混合纤维板层肝细胞癌(mFL-HCC)是一种罕见的肝肿瘤,由纯FL-HCC和常规HCC成分的存在定义。代表高达25%的FL-HCC病例,并与预后较差有关。纯FL-HCC的最新基因组表征鉴定了在常规HCC中未发现的高度复发的转录本融合(DNAJB1:PRKACA)。
我们对一例mFL-HCC进行了外显子组和转录组测序。开发了一种新的BAC捕获方法,以鉴定400kb缺失作为这种情况下DNAJB1:PRKACA融合的潜在基因组机制。在第二例mFL-HCC中,使用灵敏的NanostringElements测定法筛选该转录本融合体,112个额外的HCC样品和44个邻近的非肿瘤肝样品。
我们报告了一例mFL-HCC的首次综合基因组分析。没有发现常见的HCC相关突变。这个病例的突变率很低,大量主要是单一副本,远程拷贝数变体,ERBB2的高表达与以前报道的纯FL-HCC比常规HCC更一致。特别是,检测到与纯FL-HCC特异性相关的DNAJB1:PRKACA融合转录本的表达水平非常高.随后的分析显示,在所有原发性和转移性样本中都存在这种融合,包括混合或常规HCC病理。第二例mFL-HCC证实了我们的发现,即在常规组件中可以检测到融合。扩大的屏幕确定了第三例融合阳性HCC,经审查,同时具有常规和纤维层状特征。该筛选证实在所有常规HCC和邻近的非肿瘤肝样品中不存在融合。
这些结果表明,mFL-HCC在基因组水平上与纯FL-HCC相似,DNAJB1:PRKACA融合可用作纯和mFL-HCC的诊断工具。
Mixed fibrolamellar hepatocellular carcinoma (mFL-HCC) is a rare liver tumor defined by the presence of both pure FL-HCC and conventional HCC components, represents up to 25% of cases of FL-HCC, and has been associated with worse prognosis. Recent genomic characterization of pure FL-HCC identified a highly recurrent transcript fusion (DNAJB1:PRKACA) not found in conventional HCC.
We performed exome and transcriptome sequencing of a
case of mFL-HCC. A novel BAC-capture approach was developed to identify a 400 kb deletion as the underlying genomic mechanism for a DNAJB1:PRKACA fusion in this
case. A sensitive Nanostring Elements assay was used to screen for this transcript fusion in a second
case of mFL-HCC, 112 additional HCC samples and 44 adjacent non-tumor liver samples.
We report the first comprehensive genomic analysis of a
case of mFL-HCC. No common HCC-associated mutations were identified. The very low mutation rate of this case, large number of mostly single-copy, long-range copy number variants, and high expression of ERBB2 were more consistent with previous
reports of pure FL-HCC than conventional HCC. In particular, the DNAJB1:PRKACA fusion transcript specifically associated with pure FL-HCC was detected at very high expression levels. Subsequent analysis revealed the presence of this fusion in all primary and metastatic samples, including those with mixed or conventional HCC pathology. A second case of mFL-HCC confirmed our finding that the fusion was detectable in conventional components. An expanded screen identified a third case of fusion-positive HCC, which upon review, also had both conventional and fibrolamellar features. This screen confirmed the absence of the fusion in all conventional HCC and adjacent non-tumor liver samples.
These results indicate that mFL-HCC is similar to pure FL-HCC at the genomic level and the DNAJB1:PRKACA fusion can be used as a diagnostic tool for both pure and mFL-HCC.