Laboratoire d'Oncologie Prédictive, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm, U1068, CNRS UMR7258, Institut Paoli-Calmettes, Aix-Marseille Université, France.
Département d'Oncologie Médicale, Institut Paoli-Calmettes, Marseille, France.
Mol Oncol. 2020 Mar;14(3):504-519. doi: 10.1002/1878-0261.12621. Epub 2020 Feb 5.
Inflammatory breast cancer (IBC) is the most pro-metastatic form of breast cancer. Better understanding of its pathophysiology and identification of actionable genetic alterations (AGAs) are crucial to improve systemic treatment. We aimed to define the DNA profiles of IBC vs noninflammatory breast cancer (non-IBC) clinical samples in terms of copy number alterations (CNAs), mutations, and AGAs. We applied targeted next-generation sequencing (tNGS) and array-comparative genomic hybridization (aCGH) to 57 IBC and 50 non-IBC samples and pooled these data with four public datasets profiled using NGS and aCGH, leading to a total of 101 IBC and 2351 non-IBC untreated primary tumors. The respective percentages of each molecular subtype [hormone receptor-positive (HR+)/HER2-, HER2+, and triple-negative] were 68%, 15%, and 17% in non-IBC vs 25%, 35%, and 40% in IBC. The comparisons were adjusted for both the molecular subtypes and the American Joint Committee on Cancer (AJCC) stage. The 10 most frequently altered genes in IBCs were TP53 (63%), HER2/ERBB2 (30%), MYC (27%), PIK3CA (21%), BRCA2 (14%), CCND1 (13%), GATA3 (13%), NOTCH1 (12%), FGFR1 (11%), and ARID1A (10%). The tumor mutational burden was higher in IBC than in non-IBC. We identified 96 genes with an alteration frequency (p < 5% and q < 20%) different between IBC and non-IBC, independently from the molecular subtypes and AJCC stage; 95 were more frequently altered in IBC, including TP53, genes involved in the DNA repair (BRCA2) and NOTCH pathways, and one (PIK3CA) was more frequently altered in non-IBC. Ninety-seven percent of IBCs displayed at least one AGA. This percentage was higher than in non-IBC (87%), notably for drugs targeting DNA repair, NOTCH signaling, and CDK4/6, whose pathways were more frequently altered (DNA repair) or activated (NOTCH and CDK4/6) in IBC than in non-IBC. The genomic landscape of IBC is different from that of non-IBC. Enriched AGAs in IBC may explain its aggressiveness and provide clinically relevant targets.
炎性乳腺癌 (IBC) 是最具转移性的乳腺癌形式。更好地了解其病理生理学并确定可操作的遗传改变 (AGAs) 对于改善全身治疗至关重要。我们旨在根据拷贝数改变 (CNAs)、突变和 AGAs 定义 IBC 与非炎性乳腺癌 (non-IBC) 临床样本的 DNA 图谱。我们应用靶向下一代测序 (tNGS) 和比较基因组杂交 (aCGH) 对 57 例 IBC 和 50 例 non-IBC 样本进行了分析，并将这些数据与使用 NGS 和 aCGH 进行分析的四个公共数据集进行了合并，总共得到了 101 例 IBC 和 2351 例未经治疗的原发性肿瘤。non-IBC 中各分子亚型[激素受体阳性 (HR+)/HER2-、HER2+和三阴性]的比例分别为 68%、15%和 17%，而 IBC 中分别为 25%、35%和 40%。比较结果同时考虑了分子亚型和美国癌症联合委员会 (AJCC) 分期。IBC 中最常改变的 10 个基因是 TP53 (63%)、HER2/ERBB2 (30%)、MYC (27%)、PIK3CA (21%)、BRCA2 (14%)、CCND1 (13%)、GATA3 (13%)、NOTCH1 (12%)、FGFR1 (11%)和 ARID1A (10%)。IBC 中的肿瘤突变负担高于 non-IBC。我们确定了 96 个基因，这些基因在 IBC 和 non-IBC 之间的改变频率 (p<5%且 q<20%)不同，独立于分子亚型和 AJCC 分期；其中 95 个基因在 IBC 中更常发生改变，包括 TP53、参与 DNA 修复 (BRCA2) 和 NOTCH 途径的基因，而 PIK3CA 则更常发生改变。97%的 IBC 至少有一个 AGA。这一比例高于 non-IBC (87%)，特别是针对针对 DNA 修复、NOTCH 信号和 CDK4/6 的药物，这些途径在 IBC 中比在 non-IBC 中更常发生改变 (DNA 修复)或激活 (NOTCH 和 CDK4/6)。IBC 的基因组景观与 non-IBC 不同。IBC 中丰富的 AGAs 可能解释了其侵袭性，并提供了具有临床意义的靶点。
