Research Article: Analysis of APC promoter 1B deletions in Russian families with familial adenomatous polyposis
Abstract:
Familial adenomatous polyposis (FAP) is a severe autosomal dominant hereditary cancer syndrome. Patients develop hundreds of adenomatous polyps throughout the colon with the risk of colorectal cancer, if untreated, approaching 100%. FAP is caused by pathogenic germline variants in the APC gene. Deletions in the APC 1B promoter cause FAP in a small subgroup of patients. Previous studies suggested that the APC promoter deletions in unrelated FAP patients from the US and Italy are identical and may thus have spread from a single founder. The aim of this study was to investigate whether a similar founder effect can be detected in the Russian population.
We performed whole-genome sequencing on five unrelated patients (three males and two females) with extensive (over 100) colon polyps, family history of FAP, and germline APC 1B promoter deletions previously detected by the multiplex ligation-dependent probe amplification (MLPA) and detected precise deletion boundaries.
The patients carried deletions in the APC 1B promoter ranging from ~3 to ~122 kbp. We found no association between the deletion size and either the age of the onset or severity of the disease. All deletions were unique and no identical deletion boundaries were observed. However, in four patients, the right deletion breakpoints fell into a 1 kbp region downstream of the 1B promoter. The right breakpoints of several deletions detected in FAP patients from other countries also fell into this narrow region.
The APC 1B promoter deletions analyzed in this study had arisen independently and there is thus no evidence of a founder effect. Therefore, at least for the cohort of FAP patients with APC 1B promoter deletions studied here, WGS did not provide an added diagnostic benefit to MLPA aside from precisely determining the deletion breakpoints.
Introduction:
Familial adenomatous polyposis (FAP) is a hereditary cancer syndrome characterized by the development of hundreds, sometimes thousands, of adenomatous polyps in the colon. If proctocolectomy is not performed, the lifetime risk of colorectal cancer (CRC) approaches 100% ( 1 ). The incidence of FAP is approximately 1 in 10, 000 live births ( 2 ). The onset of the disease can occur in late teens, however, the diagnosis is made much later ( 3 ). In addition to colorectal cancer, patients with FAP may develop…
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