National Institute of Biomedical Genomics, Netaji Subhas Sanatorium (2nd Floor), Kalyani 741251, India.
Tata Memorial Centre, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai 410210, India.
Nat Commun. 2014 Dec 17;5:5835. doi: 10.1038/ncomms6835.
The arachidonic acid metabolism (AAM) pathway promotes tumour progression. Chemical inhibitors of AAM pathway prolong post-treatment survival of cancer patients. Here we test whether non-synonymous somatic mutations in genes of this pathway, acting as natural inhibitors, increase post-treatment survival. We identify loss-of-function somatic mutations in 15 (18%) of 84 treatment-naïve oral cancer patients by whole-exome sequencing, which we map to genes of AAM pathway. Patients (n = 53) who survived ≥ 12 months after surgery without recurrence have significantly (P = 0.007) higher proportion (26% versus 3%) of mutations than those who did not (n = 31). Patients with mutations have a significantly (P = 0.003) longer median disease-free survival (24 months) than those without (13 months). Compared with the presence of a mutation, absence of any mutation increases the hazard ratio for death (11.3) significantly (P = 0.018). The inferences are strengthened when we pool our data with The Cancer Genome Atlas (TCGA) data. In patients with AAM pathway mutations, some downstream pathways, such as the PI3K-Akt pathway, are downregulated.
花生四烯酸代谢（AAM）途径促进肿瘤进展。AAM 途径的化学抑制剂可延长癌症患者的治疗后生存时间。在这里，我们测试了该途径中作为天然抑制剂的基因中的非同义体细胞突变是否会增加治疗后的生存时间。我们通过全外显子组测序在 84 名未经治疗的口腔癌患者中鉴定出 15 个（18%）具有失活功能的体细胞突变，这些突变映射到 AAM 途径的基因上。手术后无复发且存活≥12 个月的患者（n=53）的突变比例（26%）明显高于未存活的患者（n=31）（3%）。有突变的患者的无病生存期（24 个月）明显长于无突变的患者（13 个月）（P=0.003）。与存在突变相比，不存在任何突变会显著增加死亡风险比（11.3）（P=0.018）。当我们将我们的数据与癌症基因组图谱（TCGA）的数据进行汇总时，这些推论得到了加强。在具有 AAM 途径突变的患者中，一些下游途径，如 PI3K-Akt 途径，被下调。
