Distinct Spectrum of APC Germline Mutations in a Familial Adenomatous Polyposis Population from the South of Portugal: Identification of a Mutational Hotspot and Suggestion of a Founder Mutation | FAPvoice

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Distinct Spectrum of APC Germline Mutations in a Familial Adenomatous Polyposis Population from the South of Portugal: Identification of a Mutational Hotspot and Suggestion of a Founder Mutation

key information

source: 6th Familial Cancer Conference, Madrid, Spain

year: 2014

authors: Bruno Filipe, Cristina Albuquerque, Pedro Lage, Isabel Claro, Sara Ferreira, Isadora Rosa, Paula Rodrigues, Isabel Spier, Stefan Aretz, Antonio Dias Pereira

summary/abstract:

Oral Communication

Familial adenomatous polyposis (FAP) is caused by APC germline mutations. These have been reported in classic and attenuated FAP (AFAP) families but only two hotspots have been described (codons 1309 and 1061- range:0-15%).

We aimed to characterize the APC mutation spectrum in a FAP/AFAP population from the South of Portugal. We performed mutation analysis in 95 index patients (61 FAP; 34 AFAP) using PTT, DGGE, sequencing and MLPA. Haplotype analysis was performed using 3 microsatellite markers flanking APC and 2 intragenic SNPs in 6 families with an intron 9 mutation and in 4 German families with the same mutation, in order to evaluate a possible founder effect. Statistical analysis: Fisher’s exact and Χ2. APC mutations were found in 47/61 (77%) FAP and in 12/34 (35%) AFAP. The majority were in exon 15 (31/59;52%), being this more frequent in FAP [30/47 (64%) vs 1/12 (8%),P=0.0007]. A high mutation frequency was also found in exon 9 (9/59;15%), contributing for the majority of AFAP with APC mutation (8/12;67%) Besides the 1309 and 1061 mutations [6/59 (10%) and 2/59 (4%)], an intron 9 mutation (c.1312+3A>G) was highly represented (6/59,10%), exclusively in AFAP (6/12;50%). This mutation was previously reported in only 9 families. Microsatellite marker analysis revealed that only two alleles are shared among our 6 families and 4 of the previously reported families (the same allele is shared by all affected members in each family). For D5S346, the shared alleles were found in 8/20 (40%) and 6/20 (30%) alleles from index patients but less frequent in a control population [20/90 (22%) and 15/90 (17%). Regarding SNPs, 8/10 families shared the same allele.

We identified a specific distribution of APC mutations and a mutational hotspot in our population. The higher frequency of the c.1312+3A>G mutation suggest a non-uniform distribution which may be explained by a founder effect. Further studies using SNPs flanking intron 9 and the analysis of more families are needed.

organisation: Molecular Pathobiology Research Unit (UIPM), Familial Cancer Risk Clinic, Instituto Português de Oncologia de Lisboa Francisco Gentil, University of Bonn

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