Epigenetics Found to Play a Role in Childhood Kidney Cancer
Researchers at the Wellcome Sanger Institute uncovered a possible pre-cancerous signature for Wilms’ tumour, a form of kidney cancer mainly affecting children under five years old. Published in Science, the research was the first to compare Wilms’ tumour tissue and healthy kidney tissue to identify any genetic changes that could possibly be predictive of disease progression.
Comparative genomic analysis identified the H19 gene to be epigenetically supressed in Wilms’ tumour and found premalignant clonal expansions of morphologically normal kidney tissues containing somatic driver mutations were shared between them.
Unveiling a new route for cancer formation in the early stages of life, the research investigated how early cells can acquire DNA modifications associated with cancer and proliferate during organ development. This research could lead the way in preventing the recurrence of Wilms tumour, and may lead to the development of new screening regimes to identify cancers like this before they cause harm.
Wilms’ tumour is the most common type of childhood kidney cancer with around 80 cases per year. It’s a type of embryonal tumour with an overall 5-year survival rate of 93%. Usually only one kidney is affected, however in around 10% of cases both kidneys develop the tumour. The most common treatment is surgical intervention to remove the affected kidney together with chemotherapy.
66 tumour and 162 normal kidney tissues in total were collected by researchers at Great Ormond Street Hospital in London and Addenbrooke’s Hospital in Cambridge. Whole genome sequences of the 229 samples were created at the Wellcome Sanger Institute, and comparative genome analysis carried out between them.
In morphologically normal kidney tissues, 14 of 23 cases (61%) were found to have premalignant clonal expansions defined by somatic mutations that preceded tumour development.
In 58% of the expansions, hypermethylation of the H19 locus, a known driver of Wilms’ tumour development, was found. The normal function of the H19 gene is unknown, but researchers believe that it may act as a tumour suppressor to prevent cells from growing and dividing too quickly or in an uncontrolled way. This epigenetic change “turns off” H19 gene expression, thereby enabling cells to grow rapidly into pre-cancerous patches of kidney tissue from which Wilms’ tumour can arise.
In two thirds of children with Wilms’ tumour, both normal kidney tissue and tumour tissue showed DNA changes associated with the disease. Microscopically, these tissues both appeared to be normal. However genetic analysis showed that there were patches of cells within the tissues that had differences in H19 expression. This suggested that these patches were likely to have developed from a single rogue cell with a DNA change that supressed the H19 gene in the tumour tissue.
This research provides a starting point for the genetic understanding of Wilms’ tumour, and using this information researchers could potentially develop a screening method for early detection.