Somatic Mutations of the Mixed-Lineage Leukemia 3 (MLL3) Gene in Primary Breast Cancers
Somatic Mutations of the Mixed-Lineage Leukemia 3 (MLL3) Gene in Primary Breast Cancers
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原发性乳腺癌中混合谱系白血病 3 (MLL3) 基因的体细胞突变
DOI：
10.1007/s12253-010-9316-0
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发表时间：
2011-06-01
影响因子：
2.8
通讯作者：
Dong, Jin-Tang
中科院分区：
文献类型：
--
作者：
Wang, Xin-Xin;Fu, Liya;Dong, Jin-Tang
混合谱系白血病 3 (MLL3) 基因编码组蛋白 H3 赖氨酸 4 甲基转移酶复合物的重要组成部分，称为含有 ASC-2 和 Mll3 的复合物 (ASCOM)，由于其在多种类型的人类肿瘤中频繁突变以及在小鼠中靶向失活该基因后诱导肿瘤，因此被认为是一种肿瘤抑制基因。然而，MLL3 在乳腺癌中的作用仍不清楚。在本研究中，我们对38例中国女性乳腺癌中MLL3的全部59个外显子（14.7 Kb编码序列）进行了测序，并在其中2例中发现了3种体细胞突变，其中包括一种截断大部分MLL3蛋白的移码突变（c.2687 ins A）和两种同义突变。除了 24 个已知的单核苷酸多态性 (SNP) 外，还在 38 名女性中检测到了 5 个新的 SNP；有趣的是，所有 5 个新的 SNP 都会改变 MLL3 的氨基酸序列，因此可能产生功能性后果。我们还检测了30个乳腺肿瘤及其匹配的正常乳腺组织中MLL3mRNA的表达。虽然没有发现表达变化与临床病理参数之间存在关联，但 40% 的样本显示癌症组织中的表达降低。这些结果表明MLL3的突变在乳腺癌的发展中发挥作用。
The mixed-lineage leukemia 3 (MLL3) gene, which encodes an important component of a histone H3 lysine 4 methyltransferase complex named the ASC-2- and Mll3-containing complex (ASCOM), has been implicated as a tumor suppressor gene due to its frequent mutations in multiple types of human tumors as well as tumor induction upon targeted inactivation of the gene in mice. The role of MLL3 in breast cancer, however, remains unknown. In this study, we sequenced all 59 exons ofMLL3(14.7 Kb coding sequence) in 38 breast cancers from Chinese women, and found three somatic mutations in two of the cases, including one frameshift mutation (c.2687 ins A) that truncates the majority of the MLL3 protein, and two synonymous mutations. In addition to 24 known single nucleotide polymorphisms (SNPs), 5 novel SNPs were also detected in the 38 women; and interestingly, all the 5 novel SNPs alter amino acid sequences of MLL3 thus could have functional consequences. We also examined the expression ofMLL3mRNA in 30 breast tumors and their matched normal breast tissues. While no associations were found between expression change and clinicopathologic parameters, 40% of the samples showed reduced expression in cancer tissues. These results suggest that mutation ofMLL3plays a role in the development of breast cancer.