Distinctive molecular genetic alterations in sporadic and familial adenomatous polyposis-associated pancreatoblastomas - Frequent alterations in the APC/beta-catenin pathway and chromosome 11p

Pancreatoblastomas are unusual malignant neoplasms of the pediatric pancrea s that may also rarely affect adults. The molecular pathogenesis of pancrea toblastomas is unknown. They are clinicopathologically distinct from adult pancreatic ductal adenocarcinomas, but their occasional occurrence in patie nts with Beckwith-Wiedemann syndrome and the case presented here of a pancr eatoblastoma in an adult patient with familial adenomatous polyposis (FAP) suggests that they might bear a genetic similarity to other infantile embry onal tumors such as hepatoblastomas. We analyzed a series of nine pancreato blastomas for mutations common to other embryonal malignancies including so matic alterations in the adenomatous polyposis coli (APC)beta -catenin path way and chromosome 11p, using immunohistochemistry for beta -catenin, 5q an d lip allelic loss assays, and direct DNA sequencing of exon 3 of the beta -catenin gene and the mutation cluster region of the APC gene. In addition, we analyzed the pancreatoblastomas for alterations found in adult-type pan creatic ductal adenocarcinomas including mutations in the K-ras oncogene an d the p53 and DPC4 tumor suppressor genes I using direct DNA sequencing of exon 1 of K-ras and immunohistochemistry for p53 and Dpc4. Allelic loss on chromosome lip was the most common genetic alteration in pancreatoblastomas , present in 86% (six of seven informative cases). Molecular alterations in the APC/beta -catenin pathway were detected in 67% (six of nine), includin g five neoplasms with activating mutations of the beta -catenin oncogene an d the one FAP-associated tumor with biallelic APC inactivation (germline tr uncating mutation combined with loss of the wild-type allele); seven neopla sms showed abnormal nuclear accumulation of beta -catenin protein. In contr ast, loss of Dpc4 protein expression was present in only two cases (one dif fuse and one focal), and no alterations in the K-ras gene or p53 expression were detected. our findings indicate that pancreatoblastomas are genetical ly distinct from the more common pancreatic ductal adenocarcinomas, but bea r a close molecular pathogenesis to hepatoblastomas. In addition, pancreato blastoma may represent an extracolonic manifestation of FAP.