Cyclooxygenase 2 expression and molecular alterations in Peutz-Jeghers hamartomas and carcinomas.
OBJECTIVE
Peutz-Jeghers syndrome (PJS) is a hamartomatous polyposis disorder with a high cancer risk. Debate exists about the premalignant potential of hamartomas. Also, treatment options other than surveillance are not available. Therefore, molecular alterations in hamartomas and PJS carcinomas were studied. The objective was (a) to evaluate expression of cyclooxygenase (COX)-2 as target for chemopreventive treatment and (b) to define the neoplastic potential of hamartomas at the molecular level.


METHODS
Paraffin-embedded samples of 24 PJS hamartomas, including 2 hamartomas with dysplastic changes, and 11 PJS carcinomas were available. Slides were stained with antibodies against COX-2, beta-catenin, cyclin D1, p21(waf1/cip1), Ki-67, and p53. DNA was studied for loss of heterozygosity (LOH) at 19p (STK11), 5q (APC), and 17p (TP53); mutations in beta-catenin, APC, and K-RAS; and microsatellite instability.


RESULTS
Moderate or strong epithelial COX-2 was present in 25% of hamartomas, including two hamartomas with dysplastic changes, and 64% of carcinomas. Several hamartomas showed focal nuclear beta-catenin (18%) and cyclin D1 overexpression (29%), both unrelated to dysplasia at histological examination. Disturbed topographical expression of Ki-67 in relation to p21(waf1/cip1) was focally present in 27% of hamartomas, including those with dysplastic changes. Most carcinomas showed nuclear beta-catenin (71%), cyclin D1 overexpression (71%), and aberrant Ki-67 staining (100%). There was LOH at 19p in 32% of hamartomas and 82% of carcinomas. p53 staining was present in four (36%) carcinomas, one of which showed LOH at 17p. No beta-catenin mutations were found. APC mutations were present in two carcinomas, but LOH at 5q was not found. Two carcinomas had K-RAS mutations, and one carcinoma had microsatellite instability.


CONCLUSIONS
The presence of COX-2 expression in PJS carcinomas and dysplastic hamartomas provides a rationale for chemoprevention with nonsteroidal anti-inflammatory drugs or COX-2 inhibitors. Focal immunohistochemical changes, which may indicate a premalignant potential, were present in some nondysplastic PJS hamartomas. Molecular changes in carcinomas and dysplastic hamartomas in PJS are distinct from the usual adenoma-carcinoma sequence.
De Leng
Wendy W J
WW
Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
Westerman
Anne Marie
AM
Weterman
Marian A J
MA
De Rooij
Felix W M
FW
Dekken Hv
Herman van
Hv
De Goeij
Anton F P M
AF
Gruber
Stephen B
SB
Wilson
J H Paul
JH
Offerhaus
G Johan A
GJ
Giardiello
Francis M
FM
Keller
Josbert J
JJ
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002277:Carcinoma / Q000201:enzymology* / Q000235:genetics*; D002886:Chromosomes, Human, Pair 17; D002888:Chromosomes, Human, Pair 19; D002895:Chromosomes, Human, Pair 5; D019938:Cyclin D1 / Q000096:biosynthesis; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D051546:Cyclooxygenase 2; D003598:Cytoskeletal Proteins / Q000096:biosynthesis; D004247:DNA / Q000737:chemistry; D043243:DNA Sequence, Unstable; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics*; D019394:Ki-67 Antigen / Q000096:biosynthesis; D007700:Kinetics; D019656:Loss of Heterozygosity; D008565:Membrane Proteins; D018895:Microsatellite Repeats / Q000235:genetics; D009154:Mutation; D010580:Peutz-Jeghers Syndrome / Q000201:enzymology* / Q000235:genetics*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics*; D015534:Trans-Activators / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D051176:beta Catenin
D000894:Anti-Inflammatory Agents, Non-Steroidal; C493956:CDKN1A protein, human; C495270:CTNNB1 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D019394:Ki-67 Antigen; D008565:Membrane Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D019938:Cyclin D1; D004247:DNA; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases