滤泡性淋巴瘤（FL）的特点是BCL2易位，常年可在血液中检测到，在FL诊断之前多年就已观察到。但也可以在健康老年人中观察到，这表明淋巴瘤发生还需要其他损伤。我们通过48个最终发展为FL的受试者的术前血液和组织标本的超深度测序直接表征了早期的共同突变。值得注意的是，CREBBP赖氨酸乙酰转移酶（KAT）结构域突变是观察到最常见的前体损伤，大多数患者发展为FL（14/48，29％）与有或没有检测到BCL2重排的健康成年人（0/13，p= 0.03和0/20，p= 0.007，分别）有区别。CREBBP变异可在FL诊断前中位数5.8年检测到，是FL肿瘤中克隆选择的，并且似乎仅限于承诺的B细胞谱系。这些结果表明，影响CREBBP KAT结构域的突变是FL癌前细胞（CPC）中常见的损伤，具有识别可能发展为FL的受试者或监测残留疾病的潜力。

Follicular lymphomas (FL) are characterized by BCL2 translocations, often detectable in blood years before FL diagnosis, but also observed in aging healthy individuals suggesting additional lesions are required for lymphomagenesis. We directly characterized early cooperating mutations by ultra-deep sequencing of pre-diagnostic blood and tissue specimens from 48 subjects who ultimately developed FL. Strikingly, CREBBP lysine acetyltransferase (KAT) domain mutations were the most commonly observed precursor lesions, and largely distinguished patients developing FL (14/48, 29%) from healthy adults with or without detected BCL2 rearrangements (0/13, p=0.03 and 0/20, p=0.007, respectively). CREBBP variants were detectable a median of 5.8 years before FL diagnosis, were clonally selected in FL tumors, and appeared restricted to the committed B-cell lineage. These results suggest that mutations affecting the CREBBP KAT domain are common lesions in FL cancer precursor cells (CPC), with potential for discriminating subjects at risk of developing FL or monitoring residual disease.