Promoter-Specific Alterations of APC are a Rare Cause for Mutation-Negative Familial Adenomatous Polyposis

NIEMINEN T.; PAVICIC W.; GYLLING A; PURSIHEIMO JP; LAIHO A; GYENESEI A; JÄRVINEN HJ; PELTOMÄKI P.

San Diego, California

Congreso; American Society of Human Genetics 64th, ASGH Annual Meeting; 2014

ASGH

Familial adenomatous polyposis (FAP) syndrome predisposes to colorectal cancer (CRC). FAP individuals suffer from even hundreds or thousands of colon adenomas and if untreated, CRC develops. The average age at onset of CRC is 39 years. FAP is caused by a germline mutation in the APC gene and it is inherited by an autosomal-dominant manner. In FAP, 20% of classical and 70% of attenuated/atypical (AFAP) cases remain mutation-negative after routine testing; yet, allelic expression imbalance may suggest an APC alteration. Our aim was to determine the share of families attributable to genetic or epigenetic changes in the APC promoter region. We studied 51 unrelated families/cases (26 with classical FAP and 25 with AFAP) with no point mutations in the exons and exon/intron borders and no rearrangements by multiplex ligation-dependent probe amplification (MLPA, P043-B1). Promoter-specific events of APC were addressed by targeted re-sequencing, MLPA (P043-C1), methylation-specific MLPA, and Sanger sequencing of promoter regions. A novel 132-kb deletion encompassing the APC promoter 1B and upstream sequence occurred in a classical FAP family with allele-specific APC expression. No promoter-specific point mutations or hypermethylation were present in any family. In conclusion, promoter-specific alterations are a rare cause for mutation-negative FAP (1/51, 2%). The frequency and clinical correlations of promoter 1B deletions are poorly defined. This investigation provides frequencies of 1/26 (4%) for classical FAP, 0/25 (0%) for AFAP, and 1/7 (14%) for families with allele-specific expression of APC. We will continue investigations with the remaining 6 families with allele-spesific expression of APC by RNA-sequencing. Clinically, promoter 1B deletions may associate with classical FAP without extracolonic manifestations.