title: Immunohistochemistry for annexin A10 can distinguish sporadic from Lynch syndrome-associated microsatellite-unstable colorectal carcinoma.
abstract: Differentiating sporadic microsatellite-unstable colorectal carcinoma due to MLH1 promoter hypermethylation from Lynch syndrome (LS)-associated tumors due to mutations in mismatch-repair proteins is time consuming, cost intensive, and requires advanced laboratory testing. A mutation in BRAF has been shown to be highly specific for sporadic tumors; however, a significant proportion of sporadic microsatellite-unstable tumors lack BRAF mutations. MLH1 promoter methylation analysis is subsequently used to differentiate LS and sporadic tumors, but both tests require specialized laboratories and are costly. Through previous gene expression profiling of serrated polyps, we identified annexin A10 as a protein highly expressed in sessile serrated adenomas/polyps. As these polyps give rise to the majority of sporadic microsatellite-unstable tumors, we evaluated the ability of annexin A10 expression to discriminate between LS and sporadic tumors. A marked increase in annexin A10 mRNA was observed in sporadic microsatellite-unstable tumors compared with LS tumors (378-fold increase, P<0.001). Using immunohistochemistry, annexin A10 was expressed in 23/53 (43%) BRAF-mutated and 9/22 (41%) BRAF wild-type sporadic tumors. In contrast, only 3/56 (5%) LS tumors were positive for annexin A10 (P<0.0001). One patient had a deleterious MSH2 mutation, and another had a variant of uncertain significance in MSH6. These 2 tumors could be easily distinguished from sporadic tumors using mismatch-repair protein immunohistochemistry. Only 1/28 (4%) LS tumors with loss of MLH1 was positive for annexin A10. This patient did not have a deleterious MLH1 mutation but rather germline promoter hypermethylation of MLH1. On the basis of these results, immunohistochemistry for annexin A10 may be a useful marker to distinguish sporadic from LS-associated microsatellite-unstable colon cancer.
authors.affiliation: *Department of Anatomic Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Departments of †Anatomic Pathology §Colorectal Surgery ‡Genomic Medicine Institute ∥Digestive Disease Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Reetesh K
authors.initials: RK
authors.lastname: Pai
authors.forename: Bonnie L
authors.initials: BL
authors.lastname: Shadrach
authors.forename: Paula
authors.initials: P
authors.lastname: Carver
authors.forename: Brandie
authors.initials: B
authors.lastname: Heald
authors.forename: Jessica
authors.initials: J
authors.lastname: Moline
authors.forename: James
authors.initials: J
authors.lastname: Church
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Kalady
authors.forename: Carol A
authors.initials: CA
authors.lastname: Burke
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Plesec
authors.forename: Keith K
authors.initials: KK
authors.lastname: Lai
authors.forename: David H
authors.initials: DH
authors.lastname: Gonzalo
authors.forename: Rish K
authors.initials: RK
authors.lastname: Pai
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000368:Aged; D017302:Annexins / Q000032:analysis / Q000096:biosynthesis*; D014408:Biomarkers, Tumor / Q000032:analysis*; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D053842:Microsatellite Instability; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C121387:ANXA10 protein, human; D048868:Adaptor Proteins, Signal Transducing; D017302:Annexins; D014408:Biomarkers, Tumor; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1