Targeted capture massively parallel sequencing analysis of LCIS and invasive lobular cancer: Repertoire of somatic genetic alterations and clonal relationships.
Targeted capture massively parallel sequencing analysis of LCIS and invasive lobular cancer: Repertoire of somatic genetic alterations and clonal relationships.
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DOI：
10.1016/j.molonc.2015.11.001
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发表时间：
2016-02
影响因子：
6.6
通讯作者：
King TA
中科院分区：
文献类型：
--
作者：
Sakr RA;Schizas M;Carniello JV;Ng CK;Piscuoglio S;Giri D;Andrade VP;De Brot M;Lim RS;Towers R;Weigelt B;Reis-Filho JS;King TA
小叶原位癌（LCIS）被认为是浸润性小叶癌（ILC）的非必然前体。在这里，我们试图使用靶向大规模并行测序来定义纯 LCIS 以及同步 LCIS 和 ILC 中的体细胞遗传改变。从 30 名患者的显微解剖 LCIS、ILC 和匹配的正常乳腺组织或外周血中提取的 DNA 样本，对 273 个基因的所有外显子进行大规模并行测序，其中包括乳腺癌中最常突变的基因和 DNA 修复相关基因。使用最先进的生物信息学方法鉴定单核苷酸变异以及插入和缺失。 LCIS (n=34) 和 ILC (n=21) 中发现的体细胞突变群相似，最常见的突变基因是 CDH1（分别为 56% 和 66%）、PIK3CA（分别为 41% 和 52%）和 CBFB（分别为 12% 和 19%）。在 19 个 LCIS 和 ILC 同步对中，14 个 (74%) 具有至少一个相同的共同突变，包括相同的 PIK3CA 和 CDH1 突变。对 3 个乳房 LCIS 独立病灶的配对分析显示，3 对乳房中的每一对（CDH1、PIK3CA、CBFB 和 PKHD1L1）中至少有一个共同突变。 LCIS 和 ILC 具有相似的体细胞突变库，其中 PIK3CA 和 CDH1 是最常见的突变基因。 LCIS-LCIS 和 LCIS-ILC 对之间存在相同突变表明 LCIS 是克隆性肿瘤病变，并提供了额外的证据表明至少某些 LCIS 是 ILC 的非专性前体。
Lobular carcinoma in situ (LCIS) has been proposed as a non-obligate precursor of invasive lobular carcinoma (ILC). Here we sought to define the repertoire of somatic genetic alterations in pure LCIS and in synchronous LCIS and ILC using targeted massively parallel sequencing. DNA samples extracted from microdissected LCIS, ILC and matched normal breast tissue or peripheral blood from 30 patients were subjected to massively parallel sequencing targeting all exons of 273 genes, including the genes most frequently mutated in breast cancer and DNA repair-related genes. Single nucleotide variants and insertions and deletions were identified using state-of-the-art bioinformatics approaches. The constellation of somatic mutations found in LCIS (n=34) and ILC (n=21) were similar, with the most frequently mutated genes being CDH1 (56% and 66%, respectively), PIK3CA (41% and 52%, respectively) and CBFB (12% and 19%, respectively). Among 19 LCIS and ILC synchronous pairs, 14 (74%) had at least one identical mutation in common, including identical PIK3CA and CDH1 mutations. Paired analysis of independent foci of LCIS from 3 breasts revealed at least one common mutation in each of the 3 pairs (CDH1, PIK3CA, CBFB and PKHD1L1). LCIS and ILC have a similar repertoire of somatic mutations, with PIK3CA and CDH1 being the most frequently mutated genes. The presence of identical mutations between LCIS-LCIS and LCIS-ILC pairs demonstrates that LCIS is a clonal neoplastic lesion, and provides additional evidence that at least some LCIS are non-obligate precursors of ILC.