CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Comprehensive molecular profiling of mucinous gastric carcinoma
Mucinous gastric carcinoma composes 2.6 percent to 8.7 percent of all gastric cancers and is characterized by abundant extracellular mucin. It has an aggressive clinical course and is associated with advanced stage and poor survival. It is often refractory to intraperitoneal chemotherapy. The authors conducted a study in which they evaluated 68 patients who had mucinous gastric carcinoma at various clinical stages. They classified the tumors into differentiated or undifferentiated mucinous gastric carcinoma. The authors extracted DNA from formalin-fixed, paraffin-embedded tissue and performed whole exome sequencing on a series of 16 carcinomas. A median of 62.5 mutations per case was identified, corresponding to a somatic mutation density of 1.9 mutations per megabase. Three tumors, all of which lacked MLH1 expression by immunohistochemistry, were found to be hypermutated, with greater than 1,000 nonsilent mutations. Based on the whole exome sequencing results and findings from previous studies, a targeted sequencing panel of 114 genes was developed and performed on a subsequent set of 52 mucinous gastric carcinomas. The most frequently mutated gene was TP53, which was mutated in 56 percent of carcinomas, followed by ARID1A (21 percent), CDH1 (21 percent), MLL2 (19 percent), RBMXL3 (19 percent), and MLL3 (15 percent). The authors found that mutations affecting chromatin structure and histone methylation appear to play a key role in mucinous gastric carcinoma, as 32 of the 68 tumors were found to have somatic mutations in any of nine genes related to chromatin remodeling. For example, the mutations affecting the MLL2 and MLL3 genes were shown to be nonsense or frameshift mutations that resulted in the production of truncated proteins lacking histone methyltransferase activity. Another recurrently mutated gene was MYH9, seen in nine of the 68 tumors, all of which were undifferentiated mucinous gastric carcinomas. The MYH9 gene encodes the heavy chain of nonmuscle myosin IIA, a component of the cytoskeleton, although its biological significance in gastric carcinoma was unclear. Using siRNA knockdown in two gastric carcinoma cell lines, the authors demonstrated that loss of MYH9 increased cell migration, reduced cell adhesion, and, in one of the cell lines, caused a signet ring phenotype. Therefore, mutations in MYH9 could represent a key event in the development of undifferentiated mucinous gastric carcinoma. Finally, the two- tiered histological subclassification of mucinous gastric carcinoma into differentiated and undifferentiated subtypes revealed clinical and molecular differences. The patients with undifferentiated carcinoma were shown to have increased nodal involvement, more advanced stage, and an overall poorer prognosis than those with differentiated mucinous gastric carcinoma. Furthermore, when comparing molecular aberrations, differentiated mucinous gastric carcinoma was found to be similar to intestinal-type gastric carcinoma, whereas undifferentiated mucinous gastric carcinoma appeared to be biologically distinct.
Rokutan H, Hosoda F, Hama N, et al. Comprehensive mutation profiling of mucinous gastric carcinoma. J Pathol. 2016;240:137–148.
Correspondence: T. Shibata at tshibata@ims.u-tokyo.ac.jp or tashibat@ncc.go.jp