Date: 03 Nov 2014
Topic: Genitourinary cancers / Translational research
New research by the international Cancer Genomics of the Kidney consortium (CAGEKID) reveals an important connection between clear cell renal cell cancer (ccRCC) and exposure to aristolochic acid, an ingredient in some herbal remedies. The findings, published in Nature Communications, have important implications for public health.
CAGEKID: Cancer Genomics of the Kidney.
Credit: CAGEKID Consortium
The incidence of RCC is increasing worldwide, and its prevalence is particularly high in some parts of Central Europe. CAGEKID, part of the International Cancer Genome Consortium (ICGC), has been studying the genetic causes of this disease in Europe. The project partners performed whole-genome and transcriptome sequencing in 100 ccRCC, the most common form of the disease, among patients from four different European countries (Czech Republic, Romania, Russia and the United Kingdom) with contrasting disease incidence.
The findings support previous reports on frequent aberrations in the epigenetic machinery and PI3K/mTOR signalling, and uncover novel pathways and genes affected by recurrent mutations and abnormal transcriptome patterns including focal adhesion, components of extracellular matrix and genes encoding FAT cadherins.
Furthermore, a large majority of patients from Romania had an unexpected high frequency of A:T>T:A transversions, consistent with exposure to aristolochic acid. These results show that this ingredient from herbal remedies may be an important ccRCC carcinogen in Romania, though it is not clear exactly how these patients became exposed to it.
The study was led by McGill University, where the genomic analyses were carried out. “While the study included only 14 patients from Romania, the specific mutation pattern was found in 12 of them,” explains Mark Lathrop of McGill University and Genome Quebec Innovation Centre. “We will analyse samples from more patients from Romania and elsewhere in the Balkan region in follow-up research that is now underway to assess the extent of exposure.”
The European Molecular Biology Laboratory (EMBL)-European Bioinformatics Institute (EBI) scientists contributed their expertise in handling and analysing very large volumes of data. “Our group analysed the very large quantity of RNA data produced in the studies, and we saw some interesting abnormalities,” says Alvis Brazma, head of Functional Genomics at EMBL-EBI. “There was clearly a loss of gene function, and that was due to changes in splicing patterns. We also saw novel fusion genes – pairs of genes that are fused together and create products that interfere with the proper functioning of the cell.”
“This tumour genomic project is unique in that it is based on samples from various countries, with potential diversity in risk factors,” says Ghislaine Scelo of the International Agency for Research on Cancer (IARC/WHO). “Our study illustrates that systematic exploration of tumour DNA via massive sequencing can identify previously unsuspected causes of cancer.”
All data from the study is available in EMBL-EBI’s controlled-access European Genome-phenome Archive ( EGA) and ArrayExpress. The datasets will be incorporated into the ICGC’s pan-cancer project, which uses the EGA for data management and EMBL-EBI’s Embassy Cloud for storage and data analysis.
Scelo G, Riazalhosseini Y, Greger L,et.al.Variation in genomic landscape of clear cell renal cell carcinoma across Europe. Nature Communications 2014; Published online 29 October. doi:10.1038/ncomms6135