London, Oct 24: Researchers have discovered the molecular mechanisms that determine cancer risk in patients with a rare form of anaemia.
Researchers from the Tumour Suppression Group at the Spanish National Cancer Research Centre (CNIO), headed by Manuel Serrano, created the first animal model that recapitulates key characteristics of Diamond-Blackfan anaemia (DBA) in humans, including high cancer susceptibility.
The finding could potentially improve current treatments for this disease, which are effective in resolving the haematological disorders but not in preventing the greater predisposition to cancer.
DBA is a rare type of anaemia that affects 5 people per million.
It is characterised by blood disorders, short stature and malformations in the heart, palate and hands.
Previous observational studies had reported that around 20 per cent of these patients develop various types of cancer during their first 46 years of life; in particular, lymphomas - tumours of the blood - but also solid tumours such as colon cancer, osteosarcoma and gynaecological cancers.
Researchers found that mice with partial deficiency of RPL11 protein (ie one of the two copies of the gene is faulty) not only suffer from the incorrect generation and maturation of red blood cells (causing anaemia), but are also predisposed to lymphomagenesis - the development of lymphomas.
DBA patients display alterations in ribosomal proteins, those that belong to the ribosomes, the organelles within cells that are responsible for synthesising proteins.
However, when other research groups generated animal models with mutations in some of these proteins, those animal models experienced haematological disorders that are typical of anaemia - red blood cells are not produced or do not mature properly - but cancer predisposition was not reported.
"Cells need the ribosomes to function properly in order to proliferate and grow; we knew that when something goes wrong in these organelles, RPL11 operates as a switch that activates the p53 gene to stop the cells from proliferating and forming tumours; this mechanism is called ribosomal stress," said Serrano.
"P53 is one of the main tumour suppressor genes identified to date, to the extent that its relevance in preventing cancer has led to it being named the guardian of the genome," Serrano said.
In addition to impairing the normal function of the p53 tumour suppressor gene, mutations in RPL11 also increase the levels of the MYC oncogene, a protein that, when produced at abnormally high levels, can promote the development of tumours.
"We believe that in DBA both factors combined contribute to induce the development of cancer," said lead author Lucia Morgado-Palacin, from CNIO. The study was published in the journal Cell Reports.