[1858] Undifferentiated Carcinomas of the Pancreas Are Characterized by KRAS Mutant Allele-Specific Imbalance

Alyssa Krasinskas, A James Moser, Sheri Kavala, Simon Chiosea. University of Pittsburgh Medical Center, Pittsburgh

Background: Activating point mutations in codon 12 of the KRAS oncogene are present in the majority of pancreatic ductal adenocarcinomas (PDAs) and in pancreatic undifferentiated carcinomas with pleomorphic or osteoclast-like giant cells. The role of KRAS mutant allele specific imbalance (MASI), which is associated with increased mutant allele transcription and kinase activity, has not been systematically studied in carcinomas of the pancreas.
Design: KRAS mutational analysis was performed using direct Sanger sequencing. Peak heights of KRAS mutant and wild-type alleles were compared on sequencing electropherograms. KRAS MASI was defined in mutated cases as mutant allele peak (M) higher than or equal to the wild type (W) allele peak (M≥W). KRAS amplification (KRAS/CEP12 >2) was evaluated in a subset of cases (18 PDA, 9 undifferentiated carcinomas) using fluorescence in situ hybridization.
Results: KRAS mutations, all at codon 12, were found in 83 of 101 (82%) cases of PDA and 10 of 11 (91%) cases of undifferentiated carcinoma. Data on the 93 KRAS mutated cases are shown below.

 Pancreatic Ductal Adenocarcinomas (n=83)Undifferentiated Carcinomas (n=10)
Female/Male39 / 445 / 5
Average age6761
Most common KRAS mutationsG12D (55%), G12V (28%)G12D (40%), G12V (40%)
KRAS allele peak heights on sequencing electropherograms:
M≥W (MASI)67
M773
KRAS/CEP12 by FISH:
>20 /185 / 9
<218 /184 / 9


KRAS MASI (M≥W) is present in 7/10 (70%) undifferentiated carcinomas of the pancreas versus 6/83 (7.2%) of typical PDA (odds ratio 30, 95% confidence interval 6.1 - 146; p<.0001). MASI is associated with KRAS gene amplification by FISH (4/8 in M≥W versus 1/19 in M < W; odds ratio 18, 95% confidence interval 1.5 - 207; p = .017).
Conclusions: KRAS MASI as determined by allelic peak height on sequencing electropherograms is present in 70% undifferentiated carcinomas of the pancreas and is associated with KRAS gene amplification by FISH. Only 7.2% of typical PDAs have MASI. This study is the first to correlate KRAS MASI with a specific morphologic tumor subtype and suggests that MASI contributes to the clinicopathologic phenotype of undifferentiated carcinomas of the pancreas.
Category: Pancreas

Tuesday, March 20, 2012 1:00 PM

Poster Session IV # 290, Tuesday Afternoon

 

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