Genome-Wide Somatic Copy Number Alterations and Mutations in High-Grade Pancreatic Intraepithelial Neoplasia

摘要

To obtain a better understanding of the genetic alterations of high-grade pancreatic intraepithelial neoplasia (HG-PanIN), we performed whole-genome copy number analysis by using single nucleotide polymorphism microarrays and targeted next-generation sequencing of 11 microdissected HG-PanIN and two low-grade PanIN lesions associated with HG-PanIN. HG-PanIN mutation profiles were compared with those of their associated invasive pancreatic ductal adenocarcinoma. All PanIN lesions harbored somaticKRASmutations. The most common copy number losses in the HG-PanIN were at theCDKN2A(9p21),TP53(17p13), andSMAD4(18q21) loci. Chromosomal losses in HG-PanIN were also found at 6p25–p24, 6q11–q27, 12q24, and 17q23–q24. Biallelic inactivation ofCDKN2AandTP53was detected in five of eight and in three of eight evaluable PanIN lesions, respectively. None of the HG-PanIN lesions hadSMAD4mutations or homozygous deletion. Copy number gains were noted at theMYC(8q24) andCCNE1(19q12) loci and at 1q25–q31. Four HG-PanINs and one low-grade PanIN harbored chromothripsis-like regions. Five of seven pancreatic ductal adenocarcinomas evaluated had additional mutations that were not found in their associated HG-PanIN. HG-PanIN harbors widespread copy number alterations and commonly shows evidence of biallelic inactivation ofCDKN2AandTP53but notSMAD4. Chromothripsis events contribute to the copy number alterations of HG-PanIN.