KRAS mutant allele-specific imbalance is associated with worse prognosis in pancreatic cancer and progression to undifferentiated carcinoma of the pancreas

• Type of Material: Article
• Authors: Alyssa Krasinskas, Emory University; A James Moser, University of Pittsburgh; Burcu Saka, Emory University; Nazmi Adsay, Emory University; Simion I Chiosea, University of Pittsburgh
• Language: English
• Date: 2013-10-01
• Publisher: Springer Nature [academic journals on nature.com]: Hybrid Journals
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 USCAP, Inc. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/modpathol.2013.71
• Title of Journal or Parent Work: Modern Pathology
• ISSN: 0893-3952
• Volume: 26
• Issue: 10
• Start Page: 1346
• End Page: 1354
• Grant/Funding Information: Support for advice regarding regulatory matters was provided by the National Institutes of Health through Grant Numbers UL1RR024153 and UL1TR000005.; The John F Fortney Charitable Pancreatic Cancer Research Group and Mellie’s Mission provided financial support.
• Keywords: CELL LUNG-CANCER; ONCOGENE MUTATIONS; pancreatic cancer; K-RAS MUTATIONS; HYBRIDIZATION; undifferentiated carcinoma; TUMOR; GENES; KRAS; AMPLIFICATIONS; CARCINOGENESIS; mutant allele-specific imbalance; Life Sciences & Biomedicine; ORIGIN; DUCTAL ADENOCARCINOMA; Pathology; fluorescence in situ hybridization; Science & Technology
• Research Categories: Health Sciences, Oncology; Health Sciences, Pathology

Abstract

KRAS codon 12 mutations are present in about 90% of ductal adenocarcinomas and in undifferentiated carcinomas of the pancreas. The role of KRAS copy number changes and resulting KRAS mutant allele-specific imbalance (MASI) in ductal adenocarcinoma (n=94), and its progression into undifferentiated carcinoma of the pancreas (n=25) was studied by direct sequencing and KRAS fluorescence in situ hybridization (FISH). Semi-quantitative evaluation of sequencing electropherograms showed KRAS MASI (ie, mutant allele peak higher than or equal to the wild-type allele peak) in 22 (18.4%) cases. KRAS FISH (performed on 45 cases) revealed a trend for more frequent KRAS amplification among cases with KRAS MASI (7/20, 35% vs 3/25, 12%, P=0.08). KRAS amplification by FISH was seen only in undifferentiated carcinomas (10/24, 42% vs 0/21 pancreatic ductal adenocarcinoma, 0%, P=0.0007). In 6 of 11 cases with both undifferentiated and well-differentiated components, transition to undifferentiated carcinoma was associated with an increase in KRAS copy number, due to amplification and/or chromosome 12 hyperploidy. Pancreatic carcinomas with KRAS MASI (compared to those without MASI) were predominantly undifferentiated (16/22, 73% vs 9/97, 9%, P<0.001), more likely to present at clinical stage IV (5/22, 23% vs 7/97, 7%, P=0.009), and were associated with shorter overall survival (9 months, 95% confidence interval, 5-13, vs 22 months, 95% confidence interval, 17-27; P=0.015) and shorter disease-free survival (5 months, 95% confidence interval, 2-8 vs 13 months, 95% confidence interval, 10-16; P=0.02). Our findings suggest that in a subset of ductal adenocarcinomas, KRAS MASI correlates with the progression to undifferentiated carcinoma of the pancreas.