小柯机器人

日本国家癌症中心研究所Keisuke Kataoka研究团队取得一项新成果。他们揭示了个体致癌基因多样突变的图谱和功能。该研究于2020年4月8日在线发表在《自然》杂志上。

研究人员对60954个癌症样品进行了全癌分析并确定了14个全癌和6个癌症类型特异性癌基因，这些基因发生多样驱动基因突变（MM）的频率比预期的高：在9％的样本中，具有MM的基因中存在至少一个突变。在各种致癌基因中，MMs优先存在于顺式元件中；与突变类型（错义突变相对于读框内插入缺失）、位置和氨基酸取代这些单个突变相比，MM突变模式明显不同，这表明顺式作用对突变选择有影响。

MMs表现出功能弱、突变频率低的特点，这些突变共同增强了致癌性。与具有单个突变的细胞相比，PIK3CA和NOTCH1基因中发生MM的细胞对突变基因本身表现出更强的依赖性，增强下游信号激活和/或对抑制药物的敏感性更高。总之，致癌性MM是相对常见的驱动事件，为克隆亚突变选择提供了潜在的机制，这些亚突变单个比较罕见，但总体上占致癌突变的大部分。

研究人员表示，在同一致癌基因中发生MM的癌症病例鲜有报道。但是，MM的总体情况和相关性仍亟待阐明。

附：英文原文

Title: Landscape and function of multiple mutations within individual oncogenes

Author: Yuki Saito, Junji Koya, Mitsugu Araki, Yasunori Kogure, Sumito Shingaki, Mariko Tabata, Marni B. McClure, Kota Yoshifuji, Shigeyuki Matsumoto, Yuta Isaka, Hiroko Tanaka, Takanori Kanai, Satoru Miyano, Yuichi Shiraishi, Yasushi Okuno, Keisuke Kataoka

Issue&Volume: 2020-04-08

Abstract: Sporadic reports have described cancer cases in which multiple driver mutations (MMs) occur in the same oncogene1,2. However, the overall landscape and relevance of MMs remain elusive. Here we carried out a pan-cancer analysis of 60,954 cancer samples, and identified 14 pan-cancer and 6 cancer-type-specific oncogenes in which MMs occur more frequently than expected: 9% of samples with at least one mutation in these genes harboured MMs. In various oncogenes, MMs are preferentially present in cis and show markedly different mutational patterns compared with single mutations in terms of type (missense mutations versus in-frame indels), position and amino-acid substitution, suggesting a cis-acting effect on mutational selection. MMs show an overrepresentation of functionally weak, infrequent mutations, which confer enhanced oncogenicity in combination. Cells with MMs in the PIK3CA and NOTCH1 genes exhibit stronger dependencies on the mutated genes themselves, enhanced downstream signalling activation and/or greater sensitivity to inhibitory drugs than those with single mutations. Together oncogenic MMs are a relatively common driver event, providing the underlying mechanism for clonal selection of suboptimal mutations that are individually rare but collectively account for a substantial proportion of oncogenic mutations.

DOI: 10.1038/s41586-020-2175-2

Source: https://www.nature.com/articles/s41586-020-2175-2

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html