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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.
摘要：
乳腺粘液表皮样癌（MEC）是一种罕见的实体。由于乳腺MEC的稀有性，其分子特征尚未得到充分研究。我们对1000例乳腺癌患者进行了回顾性研究，并确定了4例乳腺MEC。收集临床和人口统计学数据。还进行了用于诊断唾液腺MEC和乳腺癌的免疫组织化学面板。通过FISH检测MAML2重排,并通过RNA测序鉴定融合配偶体。使用全外显子组测序(WES)来揭示这四个乳腺MEC的基因组。然后，进一步比较了乳腺MEC与浸润性乳腺癌和唾液腺MEC的生物学功能和特征。根据Ellis和Auclair的方法,这4例乳腺MEC可归类为低度乳腺MEC.所有的病人都还活着,无病生存期（PFS）为20个月至67个月。在这四个乳房MEC中，两例为三阴性,另外两例被发现是ER阳性，通过免疫组织化学染色也显示HER2模棱两可，但在鱼中没有扩增。FISH分析证实在四个肿瘤中的三个肿瘤中存在MAML2易位，和CRTC1-MAML2融合在其中两个通过RNA测序得到证实。用于肿瘤突变负荷估计的WES的平均覆盖大小为32Mb。在至少三种肿瘤中发现MUC4、RP1L1和QRICH2突变，这些突变也存在于乳腺浸润性癌数据库中(TCGA，Cell2015;TCGA,《自然》2012年)。结果显示，乳腺MEC中有许多基因与上述乳腺浸润性癌数据库重叠，范围从5到63个基因（中位数：21个基因）。接下来,我们评估了这些肿瘤的免疫细胞浸润水平.在所有这些肿瘤中，M2巨噬细胞和浆细胞均为高浸润组。我们的乳腺MEC显示出与唾液腺MEC不同的结果，其浆细胞处于低浸润组。总的来说,我们首先分析了乳腺粘液表皮样癌的基因组学和肿瘤微环境，并提出了我们的假设，即尽管在乳腺中产生的MEC在表型上类似于其唾液腺对应物，我们的研究结果表明,乳腺MECs在遗传水平和免疫细胞浸润水平上可能与浸润性乳腺癌相似.更多的病例和在深刻的研讨中须要进一步懂得这一罕见癌。
