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

TitleGenome-Wide Somatic Copy Number Alterations and Mutations in High-Grade Pancreatic Intraepithelial Neoplasia.
Publication TypeJournal Article
Year of Publication2018
AuthorsHata T, Suenaga M, Marchionni L, Macgregor-Das A, Yu J, Shindo K, Tamura K, Hruban RH, Goggins M
JournalAm J Pathol
Volume188
Issue7
Pagination1723-1733
Date Published2018 07
ISSN1525-2191
KeywordsAged, Biomarkers, Tumor, Carcinoma in Situ, Carcinoma, Pancreatic Ductal, DNA Copy Number Variations, DNA, Neoplasm, Female, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Mutation, Neoplasm Grading, Pancreatic Neoplasms
Abstract

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 somatic KRAS mutations. The most common copy number losses in the HG-PanIN were at the CDKN2A (9p21), TP53 (17p13), and SMAD4 (18q21) loci. Chromosomal losses in HG-PanIN were also found at 6p25-p24, 6q11-q27, 12q24, and 17q23-q24. Biallelic inactivation of CDKN2A and TP53 was detected in five of eight and in three of eight evaluable PanIN lesions, respectively. None of the HG-PanIN lesions had SMAD4 mutations or homozygous deletion. Copy number gains were noted at the MYC (8q24) and CCNE1 (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 of CDKN2A and TP53 but not SMAD4. Chromothripsis events contribute to the copy number alterations of HG-PanIN.

DOI10.1016/j.ajpath.2018.03.012
Alternate JournalAm J Pathol
PubMed ID29684357
PubMed Central IDPMC6024190
Grant ListP50 CA062924 / CA / NCI NIH HHS / United States
R01 CA176828 / CA / NCI NIH HHS / United States
U01 CA210170 / CA / NCI NIH HHS / United States
Related Faculty: 
Luigi Marchionni, M.D., Ph.D.

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