Fighting rare cancers: lessons from fibrolamellar hepatocellular carcinoma

Abstract

The fight against rare cancers faces myriad challenges, including missed or wrong diagnoses, lack of information and diagnostic tools, too few samples and too little funding. Yet many advances in cancer biology, such as the realization that there are tumour suppressor genes, have come from studying well-defined, albeit rare, cancers. Fibrolamellar hepatocellular carcinoma (FLC), a typically lethal liver cancer, mainly affects adolescents and young adults. FLC is both rare, 1 in 5 million, and problematic to diagnose. From the paucity of data, it was not known whether FLC was one cancer or a collection with similar phenotypes, or whether it was genetically inherited or the result of a somatic mutation. A personal journey through a decade of work reveals answers to these questions and a road map of steps and missteps in our fight against a rare cancer.

Fig. 1. Mapping reads from the transcriptome onto the genome reveals the fusion transcript.

a, The short nucleotide fragments of RNA sequenced from human fibrolamellar hepatocellular carcinoma (FLC) tumours and adjacent normal tissue mapped onto the known sequence of DNA in the genome. Marks that raise up above the baseline represent RNA fragments that map within a particular exon on the DNA. Loops below the baseline are the RNA fragments that bridge two different exons. DNA has two strands, each of which contain information. b, The genes encoding PRKACA (beige) and DNAJB1 (yellow) are on the negative strand of the DNA and, by convention, are drawn from right to left. The two genes are normally separated by ~400,000 bp. In normal tissue (in grey at the top), all the RNA reads for DNAJB1 are only mapped to the DNA for DNAJB1, and all the RNA reads for PRKACA only map to PRKACA. However, in fibrolamellar tumours, there are RNA reads that bridge between the first exon of DNAJB1 and the second exon of PRKACA. This is not seen in even the adjacent non-transformed tissue from the same patient. Thus, FLC is a somatic mutation — it is not in the germline of the DNA and is therefore not inherited. RPKM, reads per kilobase of transcript per million reads mapped. Modified from ref. . © The Authors, some rights reserved; exclusive licensee, AAAS.