浸润性小叶乳腺癌的综合分子图谱
Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer.
作者信息
Ciriello Giovanni, Gatza Michael L, Beck Andrew H, Wilkerson Matthew D, Rhie Suhn K, Pastore Alessandro, Zhang Hailei, McLellan Michael, Yau Christina, Kandoth Cyriac, Bowlby Reanne, Shen Hui, Hayat Sikander, Fieldhouse Robert, Lester Susan C, Tse Gary M K, Factor Rachel E, Collins Laura C, Allison Kimberly H, Chen Yunn-Yi, Jensen Kristin, Johnson Nicole B, Oesterreich Steffi, Mills Gordon B, Cherniack Andrew D, Robertson Gordon, Benz Christopher, Sander Chris, Laird Peter W, Hoadley Katherine A, King Tari A, Perou Charles M
机构信息
Department of Medical Genetics, University of Lausanne (UNIL), 1011 Lausanne, Switzerland; Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
出版信息
Cell. 2015 Oct 8;163(2):506-19. doi: 10.1016/j.cell.2015.09.033.
Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.
浸润性小叶癌（ILC）是浸润性乳腺癌中第二常见的组织学亚型。在此，我们全面分析了817例乳腺肿瘤，包括127例ILC、490例导管癌（IDC）和88例混合性IDC/ILC。除了最著名的ILC基因特征——E-钙黏蛋白缺失外，我们还确定靶向PTEN、TBX3和FOXA1的突变是ILC富集特征。PTEN缺失与AKT磷酸化增加相关，在所有乳腺癌亚型中，ILC中的AKT磷酸化最高。空间聚集的FOXA1突变与FOXA1表达和活性增加相关。相反，GATA3突变和高表达是管腔A型IDC的特征，表明ILC和IDC中雌激素受体（ER）活性的调节存在差异。增殖和免疫相关特征确定了与生存差异相关的三种ILC转录亚型。混合性IDC/ILC病例在分子水平上被分类为ILC样和IDC样，未发现真正的混合特征。这一多维分子图谱为ILC的遗传基础提供了新的见解，并提供了潜在的临床选择。
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