Genetic evidence for the multi-step progression of mixed glandular–neuroendocrine gastric carcinomas

Abstract

A mixed glandular-neuroendocrine gastric carcinoma shows discrete, juxtaposed areas of adenocarcinoma and neuroendocrine carcinoma. In order to gain insight into the genetic events and clonality associated with the dual differentiation of a mixed gastric carcinoma, eight cases (two true composite and six neuroendocrine-dominant carcinomas) were examined by analyzing the genome-wide loss of heterozygosity (LOH). Of the eight mixed gastric carcinomas, one true composite and five neuroendocrine-dominant carcinomas showed a primary LOH that was shared by both the glandular and neuroendocrine components and a secondary LOH or mutations that were restricted to the neuroendocrine components. The glandular components contained mixed cell populations with or without primary LOH events, suggesting that a primary LOH arose during adenocarcinoma progression and that the LOH-positive cell served as a precursor for a neuroendocrine carcinoma. The neuroendocrine components were of a homogeneous population with various genetic alterations such as a LOH, p53 mutations, and microsatellite instability-associated transforming growth factor (TGF)-beta RII mutation. Therefore, most (six of eight cases) mixed glandular-neuroendocrine gastric carcinomas were likely to have sequentially evolved from a glandular precursor to a genetically heterogeneous adenocarcinoma and then to neuroendocrine differentiation. Two components of the other true composite carcinomas were shown to have reciprocally lost different alleles of identical loci on multiple chromosomes, suggesting that, occasionally (one of eight cases), dual differentiation concurrently arises from a single precursor, possibly as a result of non-disjunctional cell division.

Microallelotyping Defines the Monoclonal or the Polyclonal Origin of Mixed and Collision Endocrine-Exocrine Tumors of the Gut

“…In agreement with this model, two different studies have recently reported a microallelotyping analysis of seven colorectal PDECs (Vortmeyer et al, 1997) and of eight gastric PDECs (Kim et al, 2002) associated with adenomas or adenocarcinomas. In both studies, using a genomewide approach (Kim et al, 2002) or a loss of heterozygosity (LOH) analysis restricted to APC, DCC, and p53 loci (Vortmeyer et al, 1997), a close genetic relation-ship was observed between the two components, regardless of the typology of the mixed tumors analyzed. Because additional genetic alterations restricted to PDEC have been detected, it was speculated that a mixed exocrine-endocrine tumor evolves from a single epithelial precursor following an exocrine to endocrine cell-type sequence and not vice versa (Kim et al, 2002).…”

“…Therefore, it is not clear if the biphenotypic differentiation represents a genetic continuum from a common pluripotent stem cell or if the exocrine and endocrine tumor components arise from two distinct precursors through different tumorigenetic pathways (Kim et al, 2002;Peison and Benisch, 1983;Vortmeyer et al, 1997;Yamashita and Flinner, 1985).…”

“…In both studies, using a genomewide approach (Kim et al, 2002) or a loss of heterozygosity (LOH) analysis restricted to APC, DCC, and p53 loci (Vortmeyer et al, 1997), a close genetic relation-ship was observed between the two components, regardless of the typology of the mixed tumors analyzed. Because additional genetic alterations restricted to PDEC have been detected, it was speculated that a mixed exocrine-endocrine tumor evolves from a single epithelial precursor following an exocrine to endocrine cell-type sequence and not vice versa (Kim et al, 2002). Moreover, it was emphasized that the differentiation into PDEC may occur at a relatively early stage of carcinogenesis as demonstrated by the existence of mixed PDEC with a minimal exocrine component represented by areas of high grade dysplasia or adenoma.…”

Genetic alterations in poorly differentiated endocrine carcinomas of the gastrointestinal tract

“…14,38 Nonetheless, recent reports of frequent 18q LOH in midgut carcinoids indicate that a novel putative tumor suppressor gene (distinct from DCC or DPC4) that is located on 18q may play an important role in the pathogenesis of midgut endocrine tumors. 15,16 In an attempt to evaluate whether the pathogenesis of PDECs is more consistent with that of WDECs, as suggested by some studies, [5][6][7][8] or with that of classical nonendocrine adenocarcinomas (i.e., CRCs), as suggested by other reports, 3,4 we compared the gastric subset of PDECs with a series of gastric WDECs and also compared the colorectal subset of PDECs with a series of CRCs.…”

“…These results suggest that PDECs and nonendocrine carcinomas originate from a common multipotent stem cell. 3,4 In contrast, another study, on mixed glandular-neuroendocrine carcinomas, found different genetic alterations in the two tumor components. 5 Furthermore, some studies on gastric PDECs have revealed extensive allelic deletions in the region containing the MEN1 gene that are responsible for multiple endocrine neoplasia type 1 syndrome.…”