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. 2024 Jan 19;19(1):15.
doi: 10.1186/s13000-024-01439-8.

Genomics and tumor microenvironment of breast mucoepidermoid carcinoma based on whole-exome and RNA sequencing

Yan Ge #  1   2 , Xingtao Lin #  3 , Jiao He #  3 , Wendan Chen  3 , Danyi Lin  3 , Yihong Zheng  4 , Lingling Yang  5 , Fangping Xu  6 , Zhi Li  7
Affiliations

Genomics and tumor microenvironment of breast mucoepidermoid carcinoma based on whole-exome and RNA sequencing

Yan Ge et al. Diagn Pathol. .

Abstract

Mammary mucoepidermoid carcinoma (MEC) is a rare entity. The molecular characteristics of breast MEC have not been fully investigated due to its rarity. We performed a retrospective study among 1000 patients with breast carcinomas and identified four cases of breast MEC. Clinical and demographic data were collected. Immunohistochemistry panels which were used to diagnose salivary gland MEC and breast carcinomas were also performed. MAML2 rearrangements were detected by FISH and fusion partners were identified by RNA sequencing. Whole-exome sequencing (WES) was used to reveal the genomes of these four breast MEC. Then, the biological functions and features of breast MEC were further compared with those of invasive breast carcinomas and salivary gland MEC.According to Ellis and Auclair's methods, these four breast MEC could be classified as low-grade breast MEC. All the patients were alive, and disease-free survival (PFS) ranged from 20 months to 67 months. Among these four breast MEC, two cases were triple-negative, and the other two cases were found to be ER positive, with one also showing HER2 equivocal by immunohistochemical staining, but no amplification in FISH. FISH analysis confirmed the presence of the MAML2 translocation in three of four tumors, and CRTC1-MAML2 fusion was confirmed in two of them by RNA-sequencing. The average coverage size of WES for the tumor mutation burden estimation was 32 Mb. MUC4, RP1L1 and QRICH2 mutations were identified in at least three tumors, and these mutation also existed in breast invasive carcinoma databases (TCGA, Cell 2015; TCGA, Nature 2012). The results showed that there were many genes in breast MEC overlapping with the breast invasive carcinoma databases mentioned above, range from 5 to 63 genes (median:21 genes). Next, we assessed immune cell infiltration levels in these tumors. In all these tumors, M2 macrophages and plasma cell were in the high infiltration group. Our breast MEC showed different results from the salivary gland MEC, whose plasma cells were in the low infiltration group. Overall, we first analyzed the genomics and tumor microenvironment of breast mucoepidermoid carcinoma and proposed our hypothesis that although MECs arising in the breast resemble their salivary gland counterparts phenotypically, our findings indicate that breast MECs probably resemble invasive breast carcinomas at the genetic level and immune cell infiltration levels. More cases and in deep research need to be done to further understand this rare carcinoma.

Keywords: Breast; Mucoepidermoid carcinoma; RNA-sequencing; Whole-exome sequencing.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Morphologic features of breast mucoepidermoid carcinomas. A and B Epidermoid and intermediate cells were the major cell types found in case one and case three, mixing with a few mucinous cells and basaloid cells. C Case four was mainly composed of epidermoid and mucoid cells, with few basaloid and intermediate cells, and occasional intercellular bridges. D and E Case two was predominantly composed of basaloid cells, with different proportions of the other three types of cells. F Irregular adenoid structures could also be occationally observed in case two
Fig. 2
Fig. 2
Microphotographs of the immunohistochemistry (IHC) in mucoepidermoid carcinoma of the breast. A About 60% of tumor cells were estrogen receptor (ER)- positive in case one. B About 40% of tumor cells were estrogen receptors (ER) -positive in case two. C The tumor cells in case showed HER2 equivocal
Fig. 3
Fig. 3
Fluorescence in situ hybridization analysis of MAML2 (11q21) gene in mucoepidermoid carcinoma of the breast. The presence or absence of MAML2 translocation was determined by FISH using a dual-color, break apart probe. Cell nuclei were counterstained with DAPI (blue). A Representative images of cells (case one) without translocation. Each cell had two intact yellow signals. B Representative images of cells harboring the translocation. Each cell demonstrated one separate orange and one separate green signal
Fig. 4
Fig. 4
Schematic diagrams of CRTC1-MAML2 fusion transcripts in our cohort. A CRTC1-MAML2 rearrangement between the CRTC1 exon 1 and MAML2 exon 2 genes in case two. B CRTC1-MAML2 rearrangement between the CRTC1 exon 1 and MAML2 exon 2 genes in case three
Fig. 5
Fig. 5
Immune microenvironment status within and across tissue groups. The infiltration percentage of 15 types of immune cells was estimated for each sample with CIBERSORT using gene expression data from RNA sequencing
Fig. 6
Fig. 6
Mutation analysis of breast mucoepidermoid carcinoma patients. Mutation diagram rectangles are colored with respect to the corresponding mutation types. In the case of different types at a single position, colors of the rectangle reflect the two most frequent mutation types. The genes with significant mutations in the samples were arranged according to the mutation frequency. A A comutation plot of various types of mutations in breast mucoepidermoid carcinoma patients in our cohort. The cutoff value was 25%. MUC4, QRICH2 and RP1L1 were found in case one, case two and case three. Case four had a relatively low tumor burden and did not have common mutation genes as the other three cases. B, Comparison between case two, case three and case four. The cutoff value was 33.3%. C, Comparison between case one, case two and case three. The cutoff value was 33.3%
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