Cacheux Wulfran, Tsantoulis Petros, Briaux Adrien, Vacher Sophie, Mariani Pascale, Richard-Molard Marion, Buecher Bruno, Richon Sophie, Jeannot Emmanuelle, Lazartigues Julien, Rouleau Etienne, Mariani Odette, El Alam Elsy, Cros Jérôme, Roman-Roman Sergio, Mitry Emmanuel, Girard Elodie, Dangles-Marie Virginie, Lièvre Astrid, Bièche Ivan
Département d'oncologie médicale, Institut Curie, Ensemble hospitalier, Hôpital René Huguenin, Saint-Cloud, France.
Unité de pharmacogénomique, Département de génétique, Institut Curie, Ensemble hospitalier, Paris Cedex 05, France.
Cancer Med. 2018 Jul;7(7):3213-3225. doi: 10.1002/cam4.1533. Epub 2018 May 26.
Genomic alterations of anal squamous cell carcinoma (ASCC) remain poorly understood due to the rarity of this tumor. Array comparative genomic hybridization and targeted gene sequencing were performed in 49 cases of ASCC. The most frequently altered regions (with a frequency greater than 25%) were 10 deleted regions (2q35, 2q36.3, 3p21.2, 4p16.3, 4p31.21, 7q36.1, 8p23.3, 10q23.2, 11q22.3, and 13q14.11) and 8 gained regions (1p36.33, 1q21.1, 3q26.32, 5p15.33, 8q24.3, 9q34.3, 16p13.3, and 19p13.3). The most frequent minimal regions of deletion (55%) encompassed the 11q22.3 region containing ATM, while the most frequent minimal regions of gain (57%) encompassed the 3q26.32 region containing PIK3CA. Recurrent homozygous deletions were observed for 5 loci (ie, TGFR2 in 4 cases), and recurrent focal amplifications were observed for 8 loci (ie, DDR2 and CCND1 in 3 cases, respectively). Several of the focal amplified genes are targets for specific therapies. Integrated analysis showed that the PI3K/Akt/mTOR signaling pathway was the pathway most extensively affected, particularly in recurrences compared to treatment-naive tumors (64% vs 30%; P = .017). In patients with ASCC recurrences, poor overall survival (OS) was significantly correlated with a large number of altered regions (P = .024). These findings provide insight into the somatic genomic alterations in ASCC and highlight the key role of the druggable PI3K/Akt/mTOR signaling pathway.
由于肛管鳞状细胞癌（ASCC）较为罕见，其基因组改变仍知之甚少。对49例ASCC进行了阵列比较基因组杂交和靶向基因测序。最常发生改变的区域（频率大于25%）为10个缺失区域（2q35、2q36.3、3p21.2、4p16.3、4p31.21、7q36.1、8p23.3、10q23.2、11q22.3和13q14.11）和8个扩增区域（1p36.33、1q21.1、3q26.32、5p15.33、8q24.3、9q34.3、16p13.3和19p13.3）。最常见的最小缺失区域（55%）包含含有ATM的11q22.3区域，而最常见的最小扩增区域（57%）包含含有PIK3CA的3q26.32区域。观察到5个位点存在复发性纯合缺失（即4例中的TGFR2），8个位点存在复发性局灶性扩增（即分别在3例中的DDR2和CCND1）。一些局灶性扩增基因是特定疗法的靶点。综合分析表明，PI3K/Akt/mTOR信号通路是受影响最广泛的通路，与未经治疗的肿瘤相比，在复发肿瘤中尤其如此（64%对30%；P = 0.017）。在ASCC复发患者中，较差的总生存期（OS）与大量改变区域显著相关（P = 0.024）。这些发现为ASCC的体细胞基因组改变提供了见解，并突出了可靶向治疗的PI3K/Akt/mTOR信号通路的关键作用。
