Molecular genetic evidence for the conversion hypothesis of the origin of malignant mixed Müllerian tumours

Abstract

The origin of malignant mixed Müllerian tumours (MMMTs) has long been debated, due to the indefinite relationship between epithelial and mesenchymal malignant cells. In order to obtain insight into the clonal relationship between the two components of these tumours, molecular genetic changes were investigated at the level of loss of heterozygosity (LOH) in both cells types. LOH was studied in a series of six cases with 74 polymorphic microsatellite markers mapping to 19 different chromosomes. The epithelial and the mesenchymal neoplastic cells were separately microdissected from formalin‐fixed, paraffin‐embedded tissue, prior to DNA isolation. LOH was observed for 35 different markers mapping to chromosomes 3, 6, 8, 11, 15, 16, 17, 18, 21, and X. The most frequently involved chromosomes were 17p, 17q, 11q, 15q, and 21q. LOH was observed in five out of six cases and identical alleles were lost in the epithelial and in the mesenchymal cells. No genetic differences were observed between the two cell types for any of the informative markers. Immunohistochemistry (IHC) and TP53 mutation analysis revealed involvement of TP53 in all cases. Mutations were identified in five MMMTs. In four tumours, of which three had a missense mutation, strong nuclear staining for p53 was observed. In the remaining two cases, the mutation resulted in a stop codon, with no nuclear staining for p53 by IHC. The results support a monoclonal origin of MMMTs, with the absence of genetic changes uniquely associated with either of the phenotypes. The latter finding is compatible with current opinion that these neoplasms should be considered as metaplastic carcinomas and supports the conversion hypothesis. © 1997 John Wiley & Sons, Ltd.

Molecular genetic aberrations of ovarian and uterine carcinosarcomas—a CGH and FISH study

“…It is well known that chromosomal aberrations occur commonly in carcinosarcomas of the female genital tract. Cytogenetic studies have shown that p53 and K-ras mutations, LOH, and microsatellite instability arise in both tumor components [1,14,15,25,38]. Wada et al [38] found identical mutations of p53 and K-ras in the two different tumor components.…”

“…Regarding LOH, molecular analysis frequently showed aberrations, which were almost identically in the two tumor components [1].…”

“…Multiple chromosomal alterations were described, such as polysomy 8, loss of heterozygosity (LOH), or p53 mutations. Deoxyribonucleic acid (DNA) cytometry showed nondiploidy in most carcinosarcomas [1,3,7,21,[25][26][27][28]35].…”

Extensive and divergent chromosomal losses in squamous and spindle-cell components of esophageal sarcomatoid carcinoma

“…However, although a great deal of progress in histogenetic and genetic studies has been made toward unraveling the monoclonal origins of sarcomatoid carcinomas, few divergent genetic changes responsible for the biphasic differentiation have been identified. For example, a previous study on chromosomal losses in sarcomatoid carcinoma described the primary common chromosomal losses, but no secondary chromosomal losses were assigned for a SA component in support of a metaplastic transformation of a SCC [1].…”

“…Immunohistochemical [7,13,24,30] and electron microscopic [7,24,25] studies indicated that the SA component carried various degrees of epithelial differentiation. Limited genetic studies on sarcomatoid carcinomas have also found that the same genetic alterations are commonly shared in the SCC and SA components in the uterus, breast, lung, gastrointestinal tract, urinary bladder, pharynx, and the upper respiratory tract [1,3,28,29]. However, although a great deal of progress in histogenetic and genetic studies has been made toward unraveling the monoclonal origins of sarcomatoid carcinomas, few divergent genetic changes responsible for the biphasic differentiation have been identified.…”