Uncovering the genomic heterogeneity of multifocal breast cancer.
Uncovering the genomic heterogeneity of multifocal breast cancer.
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DOI：
10.1002/path.4540
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发表时间：
2015-08
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影响因子：
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通讯作者：
Sotiriou C
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作者：
Desmedt C;Fumagalli D;Pietri E;Zoppoli G;Brown D;Nik-Zainal S;Gundem G;Rothé F;Majjaj S;Garuti A;Carminati E;Loi S;Van Brussel T;Boeckx B;Maetens M;Mudie L;Vincent D;Kheddoumi N;Serra L;Massa I;Ballestrero A;Amadori D;Salgado R;de Wind A;Lambrechts D;Piccart M;Larsimont D;Campbell PJ;Sotiriou C
多灶性乳腺癌(MFBC)是浸润性乳腺癌的多个同步单侧病变，相对常见，与单灶性乳腺癌相比具有更多的侵袭性特征。在这里，我们的目的是调查具有相似组织病理学参数的MFBC病变之间的基因组异质性。对36例导管MFBC患者的不同病变的特征包括在360个蛋白质编码基因(171个肿瘤和36个匹配的正常样本)中识别非沉默编码突变。我们只选择了病变级别、ER和HER2状态相同的患者。在宇宙突变或影响肿瘤抑制基因的截断突变中报告的反复替换的情况下，突变被归类为“致癌”。通过使用正交平台进行深度重测序，在给定患者的所有样本中进一步询问在该患者中发现的所有突变。36例患者中有8例进行了全基因组重排筛查。24名患者(67%)的所有皮损都有替换/INDELs，其中11名患者在所有皮损中携带相同的突变，13名患者的皮损既有普通突变，也有专用突变。在这24名患者中，四分之三的人共享致癌变异。其余12例患者(33%)没有任何替换/INDELs，观察到PIK3CA、TP53、GATA3和PTEN等基因的致癌突变(S)在病变间存在异质性。基因组上的异质性病变往往比同质病变在乳腺中的距离更远。对有限数量的患者进行的全基因组分析在所有研究的MFBC中发现了共同的体细胞背景，包括那些在病变之间没有共同突变的MFBC。综上所述，随着分子靶向治疗的数量增加和由基因组筛选驱动的试验正在进行，我们的发现强调了三分之一的基因组病变间异质性的存在，尽管有相似的病理特征。这意味着有必要对所有MFBC病变进行更深入的分子表征，以便对这些癌症进行适当的治疗。©2015作者。大不列颠和爱尔兰病态学会。
Multifocal breast cancer (MFBC), defined as multiple synchronous unilateral lesions of invasive breast cancer, is relatively frequent and has been associated with more aggressive features than unifocal cancer. Here, we aimed to investigate the genomic heterogeneity between MFBC lesions sharing similar histopathological parameters. Characterization of different lesions from 36 patients with ductal MFBC involved the identification of non‐silent coding mutations in 360 protein‐coding genes (171 tumour and 36 matched normal samples). We selected only patients with lesions presenting the same grade, ER, and HER2 status. Mutations were classified as ‘oncogenic’ in the case of recurrent substitutions reported in COSMIC or truncating mutations affecting tumour suppressor genes. All mutations identified in a given patient were further interrogated in all samples from that patient through deep resequencing using an orthogonal platform. Whole‐genome rearrangement screen was further conducted in 8/36 patients. Twenty‐four patients (67%) had substitutions/indels shared by all their lesions, of which 11 carried the same mutations in all lesions, and 13 had lesions with both common and private mutations. Three‐quarters of those 24 patients shared oncogenic variants. The remaining 12 patients (33%) did not share any substitution/indels, with inter‐lesion heterogeneity observed for oncogenic mutation(s) in genes such as PIK3CA, TP53, GATA3, and PTEN. Genomically heterogeneous lesions tended to be further apart in the mammary gland than homogeneous lesions. Genome‐wide analyses of a limited number of patients identified a common somatic background in all studied MFBCs, including those with no mutation in common between the lesions. To conclude, as the number of molecular targeted therapies increases and trials driven by genomic screening are ongoing, our findings highlight the presence of genomic inter‐lesion heterogeneity in one‐third, despite similar pathological features. This implies that deeper molecular characterization of all MFBC lesions is warranted for the adequate management of those cancers. © 2015 The Authors. Pathological Society of Great Britain and Ireland.