Sporadic Colonic Adenocarcinomas with a High Degree of Microsatellite Instability (MSI-H) Do Not Show Evidence of Wnt Signaling Abnormalities
Nicole C Panarelli, Cecily Vaughn, Wade S Samowitz, Rhonda K Yantiss. Weill Cornell Medical College, New York, NY; University of Utah, Salt Lake City, UT
Background: Most sporadic colonic adenocarcinomas arise from adenomas via dysregulation of the Wnt signaling pathway, as evidenced by nuclear B-catenin immunostaining, and are microsatellite stable (MSS). Sessile serrated polyps are not dysplastic, but do show BRAF mutations and DNA methylation, and have been implicated in the serrated neoplastic pathway. Onset of MSI-H in serrated polyps coincides with progressive dysplasia and leads to sporadic cancers with BRAF mutations, MSI-H, and widespread promoter hypermethylation. Wnt signaling and MSI-H are generally considered to be mutually exclusive cancer progression models. However, several studies have described abnormal B-catenin staining in serrated polyps, suggesting a role for Wnt signaling in development of sporadic MSI-H cancers. We evaluated B-catenin staining in sporadic colon cancers to determine whether Wnt activation promotes carcinogenesis in MSI-H tumors.
Design: 43 colon cancer resection specimens were evaluated. All patients were >60 years old with tumors proximal to the splenic flexure. Immunostains for MLH1, PMS2, MSH2, MSH6, and B-catenin were performed. Aberrant B-catenin staining was defined by moderate-to-strong nuclear, and diminished membranous, staining in ≥30% of the tumor cells. Tumor DNA was extracted and assessed by PCR for MSI using 5 mononucleotide repeats (BAT-25, BAT-26, NR-21, NR-24, MONO-27). Pyrosequencing was carried out to assess for BRAF codon V600E mutations.
Results: 23 tumors showed complete loss of MLH1 and PMS2 staining with MSI-H, including 16 (70%) with BRAF mutations (M/F=6/17, mean age: 72 years). Only 1 (4%) MSI-H tumor displayed aberrant B-catenin staining and it was BRAF wild-type. Twenty cancers had preserved staining for DNA repair proteins, MSS, and wild-type BRAF (M/F: 11/9, mean age: 71 years). Of these, 75% showed abnormal B-catenin staining, which was significantly more than MSI-H tumors (p<0.0001).
Conclusions: MSS colonic carcinomas are usually BRAF wild-type and show nuclear localization of B-catenin with diminished cell membrane staining, reflecting aberrant Wnt signaling. Abnormal B-catenin staining is rare in sporadic MSI-H cancers and, in fact, we found no abnormal B-catenin expression among MSI-H cancers with BRAF mutations. Despite reports of nuclear B-catenin accumulation in serrated polyps, we conclude that Wnt signaling alterations are unlikely to be biologically important in sporadic MSI-H tumors.
Monday, March 19, 2012 1:00 PM
Poster Session II # 123, Monday Afternoon