PTEN Loss of Heterozygosity Correlates with Decreased PTEN Expression and Increased p53 Expression in Intraductal Papillary Mucinous Neoplasms of the Pancreas.
Andrew T Turk, Dario Garcia-Carracedo, Benjamin C Tweel, Gloria H Su, John A Chabot, Helen E Remotti. Columbia University, New York, NY
Background: Proposed functions of the tumor suppressor PTEN include a role in cellular senescence via interaction with p53. Mutations of PTEN appear to occur late during tumorigenesis. Previous studies have shown that PTEN loss of heterozygosity (LOH) occurs in a significant proportion of pancreatic adenocarcinoma cases. We sought to determine the frequency of PTEN LOH in pancreatic intraductal papillary mucinous neoplasms (IMPN), and to determine the relationship between PTEN LOH and expression of PTEN and p53 by immunohistochemistry (IHC) using tissue microarrays (TMA).
Design: We analyzed 36 cases of IPMN. DNA was extracted from paraffin-embedded tissue. LOH was assessed by PCR amplification using primers corresponding to a polymorphism within the PTEN locus (RefSNP# rs34421660). TMA's consisting of 3 representative cores per case were constructed. Expression of PTEN and p53 was assessed by IHC. PTEN expression in lesional epithelium (compared to normal epithelium) was scored as normal (2 points), decreased (1 point), or negative (0 points). Expression of p53 was scored as a product of intensity (0-3 points) multiplied by proportion of lesional epithelium with positive staining. Average scores for PTEN and p53 staining were calculated for each case.
Results: Of our 36 cases, 17 showed heterozygosity for PTEN by PCR, and 19 showed homozygosity. Of the 17 heterozygous cases, 7 showed LOH; DNA was not extracted from lesional epithelium of one case. The LOH cases showed significantly lower expression of PTEN (average score = 1.12/2.00) compared to cases without LOH (average score = 1.58/2.00). Additionally, the LOH cases showed significantly higher expression of p53 (average score = 0.31/3.00) compared to cases without LOH (average score = 0.03/3.00).
Conclusions: Of 36 IPMN cases, 7 showed PTEN LOH. Cases with PTEN LOH showed significantly lower PTEN expression, and significantly higher p53 expression by IHC. These findings are consistent with patterns of expression of these markers in other tumor types, and provide insight into changes in regulatory processes that occur in IPMN. Limitations of the current study include potentially low sensitivity for LOH, resulting from assessment of a single polymorphism. Future directions include assessment of LOH using additional polymorphisms, FISH analysis to evaluate PTEN deletions, and assessment of changes in expression of additional markers.
Tuesday, March 1, 2011 1:00 PM
Poster Session IV # 67, Tuesday Afternoon