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Major Genetic Syndromes

    Introduction

    Originally described in the 1800s and 1900s by their clinical findings, the colon cancer susceptibility syndrome names often reflected the physician or patient/family associated with the syndrome (e.g., Gardner syndrome, Turcot syndrome, Muir-Torre syndrome, Lynch I and II syndromes, Peutz-Jeghers syndrome (PJS), Bannayan-Riley-Ruvalcaba syndrome, and Cowden syndrome). These syndromes were associated with an increased lifetime risk of colorectal adenocarcinoma. They were mostly thought to have autosomal dominant inheritance patterns. Adenomatous colonic polyps were characteristic of the first five, while hamartomas were found to be characteristic in the last three.

    With the development of the Human Genome Project and the identification in 1990 of the Adenomatous Polyposis Coli (APC) gene on chromosome 5q, overlap and differences between these familial syndromes became apparent. Gardner syndrome and familial adenomatous polyposis (FAP) were shown to be synonymous, both caused by mutations in the APC gene. Attenuated FAP (AFAP) was recognized as a syndrome with less adenomas and extraintestinal manifestations as having FAP mutation on the 3' and 5' ends of the gene. Turcot syndrome families were shown to be genetically part of FAP with medulloblastomas and Lynch syndrome (LS) with glioblastomas. Muir-Torre and LS were shown to have genetic similarities. MYH-associated polyposis (MAP) was recognized as a separate adenomatous polyp syndrome with autosomal recessive inheritance. Once the mutations were identified, the absolute risk of colorectal cancer (CRC) could be better assessed for mutation carriers (Table 4).

    Table 4. Absolute Risks of Colorectal Cancer for Mutation Carriers in Hereditary Colorectal Cancer Syndromes

    SyndromeAbsolute Risk in Mutation Carriers
    FAP = familial adenomatous polyposis.
    a Refer to theLynch syndrome (LS)section of this summary for a full discussion of risk.
    FAP90% by age 45 y[1]
    Attenuated FAP69% by age 80 y[2]
    Lynch40% to 80% by age 75 ya[3,4]
    MYH-associated polyposis35% to 53%[5]
    Peutz-Jeghers39% by age 70 y[6]
    Juvenile polyposis17% to 68% by age 60 y[7,8]

    With these discoveries genetic testing and risk management became possible. Genetic testing refers to searching for mutations in known cancer susceptibility genes using a variety of techniques. Comprehensive genetic testing includes sequencing the entire coding region of a gene, the intron -exon boundaries (splice sites), and assessment of rearrangements, deletions, or other changes in copy number (with techniques such as multiplex ligation-dependent probe amplification [MLPA] or Southern blot). Despite extensive accumulated experience that helps distinguish pathogenic mutations from benign variants and polymorphisms, genetic testing sometimes identifies variants of uncertain significance that cannot be used for predictive purposes.

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