Genetic alterations in the BMPR2 gene may be linked to certain cases of the hereditary predisposition to develop colon polyps that can lead to colorectal cancer. This is the conclusion of a study published in the journal Gastroenterology. The work was led by researchers from the Galician Public Foundation of Genomic Medicine (FPGMX) and the Health Research Institute of Santiago de Compostela, in cooperation with Laia Bonjoch, a researcher in the IDIBAPS Genetic predisposition to gastrointestinal cancer group, and Sergi Castellví-Bel, leader of the same group.
Colorectal cancer is one of the most common types of cancer worldwide. In most cases, it begins with a precursor lesion called a polyp. Some individuals present multiple polyps in the colon, a condition known as polyposis, which increases the risk of developing this type of cancer. Polyposis can be caused by hereditary genetic factors, but the specific genetic alteration that triggers it is known in only 5% of cases.
The paper published by Gastroenterology describes the study of a cohort of patients with unexplained colonic polyposis with a clear familial component, that is, they formed part of families that presented many more cases of polyposis than the general population, leading to the suspicion that there was a hereditary genetic cause. Mass sequencing tools were used to detect alterations to the germline DNA that could explain the predisposition of these patients to contracting the illness.
The study showed that loss-of-function variants in the BMPR2 gene were present in up to 2% of patients. Loss of function of this gene alters the BMP signalling pathway – one of the pathways that controls the growth and differentiation of stem cells which develop into different tissue cell types. If the pathway is altered, greater cell proliferation takes place. In fact, alterations in other components of the pathway also cause other hereditary polyposis syndromes, such as juvenile polyposis syndrome and hereditary mixed polyposis syndrome.
The data obtained was later validated using lab-generated cellular models. Specifically, the researchers in the group led by Sergi Castellví generated cellular models genetically edited with CRISPR-Cas9 to express the BMPR2 variants detected in the patients. Cell proliferation and signalling experiments were also conducted to demonstrate that the variants altered the BMP signalling pathway and cell growth.
Laia Bonjoch, Ceres Fernández-Rozadilla, Miriam Alvarez-Barona, Anael López-Novo, Cristina Herrera-Pariente, Jorge Amigo, Luis Bujanda, David Remedios, Andrés Dacal, Joaquín Cubiella, Francesc Balaguer, Fernando Fernández-Bañares, Angel Carracedo, Rodrigo Jover, Sergi Castellví-Bel, Clara Ruiz-Ponte BMPR2 as a Novel Predisposition Gene for Hereditary Colorectal Polyposis Gastroenterology.