Annexin A10 expression correlates with serrated pathway features in colorectal carcinoma with microsatellite instability.

Annexin A10 (ANXA10) has recently been identified as a marker of sessile serrated adenomas/polyps of the colorectum. Although the serrated neoplasia pathway is thought to be involved in the majority of microsatellite instability-high (MSI-H) sporadic colorectal carcinomas (CRCs), the clinicopathological implications of ANXA10 expression in CRC are unknown. Here, we evaluated ANXA10 expression status in 168 MSI-H CRCs by immunohistochemistry. Among 168 MSI-H CRCs, nuclear staining for ANXA10 in tumor cells revealed 28 cases (17%) with ANXA10-positive (ANXA10+) tumors. Most of the ANXA10+ tumors were located in the proximal colon (96%, p < 0.001). The ANXA10+ phenotype in MSI-H CRC was significantly associated with female gender (68%, p = 0.016), CpG island methylator phenotype-high (CIMP-H) (68%, p < 0.001), MLH1 promoter hypermethylation (61%, p < 0.001), loss of MLH1 expression (82%, p = 0.019), and wild-type KRAS status (96%, p = 0.023). Survival analysis revealed no prognostic significance of ANXA10 expression in MSI-H CRC. In conclusion, ANXA10+ MSI-H colon carcinomas are characterized by serrated pathway features, including proximal location, female predominance, and high frequencies of CIMP-H status and MLH1 methylation.

Kim JH ，Rhee YY ，Kim KJ ，Cho NY ，Lee HS ，Kang GH ... -  《-》

Possible role of Cdx2 in the serrated pathway of colorectal cancer characterized by BRAF mutation, high-level CpG Island methylator phenotype and mismatch repair-deficiency.

Colorectal cancer is a heterogeneous disease at the histomorphological, clinical and molecular level. Approximately 20% of cases may progress through the "serrated" pathway characterized by BRAF mutation and high-level CpG Island Methylator Phenotype (CIMP). A large subgroup are additionally microsatellite instable (MSI) and demonstrate significant loss of tumor suppressor Cdx2. The aim of this study is to determine the specificity of Cdx2 protein expression and CpG promoter hypermethylation for BRAF(V600E) and high-level CIMP in colorectal cancer. Cdx2, Mlh1, Msh2, Msh6, and Pms2 were analyzed by immunohistochemistry using a multi-punch tissue microarray (TMA; n = 220 patients). KRAS and BRAF(V600E) mutation analysis, CDX2 methylation and CIMP were investigated. Loss of Cdx2 was correlated with larger tumor size (P = 0.0154), right-sided location (P = 0.0014), higher tumor grade (P < 0.0001), more advanced pT (P = 0.0234) and lymphatic invasion (P = 0.0351). Specificity was 100% for mismatch repair (MMR)-deficiency (P < 0.0001), 92.2% (P < 0.0001) for BRAF(V600E) and 91.8% for CIMP-high. Combined analysis of BRAF(V600E)/CIMP identified Cdx2 loss as sensitive (80%) and specific (91.5%) for mutation/high status. These results were validated on eight well-established colorectal cancer cell lines. CDX2 methylation correlated with BRAF(V600E) (P = 0.0184) and with Cdx2 protein loss (P = 0.0028). These results seem to indicate that Cdx2 may play a role in the serrated pathway to colorectal cancer as underlined by strong relationships with BRAF(V600E), CIMP-high and MMR-deficiency. Whether this protein can only be used as a "surrogate" marker, or is functionally involved in the progression of these tumors remains to be elucidated.

Dawson H ，Galván JA ，Helbling M ，Muller DE ，Karamitopoulou E ，Koelzer VH ，Economou M ，Hammer C ，Lugli A ，Zlobec I ... -  《-》

Distinct features between MLH1-methylated and unmethylated colorectal carcinomas with the CpG island methylator phenotype: implications in the serrated neoplasia pathway.

Kim JH ，Bae JM ，Cho NY ，Kang GH ... -  《Oncotarget》

Comparison of microsatellite instability, CpG island methylation phenotype, BRAF and KRAS status in serrated polyps and traditional adenomas indicates separate pathways to distinct colorectal carcinoma end points.

O'Brien MJ ，Yang S ，Mack C ，Xu H ，Huang CS ，Mulcahy E ，Amorosino M ，Farraye FA ... -  《AMERICAN JOURNAL OF SURGICAL PATHOLOGY》

Annexin A10 expression in colorectal cancers with emphasis on the serrated neoplasia pathway.

Bae JM ，Kim JH ，Rhee YY ，Cho NY ，Kim TY ，Kang GH ... -  《-》