Genetic evidence that juvenile nasopharyngeal angiofibroma is an integral FAP tumour

Juvenile nasopharyngeal angiofibroma (JNA) is a rare locally invasive neoplasm composed
of cavernous vascular channels set in an abundant myxoid stroma of fibroblasts and
myofibroblasts. The frequency of JNA is significantly increased in male familial adenomatous
polyposis (FAP) patients, suggesting that it may arise through alterations of the adenomatous
polyposis coli (APC)/beta-catenin gene pathway. This was supported by the high frequency of recurrent beta-catenin gene mutations detected in sporadic JNA, but no APC mutations have thus far been found. We analysed the sequence of the APC gene and the presence of recurrent beta-catenin mutations in matched blood and tumour DNA from a 24 year old JNA affected FAP carrier who underwent restorative proctocolectomy and resection of an abdominal wall desmoid. A frameshift APC mutation, c.3927-3931delAAAGA, was detected in both blood and JNA tissue. This mutation introduces a stop codon (pGlu1309fsX1312) in theAPC gene region between the first and second 20 amino acid beta-catenin binding repeats. Another frameshift APC mutation, consisting in a 5 bp deletion, c.3183-3187delACAAA, that introduces a stop codon (p.Lys1061fsX1062) in the region encoding the first 20 amino acid beta-catenin binding repeat, was detected only in JNA DNA. The presence of the JNA associated activating mutations was ruled out at codons 32 and 34 in exon 3 of the beta-catenin gene. This study documents for the first time the association between a somatic and a germline APC mutation in an FAP related JNA. Our findings agree with the well known evidence of double hit APC inactivation in FAP associated fibroblastic tumours.