Molecular Profile of Crohn's Colitis-Associated Colorectal Adenocarcinoma Is More Similar to the 'Sporadic' Rather Than Ulcerative Colitis-Associated Profile
JK Lennerz, A Srivastava, J Batten, JH Chen, AJ Iafrate, G Lauwers. Massachusetts General Hospital, Boston; Dartmouth-Hitchcock Medical Center, Lebanon; Indiana University, Indianapolis
Background: It is now recognized that Crohn's disease (CD) carries a 20-fold higher cancer risk and similarily to ulcerative colitis (UC), one of the major long-term complications is the development of colorectal adenocarcinoma (CRC). Molecular profiling of CRC in UC demonstrated ∼25% microsatellite instability (MSI) and ∼10% BRAF mutations. In contrast, much less is known about Crohn's colitis-associated CRC. The aim is to examine MSI- and BRAF status in a large series of CRC arising in Crohn's colitis.
Design: Based on a previous Patient Database Registry analysis (IBD 2006;12:491-496) we identified patients with CD that showed a) involvement of at least one third of the colon and b) a confirmed diagnosis of CRC. Formalin-fixed paraffin embedded material was analyzed for BRAF and MSI. BRAF analysis employed chain termination sequencing with assessment of exon 15; in particular the common V600E mutation (GTG>GAG). Microsatellite analysis combined a) multiplex PCR with fluorescent primers for the following five MSI consensus microsatellite loci ('Bethesda markers'): BAT25, BAT26, D2S123, D5S346, D17S250 and b) IHC for MLH1, MSH2, MSH6 and PMS2.
Results: In a series of 227 patients of Crohn's colitis we identified 33 cases of CRC (∼14%). The 33 patients were 24 males, average age 59 (range 34-77), and mean time since initial diagnosis of CD 26 years. The CRC characteristics were: 22 left-sided (66%) and tumor staging: 0(n=2); I(n=10); IIA(n=7); IIB(n=3); IIIB(n=4); IIIC(n=4); IV(n=3). There was no family history of IBD in 26/27 cases. All informative cases were BRAF-WT (=GTG; n=20/20). Combined PCR/IHC MSI assessment showed 2 of 27 cases with MSI-H (>2 unstable markers); the remainder of cases were microsatellite stable (0 unstable markers).
Conclusions: CRC complicating Crohn's colitis are BRAF wild-type and the vast majority (∼93%; 25/27) are microsatellite-stable. Thus, the molecular profile of these tumors is more similar to the 'sporadic pathway' of CRC rather than that observed in the setting of UC. These findings may suggest a role of CD-associated inflammation, epithelial injury and repair in carcinogenesis. Nonetheless, the genetic similarity to sporadic CRC does not lessen the importance of surveillance programs for CD-patients since the incidence of CRC is still higher than the general population.
Monday, March 22, 2010 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 96, Monday Morning