Cutaneous carcinosarcoma: further insights into its mutational landscape through massive parallel genome sequencing

Abstract

Cutaneous carcinosarcoma (CCS) is an extraordinarily rare neoplasm with a biphasic morphological pattern exhibiting both epithelial and sarcomatoid components. Although its histogenesis and biological aspects remain poorly understood, previous studies have postulated that this tumor may arise from single cancer stem cells which subsequently differentiate into distinct tumor lineages. In this study, we explored a wide array of mutational hot spot regions, through high-depth next-generation sequencing of 47 cancer-associated genes in order to assess the mutational landscape of these tumors and investigate whether the epithelial and mesenchymal components shared the same genetic signatures. Results from this study confirm that despite their striking phenotypic differences, both elements of this infrequent tumor indeed share a common clonal origin. Additionally, CCS appears to embrace a heterogeneous spectrum with specific underlying molecular signatures correlating with the defining epithelial morphotype, with those carcinosarcomas exhibiting a squamous cell carcinoma epithelial component exhibiting diverse point mutations and deletions in the TP53 gene, and those with a basal cell carcinoma morphotype revealing a more complex mutational landscape involving several genes. Also, the fact that our findings involve several targetable gene pathways suggests that the underlying molecular events driving the pathogenesis of CCS may represent future potential targets for personalized therapies.

Cutaneous carcinosarcoma and the EMT: to transition, or not to transition? That is the question

“…As we proposed in our paper, primary carcinosarcomas of the skin are rare biphenotypic cutaneous tumors which simultaneously express both epithelial and mesenchymal elements, suggesting that in their development an EMT process might be involved [5]. We explored this possibility by assessing loss of E-cadherin expression and upregulation of vimentin expression, a pattern that is considered to be the hallmark of EMT changes in epithelial cells [5].…”

“…Although different epithelial morphotypes of cutaneous carcinosarcoma exist (squamous cell or basal cell derived), the presence of a spindle cell component is obligatory and a feature of all cases we studied. In all cases we studied, β-catenin and E-cadherin were expressed in the cytoplasmic membrane of benign epithelium, while tumor cells showed decreased E-cadherin membranous expression along with cytoplasmic and focal nuclear expression β-catenin [5]. Downregulation of E-cadherin represents a crucial molecular change in EMT as it reduces cell-cell adhesion and destabilizes epithelial architecture [3].…”

The history of dermatology, venereology and dermatopathology in different countries - China

“…Five objective responses were seen in 6 assessable patients with V600R BRAF mutation (total number of treated patients, n=9). The findings suggested that patients with BRAF V600R mutations can be treated successfully with oral BRAF inhibitors [52].…”

“…Limited small individual trials showed that BRAF K601E and L597Q are at least partially sensitive to trametinib (MEK inhibitor), with 3 of 5 treated patients showing objective clinical and radiological response with a very manageable toxicity profile [51]. Similarly, another study including 45 patients with advanced/metastatic BRAF V600R mutant melanoma showed an overall response rate of 50% for the whole population, with a progression-free survival of 5.5 months [52]. Five objective responses were seen in 6 assessable patients with V600R BRAF mutation (total number of treated patients, n=9).…”

“…Although promising for BRAF V600E and K, there are very limited findings for BRAF inhibitors in melanomas harboring non-BRAF V600E mutations, which include BRAFV600R, BRAFV601K, and BRAF L597K [51,52]. Limited small individual trials showed that BRAF K601E and L597Q are at least partially sensitive to trametinib (MEK inhibitor), with 3 of 5 treated patients showing objective clinical and radiological response with a very manageable toxicity profile [51].…”