Genomic evidence suggests that cutaneous neuroendocrine carcinomas can arise from squamous dysplastic precursors

Abstract

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma without a known dysplastic precursor. In some cases, MCC is associated with SCCIS in the overlying epidermis; however, the MCC and SCCIS populations display strikingly different morphologies, and thus far a relationship between these components has not been demonstrated. To better understand the relationship between these distinct tumor cell populations, we evaluated 7 pairs of MCC-SCCIS for overlapping genomic alterations by cancer profiling panel. A subset was further characterized by transcriptional profiling and immunohistochemistry. In 6 of 7 MCC-SCCIS pairs there was highly significant mutational overlap including shared TP53 and/or RB1 mutations. In some cases, oncogenic events previously implicated in MCC ( MYCL gain, MDM4 gain, HRAS mutation) were detected in both components. Although FBXW7 mutations were enriched in MCC, no gene mutation was unique to the MCC component across all cases. Transcriptome analysis identified 2,736 differentially expressed genes between MCC and SCCIS. Genes upregulated in the MCC component included Polycomb repressive complex targets; downregulated transcripts included epidermal markers, and immune genes such as HLA-A . Immunohistochemical studies revealed increased expression of SOX2 in the MCC component, with diminished H3K27Me3, Rb, and HLA-A expression. In summary, MCC-SCCIS pairs demonstrate clonal relatedness. The shift to neuroendocrine phenotype is associated with loss of Rb protein expression, decrease in global H3K27Me3, and increased expression of Merkel cell genes such as SOX2 . Our findings suggest an epidermal origin of MCC in this setting, and to our knowledge provide the first molecular evidence that intraepithelial squamous dysplasia may represent a direct precursor for small cell carcinoma.

The Origins of Merkel Cell Carcinoma: Defining Paths to the Neuroendocrine Phenotype

“…These may seem to be contradictory because H3K27me3 is associated with closed chromatin and transcriptional repression, whereas H3K27ac is associated with open chromatin. However, the comparisons made were not identical, and Harms et al (2021) rightly posit that MCC-associated SCCIS components represent a minority subset of RB1-inactivated SCCIS. They are thus unusually permissive for a neuroendocrine switch, occupying an intermediate unique genetic and epigenetic state between typical cutaneous SCCIS or SCC and UV-induced MCC.…”

“…First, on the basis of the mutational profiles and greater number of mutations in MCC than in SCCIS, MCPyV-negative MCC can arise from SCCIS. Second, although no mutational event clearly appears to be required for the MCC transition, RB1 inactivation is likely obligate, especially given the additional decrease in expression in the MCC component noted by Harms et al (2021) H3K27me1 and H3K27ac levels. These may seem to be contradictory because H3K27me3 is associated with closed chromatin and transcriptional repression, whereas H3K27ac is associated with open chromatin.…”

Scientific Research Directions on the Histopathology and Immunohistochemistry of the Cutaneous Squamous Cell Carcinoma: A Scientometric Study

“…For assessing the impact of and to establish the research directions for squamous cell carcinomas, we used the scientometric method [ 3 , 4 ]. A set of instructions was defined based on the keywords from the 76 articles we assessed [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , …”

Genetic evidence of a sarcomatoid transformation in Merkel cell carcinoma

“…Furthermore, the loss of the repressive H3K27me3 mark was observed in all components, which is a recently described determinant of MCPyV-negative MCC development. 5 The MCPyV sequence was not detected by qPCR. 7 After dissection by needle sampling 6 of the three components in case #1 and of the MCC and sarcomatoid components in case #2, MPS using a panel of 93 cancer-related genes confirmed the presence of two shared pathogenic variants in the three components in case #1 and of five shared pathogenic variants in the two available components in case #2 (Table 1).…”

“…4 Recently, applying massive parallel sequencing (MPS) to paired MCC and in situ SCC cases, we and others have shown that in combined tumours, MCC derived from SCC, thus demonstrating the keratinocytic origin of these cases. 5,6 Beyond SCC, several differentiation lineages have been observed in association with MCC. 4 Among these, combined MCC with a sarcomatoid component was rarely reported (13 cases).…”