Brash Douglas E
Departments of Therapeutic Radiology and Dermatology, Yale School of Medicine, New Haven, CT.
Photochem Photobiol. 2015 Jan-Feb;91(1):15-26. doi: 10.1111/php.12377. Epub 2014 Nov 28.
Sequencing complete tumor genomes and exomes has sparked the cancer field's interest in mutation signatures for identifying the tumor's carcinogen. This review and meta-analysis discusses signatures and their proper use. We first distinguish between a mutagen's canonical mutations—deviations from a random distribution of base changes to create a pattern typical of that mutagen—and the subset of signature mutations, which are unique to that mutagen and permit inference backward from mutations to mutagen. To verify UV signature mutations, we assembled literature datasets on cells exposed to UVC, UVB, UVA, or solar simulator light (SSL) and tested canonical UV mutation features as criteria for clustering datasets. A confirmed UV signature was: ≥60% of mutations are C→T at a dipyrimidine site, with ≥5% CC→TT. Other canonical features such as a bias for mutations on the nontranscribed strand or at the 3' pyrimidine had limited application. The most robust classifier combined these features with criteria for the rarity of non-UV canonical mutations. In addition, several signatures proposed for specific UV wavelengths were limited to specific genes or species; UV's nonsignature mutations may cause melanoma BRAF mutations; and the mutagen for sunlight-related skin neoplasms may vary between continents.
对完整肿瘤基因组和外显子组进行测序引发了癌症领域对用于识别肿瘤致癌物的突变特征的兴趣。本综述和荟萃分析讨论了这些特征及其正确应用。我们首先区分诱变剂的典型突变（即碱基变化随机分布的偏差，以形成该诱变剂特有的模式）和特征性突变子集，后者是该诱变剂所特有的，能够允许从突变反向推断诱变剂。为了验证紫外线特征性突变，我们收集了关于暴露于紫外线C、紫外线B、紫外线A或太阳模拟器光（SSL）的细胞的文献数据集，并测试了典型紫外线突变特征作为聚类数据集的标准。一个得到确认的紫外线特征是：在二嘧啶位点，≥60%的突变是C→T，且≥5%是CC→TT。其他典型特征，如非转录链或3'嘧啶处的突变偏好，应用有限。最可靠的分类器将这些特征与非紫外线典型突变的稀有性标准相结合。此外，针对特定紫外线波长提出的几个特征仅限于特定基因或物种；紫外线的非特征性突变可能导致黑色素瘤BRAF突变；与阳光相关的皮肤肿瘤的诱变剂可能因大陆而异。
