Cacheux Wulfran, Dangles-Marie Virginie, Rouleau Etienne, Lazartigues Julien, Girard Elodie, Briaux Adrien, Mariani Pascale, Richon Sophie, Vacher Sophie, Buecher Bruno, Richard-Molard Marion, Jeannot Emmanuelle, Servant Nicolas, Farkhondeh Fereshteh, Mariani Odette, Rio-Frio Thomas, Roman-Roman Sergio, Mitry Emmanuel, Bieche Ivan, Lièvre Astrid
Département d'oncologie médicale, Ensemble Hospitalier de l'Institut Curie, Hôpital René Huguenin, Saint-Cloud, 92210 Saint-Cloud, France.
Département de Génétique, Unité de pharmacogénomique, Ensemble Hospitalier de l'Institut Curie, 75248 Paris Cedex 05, France.
Oncotarget. 2017 Dec 8;9(1):464-476. doi: 10.18632/oncotarget.23066. eCollection 2018 Jan 2.
Anal squamous cell carcinomas (ASCC) are rare tumours in humans. The etiological role of HPV infection is now well established but little is known about the molecular landscape and signalling pathways involved in the pathogenesis of this cancer. Here we report the results from a whole exome sequencing of a homogeneous group of 20 treatment-naive ASCC. A total of 2422 somatic single nucleotide variations (SNV) were found, with an overall moderate rate of somatic mutations per tumour (median: 105 relevant SNV per tumour) but a high mutational load in 3 tumours. The mutational signatures associated with age and APOBEC were observed in 100% and 60% of tumours respectively. The most frequently mutated genes were (25%) followed by (15%), (15%) and (15%), the two last ones having never been described in ASCC. The main copy number alterations were gains of chromosome 3q (affecting ) and losses of chromosome 11q (affecting . The combined analysis of somatic mutations and copy number alterations show that recurrent alterations of the PI3K/AKT/mTOR pathway are frequent (60%) in these tumours, as well as potentially targetable alterations of other signalling pathways that have never been described in ASCC such as chromatin remodelling (45%) and ubiquitin mediated proteolysis (35%). These results highlight the possible implication of these aberrant signalling pathways in anal carcinogenesis and suggest promising new therapeutic approaches in ASCC. The high somatic mutation burden found in some tumours, suggesting an elevated neoantigen load could also predict sensitivity of ASCC to immunotherapy.
肛管鳞状细胞癌（ASCC）在人类中是罕见肿瘤。HPV感染的病因学作用现已明确，但对于该癌症发病机制中涉及的分子格局和信号通路知之甚少。在此，我们报告了对20例未经治疗的ASCC同质组进行全外显子测序的结果。共发现2422个体细胞单核苷酸变异（SNV），每个肿瘤的体细胞突变率总体适中（中位数：每个肿瘤105个相关SNV），但有3个肿瘤的突变负荷较高。分别在100%和60%的肿瘤中观察到与年龄和载脂蛋白B mRNA编辑酶催化多肽样蛋白（APOBEC）相关的突变特征。最常发生突变的基因是[具体基因1]（25%），其次是[具体基因2]（15%）、[具体基因3]（15%）和[具体基因4]（15%），后两个基因在ASCC中从未被描述过。主要的拷贝数改变是3号染色体长臂（3q）增益（影响[具体基因或区域]）和11号染色体长臂（11q）缺失（影响[具体基因或区域]）。体细胞突变和拷贝数改变的联合分析表明，PI3K/AKT/mTOR通路的复发性改变在这些肿瘤中很常见（60%），以及其他在ASCC中从未被描述过的信号通路的潜在可靶向改变，如染色质重塑（45%）和泛素介导的蛋白水解（35%）。这些结果突出了这些异常信号通路在肛管癌发生中的可能作用，并提示ASCC有前景的新治疗方法。在一些肿瘤中发现的高体细胞突变负担，提示新抗原负荷升高，这也可能预测ASCC对免疫治疗的敏感性。
