Pfarr Nicole, Kriegsmann Mark, Sinn Peter, Klauschen Frederick, Endris Volker, Herpel Esther, Muckenhuber Alexander, Jesinghaus Moritz, Klosterhalfen Bernd, Penzel Roland, Lennerz Jochen K, Weichert Wilko, Stenzinger Albrecht
Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.
Institute of Pathology, Charité University Hospital, Charitéplatz 1, 10117, Berlin, Germany.
Genes Chromosomes Cancer. 2015 Jul;54(7):444-52. doi: 10.1002/gcc.22256. Epub 2015 Apr 30.
Somatic mutations in exon 2 of MED12 have been described in benign and malignant smooth muscle cell tumors suggesting a functional role in these neoplasms. Recently fibroadenomas of the breast were also reported to harbor MED12 mutations. Hence, we explored MED12 mutations in fibroepithelial tumors of the breast, histological subtypes of fibroadenomas and phyllodes tumors, to validate and extend previous efforts. Using conventional Sanger sequencing, we profiled 39 cases of fibroepithelial breast tumors comprising classic histological subtypes of fibroadenomas as well as benign and malignant phyllodes tumors for mutations in exon 2 of MED12. MED12 mutations were detected in 60% of all tumor samples with the majority being missense mutations affecting codon 44. Additionally, we report novel in-frame deletions that have not been described previously. Sixty-two percent of the fibroadenomas harbored mutated MED12 with intracanalicular fibroadenomas being the most frequently mutated histological subtype (82%). Of note, 8/11 of benign phyllodes tumors had MED12 mutations while only 1/5 of malignant phyllodes tumors showed mutations in exon 2 of MED12. In conclusion, we confirm the frequent occurrence of MED12 mutations in fibroadenomas, provide evidence that most intracanalicular fibroadenomas closely resembling benign phyllodes as well as benign phyllodes tumors harbor MED12 mutations, and conclude that MED12 mutations in malignant phyllodes tumors appear to be relatively rare.
MED12基因外显子2中的体细胞突变已在良性和恶性平滑肌细胞瘤中被描述，提示其在这些肿瘤中发挥功能作用。最近有报道称乳腺纤维腺瘤也存在MED12突变。因此，我们对乳腺纤维上皮性肿瘤、纤维腺瘤的组织学亚型及叶状肿瘤中的MED12突变进行了探索，以验证和拓展之前的研究成果。我们采用传统的桑格测序法，对39例乳腺纤维上皮性肿瘤进行分析，这些肿瘤包括纤维腺瘤的经典组织学亚型以及良性和恶性叶状肿瘤，检测MED12基因外显子2中的突变情况。在所有肿瘤样本中，60%检测到MED12突变，其中大多数为影响密码子44的错义突变。此外，我们还报告了此前未被描述的新型框内缺失突变。62%的纤维腺瘤存在MED12突变，其中管内型纤维腺瘤是最常发生突变的组织学亚型（82%）。值得注意的是，11例良性叶状肿瘤中有8例存在MED12突变，而恶性叶状肿瘤中只有1/5在MED12基因外显子2中显示有突变。总之，我们证实了纤维腺瘤中频繁发生MED12突变，提供了证据表明大多数与良性叶状肿瘤极为相似的管内型纤维腺瘤以及良性叶状肿瘤均存在MED12突变，并得出结论：恶性叶状肿瘤中的MED12突变似乎相对少见。
