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Genetics of Colorectal Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Introduction

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Research, however, suggests increased CRC risk in some families who have multiple members affected with juvenile polyposis, Peutz-Jeghers syndrome, and hyperplastic polyposis.[7,8,9]

Epidemiologic studies have shown that a personal history of colon adenomas places one at an increased risk of developing colon cancer.[10]

Two complementary interpretations of this observation are as follows:

  1. The adenoma may reflect an innate or acquired tendency of the colon to form tumors.
  2. Adenomas are the primary precursor lesion of colon cancer.

More than 95% of CRCs are carcinomas, and about 95% of these are adenocarcinomas. It is well recognized that adenomatous polyps are benign tumors that may undergo malignant transformation. They have been classified into three histologic types, with increasing malignant potential: tubular, tubulovillous, and villous. While there is no direct proof that most CRCs arise from adenomas, adenocarcinomas are generally considered to arise from adenomas,[11,12,13,14,15] based upon the following important observations:

  1. Benign and malignant tissue occur within colorectal tumors.[16]
  2. When patients with adenomas were followed for 20 years, the risk of cancer at the site of the adenoma was 25%, a rate much higher than that expected in the normal population.[17]

The following three characteristics of adenomas are highly correlated with the potential to transform into cancer:[16]

  1. Larger size.
  2. Villous pathology.
  3. The degree of dysplasia within the adenoma.

In addition, removal of adenomatous polyps is associated with reduced CRC incidence.[18,19] While most adenomas are polypoid, flat and depressed lesions may be more prevalent than previously recognized. Large, flat, and depressed lesions may be more likely to be severely dysplastic, although this remains to be clearly proven.[20,21] Specialized techniques may be needed to identify, biopsy, and remove such lesions.[22]

Molecular Events Associated With Colon Carcinogenesis

The transition from normal epithelium to adenoma to carcinoma is associated with acquired molecular events.[23,24,25] This tumor progression model was deduced from comparison of genetic alterations seen in normal colon epithelium, adenomas of progressively larger size, and malignancies.[26,27] At least five to seven major deleterious molecular alterations may occur when a normal epithelial cell progresses in a clonal fashion to carcinoma. There are at least two major pathways by which these molecular events can lead to CRC. While the majority of CRCs are due to events that result in chromosomal instability (CIN), 20% to 30% of CRCs display characteristic patterns of gene hypermethylation, termed CpG island methylator phenotype (CIMP), of which a portion display microsatellite instability (15% of CRCs).[25,28,29,30,31,32]

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