Ectopic Expression of Gastric Mucin MUC6 in Colorectal Adenomas and Carcinomas Is Associated with Microsatellite Unstable Pathway
DJ Hartman, SF Kuan. University of Pittsburgh, Pittsburgh, PA
Background: Microsatellite unstable (MSI) colorectal cancer (CRC) has better prognosis and different response to chemotherapy than microsatellite stable (MSS) colon cancer. The distinction between MSI and MSS CRC is important but the molecular tests are expensive and time-consuming. Sporadic MSI CRC commonly arises from sessile serrated adenoma (SSA) while its hereditary form, herediatary non-polyposis colorectal cancer (HNPCC) develops in adenomatous polyp (AP). Our previous study showed that MUC6 was expressed in SSA and subsequent dysplasia (Modern Pathology 2008;21:660-9). We now test the hypothesis that MUC6 is a potential marker for MSI CRC and precursor lesions.
Design: Twenty-five MSI-high CRCs (15 sporadic, 10 HNPCC), 20 MSS CRCs (17 sporadic, 3 familial adenomatous polyposis (FAP)), and 35 APs (20 MSS-sporadic, 10 MSS-FAP, and 5 MSI-HNPCC) were reviewed. A clinical diagnosis of HNPCC is based on modified Bethesda criteria. FAP is diagnosed based on germ-line mutation of APC gene. The microsatellite status was confirmed by a panel of 5 NCI markers or an immunohistochemical panel of MLH1, MSH2, and MSH6. Formalin-fixed paraffin-embedded sections were stained with an antibody to MUC6.
Results: Of the 25 MSI CRCs, 14 of 15 (93%) sporadic subtype and 8 of 10 (80%) HNPCC subtypes were positive for MUC6. Four of 5 (80%) HNPCC APs were positive for MUC6. The MUC6 positivity has no correlation with mucinous differentiation. Either mucinous or non-mucinous components may be MUC6(+). The extent and intensity of MUC6 staining tends to decrease with poorer grade of differentiation or higher grade of dysplasia. None of 20 MSS CRCs and 30 MSS APs, either sporadic or APC subtype, were positive for MUC6.
MUC6 in colorectal cancers and adenomatous polyps*p= <0.0001(Chi-Square);p=0.035;p=<0.0001(Fisher's exact test)
|Diagnosis||Microsatellite Status||Case No.||MUC6(+)||Percent|
|Sporadic CRC||MSI||15||14 *||93%|
|Sporadic CRC||MSS||17||0 *||0%|
|Hereditary CRC, HNPCC||MSI||10||8 ||80%|
|Hereditary CRC, FAP||MSS||3||0 ||0%|
|AP, HNPCC||MSI||5||4 ||80%|
|AP, sporadic or FAP||MSS||30||0 ||0%|
Conclusions: Ectopic expression of a gastric mucin MUC6 in colorectal cancers and adenomatous polyps, both sporadic and hereditary forms, is highly associated with microsatellite unstable pathway. MUC6 may be a useful marker for the screening of the microsatellite status before the expensive molecular study. MUC6 or its related DNA loci may be susceptible targets for mismatch repair mechanism.
Tuesday, March 10, 2009 1:45 PM
Platform Session: Section B, Tuesday Afternoon