Thesis

Prevalence of APC 1B promoter deletion in a cohort of mutation-negative familial adenomatous polyposis patients

Familial adenomatous polyposis (FAP), estimated to occur in 1 in 8,000 to 1 in 10,000 individuals, is caused by mutations in the APC gene. Advances in technology have allowed for more mutations to be detected, providing a genetic etiology for the clinical diagnosis of hundreds to thousands of precancerous colon polyps. Traditionally, the use of sequencing had sufficed in detection of disease-causing mutations. However, it is now recognized that large rearrangements (deletions or duplications) involving the APC gene explain a subset of mutation-negative cases that are not easily detected by sequencing alone. Several recent studies have described families in which deletions involving the APC 1B promoter, resulting in a classic presentation of FAP, were detected using multiplex ligation-dependent probe amplification (MLPA) analysis. This study aimed to re-test mutation-negative individuals with a clinical diagnosis of FAP in hope of detecting and further characterizing deletions in the 1B promoter of the APC gene. Although no 1B promoter deletions were detected through this study, two previously undetected deletions in the APC gene were discovered. These two deletions highlight the value of re-referral for complete genetic testing to detect all possible disease-causing mutations. The results of this study support the need to retest mutation-negative individuals using new, advanced technologies to reveal previously missed genetic etiologies for polyposis.

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