    1. Diet: There is a correlation between colorectal cancer mortality and the consumption of calories, meat protein and animal fat.
    2. Inflammatory Bowel Disease [more]
    3. Hereditary syndromes
      1. Familial adenomatous polyposis (FAP)
      2. Hereditary Nonpolyposis Colon Cancer (HNPCC)

Polyps

  1. Most colorectal cancers arise from adenomatous polyps. Other types of polyps (e.g., juvenile and hyperplastic polyps) are not clearly premalignant.
  2. Adenomatous polyps are found in 30% of the U.S. population >50 years old. The lifetime risk of developing additional adenomatous polyps is 30 - 50%.
  3. Less than 1% of adenomatous polyps become malignant.
  4. Risk of conversion of an adenomatous polyp to a carcinoma is dependent on gross appearance, histology and size. Sessile (flat-based), villous and larger polyps are more likely to transform to a carcinoma.

Molecular Pathogenesis

  1. There seems to be a defined genetic pathway involved in the conversion of an adenoma to a carcinoma.
  2. The current defined sequence of genetic alterations is:

    Mutations of APC® Alterations in DNA Methylation® Mutations of K-RAS® Loss of heterozygosity (LOH) on 18q® Mutations in TP53.

    1. Adenomatous Polyposis Coli (APC):
      1. A tumor suppressor gene located on chromosome 5q21.
      2. Mutated in 60-80% of sporadic colorectal cancers.
      3. Mutations often give the phenotype of Familial Adenomatous Polyposis (FAP).
      4. Location of mutation determines phenotype
        1. Mutations in the central region of the protein give a severe polyposis phenotype with the development of a large number of polyps and early cancer.
        2. Mutations altering the 5' or 3' region of gene result in an attenuated phenotype with few adenomas and a later onset of cancer.
        3. Mutations within codons 450 to 1444 result in congenital hypertrophy of retinal pigment epithelium (CHRPE) in addition to adenomas.
      5. Most mutations in APC are truncating mutations with loss of function of the region 3' of a mutation cluster region.
      6. The APC mutation I1307K is highly prevalent in Ashkenazi Jews and is associated with an increased risk of colorectal cancer. 28% of Ashkenazi Jewish persons with colorectal cancer and a positive family history had this mutation, while those of other ethnic backgrounds did not. Interestingly, this mutation does not alter the function of the APC gene product.
    2. Changes in DNA methylation: demethylation and focal hypermethylation
      1. Changes in methylation have been shown to cause mitotic non-disjunction and chromosomal irregularities.
      2. Knockout mice for the DNA methyltransferase enzyme are relatively resistant to tumor development.
    3. K-RAS
      1. An oncogene that belongs to the surface receptor signaling family.
      2. Mutated in 50% of sporadic colorectal cancers.
      3. K-RAS mutations can exist in histologically normal colonic mucosa.
    4. Loss of heterozygosity (LOH) -- loss of one or more gene activity on the distal arm of chromosome 18.
      1. Genes in this region include the DCC gene, which is a receptor for a nerve growth factor, and Smad (DPC4) and Smad2, which are involved in the TGF-bsignaling pathway.
    5. TP53 -- on chromosome 17p
      1. A tumor suppressor gene.
      2. Normally involved in apoptosis (programmed cell death).
      3. Mutations are found in up to 70% of colorectal cancers.
      4. Mutations mark the beginning of conversion from adenoma to carcinoma.

Familial Adenomatous Polyposis (FAP)

  1. Autosomal dominant.
  2. Clinically, the disease is characterized by the development of hundreds to thousands of polyps in the entire large bowel, and often the duodenum.
  3. Polyps occur at a mean age of 16 years and adenomas by age 35.
  4. There is a high risk of transformation of adenomas to malignancy (90% by age 45, if untreated).
  5. FAP is a result of a mutation in the APC gene.
  6. Other intestinal manifestations in FAP include gastric polyps (>50% of patients) and duodenal polyps (>90% of patients).
  7. Extraintestinal manifestations of FAP include:
    1. Congenital hypertrophy of retinal pigment epithelium (CHRPE). These lesions are a good indicator of the affected status of other individuals within a FAP family.
    2. Osteomas (especially located at the angle of the mandible).
    3. Soft tissue tumors of the skin.

Gardner Syndrome

  1. Phenotypic variant of FAP defined as FAP with extraintestinal manifestations (usually osteomas and soft tissue tumors).
  2. APC gene mutations are found in Gardner Syndrome. Therefore, it is postulated that the extraintestinal manifestations may be the consequence of a modifier gene.

Turcot Syndrome

  1. A syndrome defined by adenomatous polyps and central nervous system malignancies.
  2. Two-thirds of cases are caused by mutations in the APC gene. CNS tumors include medulloblastomas and anaplastic astrocytomas.
  3. One-third of cases are caused by mutations in mismatch repair (MMR) genes. In these cases, CNS tumors are usually glioblastomas.

Management of FAP and Related Syndromes

  1. Patients with FAP or a related syndrome have a high risk for malignant transformation and should have a prophylactic total colectomy with an ileoanal anastomosis.
  2. Patients with a family history of FAP should have a screening colonoscopy in the second decade of life and those with polyps followed annually by repeat colonoscopy.

Hereditary Nonpolyposis Colon Cancer (HNPCC)

  1. Autosomal dominant.
  2. Affects 1:200 - 1:400 people.
  3. Average age at diagnosis (age 45) is approximately 10 years younger than for sporadic colorectal cancer.
  4. Lifetime risk for an intestinal malignancy is 80% for mutation carriers.
  5. Female patients also carry a 50% lifetime risk of developing endometrial cancer.
  6. Patients do not exhibit polyposis. Patients develop adenomas at a younger age than the normal population.
  7. Associated with extraintestinal tumors, especially ovarian and endometrial cancers.
  8. Diagnosis is based on Bethesda Criteria.
  9. Recommended screening for patients with a family history of HNPCC includes biennial colonoscopy with intermittent pelvic imaging, beginning at age 25.

Genetics of HNPCC

  1. 80% of colorectal tumors associated with HNPCC show microsatellite instability (MSI).
    1. Microsatellites are DNA motifs of 1-6 nucleotides that are tandemly repeated 10-60 times. In any given individual, the length of a microsatellite is usually somatically stable, but with instability there are subtle length alterations.
    2. The MSI phenotype is defined by instability of at least two microsatellite loci.
    3. Tumors with MSI are different at the molecular level and do not follow the classical pathway of carcinogenesis with accumulation of mutations in APC, TP53, K-RAS and LOH leading to malignant transformation. These tumors have fewer aberrations in comparison to tumors without MSI.
  2. HNPCC is known to be caused by germline mutations in any of four DNA mismatch repair (MMR) genes (hMSH2, hMLH1, PMS1, PMS2). The MMR system appears to be exclusively responsible for the recognition and repair of MSI. Tumors characterized by MSI are thought to have a global defect in MMR function leading to genomic instability.
  3. 60% of HNPCC is a result of hMSH2 (on chromosome 2p) gene mutation while hMLH1 (on chromosome 3p) gene alteration is responsible for an additional 30%.
  4. Mismatch repair dysfunction accelerates the accumulation of mutations in tumor suppressor genes and oncogenes, thereby speeding the development of malignancy.

Diagnostic Algorithm for Suspected HNPCC

  1. Make a clinical diagnosis based on the Bethesda Criteria.
  2. Use MSI analysis to ascertain the mutator phenotype.
    1. Use a series of markers recommended by the International Collaborative Group for HNPCC and the National Cancer Institute as a reference panel.
    2. Tumors that show instability at two of the five defined markers are classified as having microsatellite instability.
  3. Do immunohistochemistry to ascertain alterations in the expression of the MMR proteins.
  4. Analyze DNA.
  5. Genetic counseling.

Consequences of Molecular Diagnostics for HNPCC

If a mutation is found,

  1. Closely monitor the patient for the development of metachronous and other HNPCC related cancers.
  2. NSAIDs are beneficial as prophylaxis against the development of further colorectal cancers in HNPCC patients.
  3. Prophylactic surgery is controversial.

Discussion

The impact of genetics is acutely relevant in the field of oncology. Colorectal cancer has a defined molecular pathogenesis that involves stepwise genetic alterations resulting in the eventual development of a carcinoma. In addition to understanding the pathogenesis of sporadic colorectal cancer, genetics has helped identify susceptibility genes that may be transmitted in families. Although, syndromes such as FAP, Gardner and Turcot syndromes are relatively rare and likely not encountered by most primary care physicians, HNPCC constitutes approximately 5-13% of all colorectal cancers. The diagnosis is based on clinical and family history. Molecular testing allows definition of the genetic basis of HNPCC and the identification of at-risk family members. Therefore, understanding the genetics of HNPCC allows for appropriate management of patients and counseling of family members regarding the decision to test and the implications associated with a positive test.