Unique genomic profile of fibrolamellar hepatocellular carcinoma.
Unique genomic profile of fibrolamellar hepatocellular carcinoma.
复制标题
DOI：
10.1053/j.gastro.2014.12.028
复制
发表时间：
2015-04
期刊：
影响因子：
29.4
通讯作者：
Llovet JM
中科院分区：
文献类型：
--
作者：
Cornella H;Alsinet C;Sayols S;Zhang Z;Hao K;Cabellos L;Hoshida Y;Villanueva A;Thung S;Ward SC;Rodriguez-Carunchio L;Vila-Casadesús M;Imbeaud S;Lachenmayer A;Quaglia A;Nagorney DM;Minguez B;Carrilho F;Roberts LR;Waxman S;Mazzaferro V;Schwartz M;Esteller M;Heaton ND;Zucman-Rossi J;Llovet JM
Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer that develops in children and young adults without cirrhosis. Little is known about its pathogenesis, and it can only be treated with surgery. We performed an integrative genomic analysis of a large series of patients with FLC to identify associated genetic factors. Using 78 clinically annotated FLC samples, we performed whole-transcriptome (n=58), single-nucleotide polymorphism array (n=41), and next-generation sequencing (n=48) analyses; we also assessed the prevalence of the DNAJB1–PRKACA fusion transcript associated with this cancer (n=73). We performed class discovery using non-negative matrix factorization, and functional annotation using gene set enrichment analyses, nearest template prediction, ingenuity pathway analyses, and immunohistochemistry. The genomic identification of significant targets in cancer algorithm was used to identify chromosomal aberrations, MuTect and VarScan2 were used to identify somatic mutations, and the random survival forest was used to determine patient prognoses. Findings were validated in an independent cohort. Unsupervised gene expression clustering revealed 3 robust molecular classes of tumors: the proliferation class (51% of samples) had altered expression of genes that regulate proliferation and mTOR signaling activation; the inflammation class (26% of samples) had altered expression of genes that regulate inflammation and cytokine production; and the unannotated class (23% of samples) had a gene expression signature not previously associated with liver tumors. Expression of genes that regulate neuroendocrine function, as well has histologic markers of cholangiocytes and hepatocytes, were detected in all 3 classes. FLCs had few copy number variations; the most frequent were focal amplification at 8q24.3 (in 12.5% of samples) and deletions at 19p13 (in 28% of samples) and 22q13.32 (in 25% of samples). The DNAJB1–PRKACA fusion transcript was detected in 79% of samples. FLC samples also contained mutations in cancer-related genes such as BRCA2 (in 4.2% of samples), which are uncommon in liver neoplasms. However, FLCs did not contain mutations most commonly detected in liver cancers. We identified an 8-gene signature that predicted survival of patients with FLC. In a genomic analysis of 78 FLC samples, we identified 3 classes based on gene expression profiles. FLCs contain mutations and chromosomal aberrations not previously associated with liver cancer, and almost 80% contain the DNAJB1–PRKACA fusion transcript. Using this information, we identified a gene signature that is associated with patient survival time.
