Distinct molecular features of colorectal carcinoma with signet ring cell component and colorectal carcinoma with mucinous component

Abstract

Signet ring cell carcinoma and mucinous carcinoma are distinct subtypes of colorectal adenocarcinoma. The morphologic and molecular spectra of colorectal carcinomas with various signet ring cell components and colorectal carcinomas with various mucinous components, compared to non-mucinous adenocarcinomas, have not been examined. The study groups consisted of 39 carcinomas with various signet ring cell components ('the signet group'), 167 carcinomas with various mucinous components ('the mucinous group'), and 457 nonmucinous adenocarcinoma. We visually estimated the amounts of signet ring cell and mucinous components in tumors, and subclassified the signet and mucinous groups according to the amount of each component (r19, 20-49, and Z50%). We sequenced BRAF and KRAS, analyzed for microsatellite instability (MSI) and 18q loss of heterozygosity (LOH), and performed immunohistochemistry for TP53, cyclooxygenase-2 (COX2), MLH1, O-6-methylguanine DNA methyltransferase (MGMT), p16 (CDKN2A), and fatty acid synthase (FASN). Signet ring cell carcinoma (Z50% signet ring cell tumors) and r49% signet ring cell tumors showed similar molecular features. Except for MSI and MGMT, Z50% mucinous tumors and r49% mucinous tumors also showed similar molecular features. BRAF mutations, MSI, and MLH1 loss were more frequent in both the signet and mucinous groups than nonmucinous carcinoma. More frequent KRAS mutations and less frequent p16 loss and TP53 positivity were observed in the mucinous group than nonmucinous carcinoma. 18q LOH and COX2 overexpression were less common in the signet group than nonmucinous carcinoma. FASN levels were highest in the mucinous group, followed by nonmucinous carcinoma, and lowest in the signet group. In conclusion, a minor (r49%) signet ring cell or mucinous component in colorectal carcinoma suggests molecular features similar to Z50% signet ring cell or mucinous carcinoma, respectively. Signet ring cell carcinoma and mucinous carcinoma are related subtypes of colorectal adenocarcinoma, but have molecular features distinct from each other. Keywords: BRAF; colon cancer; COX2; fatty acid synthase; MSI; mucinous; signet ring cell Signet ring cell colorectal carcinoma and mucinous colorectal carcinoma are subtypes of colorectal adenocarcinoma with prominent mucin secretion. A unique pathologic feature of signet ring cell carcinoma is the presence of signet ring cells, which are single tumor cells with intracytoplasmic mucin displacing their nuclei aside. In contrast, mucinous colorectal carcinoma is characterized by abundant extracellular mucin produced by tumor cells. By definition, a 50% or greater signet ring cell component is required for the designation of signet ring cell colorectal carcinoma. Mucinous colorectal carcinoma has also 50% or more mucinous components. Signet ring cell colorectal carcinoma has been associated with poor clinical outcomes. [1][2][3][4][5][6] A number of studies have examined the molecular features of signet ring cell colorectal carcinoma and mucinous

Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

“…25,28,44 BRAF V600E mutation occurs in the majority of sporadic colorectal cancers with high-level microsatellite instability and in 5-20% of microsatellite status colorectal cancers. In this study, BRAF V600E mutation was identified in one-third of signet ring cell carcinomas, which is comparable to the 22% figure reported by Ogino et al 35 BRAF V600E mutation in our series has strong correlation with CpG island methylation phenotype-positive status, but not with any clinicopathologic or molecular features. Several studies have shown that BRAF V600E mutation does not affect prognosis in colorectal cancers with high-level microsatellite instability, but adversely affects survival in microsatellitestable colorectal cancers.…”

“…In this study, we analyzed the molecular features of 33 resected signet ring cell carcinomas and explored their correlation with outcome. High-level microsatellite instability has been reported in 25-31% of signet ring cell carcinomas, 15,35 which is similar to the 24% figure observed in this series. High-level microsatellite instability is a marker of favorable outcome in sporadic colorectal cancer, but does not favorably influence survival in signet ring cell carcinoma.…”

“…In one study, LOH at 18q was observed in 57% of signet ring cell carcinomas, but other loci were not examined. 35 In comparison, we have previously reported LOH in 62% of mucinous and 70% of conventional colorectal adenocarcinomas. In contrast to LOH in 80% of signet ring cell carcinomas with high-level microsatellite instability, this phenomenon is observed in only 14% of cases with high-level microsatellite instability in mucinous and conventional adenocarcinomas.…”

“…The literature contains limited data on the molecular features of signet ring cell carcinoma. Some molecular features (high-level microsatellite instability, BRAF mutation and KRAS mutation) were examined by Ogino et al, 35 but the authors acknowledged that their series of eight cases was small. In this study, we analyzed the molecular features of 33 resected signet ring cell carcinomas and explored their correlation with outcome.…”

“…31 Although genetic and epigenetic changes in colorectal cancer have been extensively studied, there are sparse data on the molecular features of signet ring cell carcinoma. 15,35 The relationship of molecular changes and survival in signet ring cell carcinoma remains unclear. It is likely that signet ring morphology is a marker for genetic abnormalities that confer the aggressive behavior associated with signet ring cell carcinoma irrespective of microsatellite-instability status.…”