A study examining the genetic predisposition of Europeans to develop kidney cancer has found a link between exposure to aristolochic acid and the manifestation of the condition, particularly in Romania.

Aristolochic acid, naturally occurring in plants such as wild ginger and plants belonging to the Aristolochia family, such as birthwort, pipevine, or Dutchman's pipe are known to be carcinogenic, mutagenic, and nephrotoxic. The acid is used judiciously to prepare Chinese herbal medicines, but copious amounts can be lethal.

The European birthwort or Aristolochia clematitis is widespread in the Balkans and is especially found along the tributaries of the Danube River in Croatia, Bosnia and Herzegovina, Serbia, Bulgaria, and Romania. The acid has been previously implicated in the development of a kidney disease known as Balkan endemic nephropathy, in small communities along the Danube.

In this study, the researchers assessed the correlation between clear-cell renal cell carcinoma and exposure to aristolochic acid. The results were published in Nature Communications. The aim of the study was also to identify the cause of high-incidence of renal cancer among Europeans, which accounts for 2.4 percent of all adult cancers and kills more than 140,000 people each year.

With the help of whole-genome sequencing conducted on DNA isolated from the blood and tumors of 94 kidney-cancer patients from the Czech Republic, Romania, Russia, and the United Kingdom, scientists found something interesting.

"The most striking observation was the high frequency of a specific type of mutation pattern found in the Romanian patients," said lead author Yasser Riazalhosseini in a statement. "The specific sequence context surrounding these mutations and their predominance on the non-transcribed strand of DNA enabled us to hypothesize that the mutation is due to exposure to aristolochic acid during the patient's lifetime."

The same pattern was also found in patients who had developed urinary-tract cancer, an offshoot of the Balkan endemic nephropathy. The acid may have entered human blood stream due to consumption of wheat flour contaminated with seeds of Aristolochia clematitis.

"While the study included only 14 patients from Romania, the specific mutation pattern was found in 12 of them. As a result, we will analyze 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," said coresearcher Professor Mark Lathrop.

The studies also revealed the deregulation of the PI3K/mTOR signaling pathway in the development of renal cancer. This pathway controls multiple cell responses, including proliferation, survival, and metabolism, and has been implicated in the development of cancers. The study also showed that another pathway called focal adhesion is affected by molecular aberrations in many patients.

"This finding adds to evidence that targeted therapies for PI3K/mTOR signaling may be applied effectively to kidney cancer and may help patients affected by abnormalities of the focal adhesion pathway as well," Riazalhosseini said.

This was a large-scale cohort study conducted by the Cancer Genomics of the Kidney (CAGEKID) program. The aim of this program is to look into the genetics of cancers.

"This tumour genomic project is unique in that it is based on samples from various countries, with potential diversity in risk factors," said coauthor Ghislaine Scelo. "Our study illustrates that systematic exploration of tumour DNA via massive sequencing can identify previously unsuspected causes of cancer."

Source: Scelo G , Riazalhosseini Y, Lathrop M. Variation in genomic landscape of clear cell renal cell carcinoma across Europe. Nature Communications. 2014.