Nature：PPM1D基因变异或提示患癌

　　近日，英国癌症研究院(ICR)的一个研究团队发现，PPM1D基因出现变异可增加乳腺癌和卵巢癌的风险。研究人员表示，这或能成为未来相关疗法的靶向作用目标，为预防提供了潜在指导方向。

　　出现PPM1D基因变异的女性患乳腺癌和卵巢癌的风险会上升20个百分点，而与普通人相比，其患乳腺癌和卵巢癌的风险分别是他们的2倍和10多倍。

　　这项于本周发表在《自然》杂志上的研究显示，似乎与BRCA1和BRCA2等其他可增加乳腺癌和卵巢癌风险的基因不同，PPM1D基因会以一种完全不同方式发挥其相关作用。

　　首席研究员、ICR基因科主任Nazneen Rahman教授表示：“此项研究结果引起了人们的很大兴趣，令人振奋。研究各个阶段所得出的结果都与之前普遍认可的理论不尽相同。虽然目前我们对PPM1D基因变异会增加乳腺癌和卵巢癌风险的具体机制尚不清楚，但这一发现却能激发我们的发散思维，有助于我们探索那些潜在的相关基因和癌症。研究结果临床试验也非常有帮助，特别是对于卵巢癌这种常常到晚期才能被发现的癌症。如果女性知道了自己携带有PPM1D基因变异并且有20%的几率会出现卵巢癌，那么她们就会考虑在生育之后通过手术将自己的卵巢切除。”

　　研究人员对1150名患有乳腺癌和卵巢癌的女性体内的507中参与DNA修复过程的基因进行了分析，结果在5名患者体内发现了PPM1D基因变异。研究人员接着又把7781名乳腺癌和卵巢癌患者与5861名健康人群的PPM1D基因分别进行了排序，结果发现前者的PPM1D基因有25处变异，而后者的PPM1D基因只出现了1处异常，二者在数量上存在明显差异。

　　ICR首席行政官、研究员Alan Ashworth教授称：“这项发现真正颠覆了传统的关于基因变异可导致癌症的理论。解开这一迷惑之后，我们很可能将会弄明白癌症发展的机制，以及研发出可帮助人们评估风险的工具和相关的预防措施。”

Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer

Improved sequencing technologies offer unprecedented opportunities for investigating the role of rare genetic variation in common disease. However, there are considerable challenges with respect to study design, data analysis and replication¹. Using pooled next-generation sequencing of 507 genes implicated in the repair of DNA in 1,150 samples, an analytical strategy focused on protein-truncating variants (PTVs) and a large-scale sequencing case–control replication experiment in 13,642 individuals, here we show that rare PTVs in the p53-inducible protein phosphatase PPM1Dare associated with predisposition to breast cancer and ovarian cancer. PPM1D PTV mutations were present in 25 out of 7,781 cases versus 1 out of 5,861 controls (P = 1.12 × 10⁻⁵), including 18 mutations in 6,912 individuals with breast cancer (P = 2.42 × 10⁻⁴) and 12 mutations in 1,121 individuals with ovarian cancer (P = 3.10 × 10⁻⁹). Notably, all of the identified PPM1D PTVs were mosaic in lymphocyte DNA and clustered within a 370-base-pair region in the final exon of the gene, carboxy-terminal to the phosphatase catalytic domain. Functional studies demonstrate that the mutations result in enhanced suppression of p53 in response to ionizing radiation exposure, suggesting that the mutant alleles encode hyperactive PPM1D isoforms. Thus, although the mutations cause premature protein truncation, they do not result in the simple loss-of-function effect typically associated with this class of variant, but instead probably have a gain-of-function effect. Our results have implications for the detection and management of breast and ovarian cancer risk. More generally, these data provide new insights into the role of rare and of mosaic genetic variants in common conditions, and the use of sequencing in their identification.