Colorectal cancer is one of the most prevalent cancers worldwide. Although it has traditionally been associated with older people, in recent decades its incidence has been reduced in people over 50 years of age. However, paradoxically, the incidence of colorectal cancer has been increasing in young adults. Most cases of early-onset colorectal cancer do not yet have a clear explanation, especially when there is no family history of cancer.
Now, a new study led by Dr. Laura Valle, principal investigator of the Hereditary Cancer group at IDIBELL and ICO and also a CIBERONC researcher, and signed as first author by Mariona Terradas, from the same group and recently appointed lecturer at the UAB, could help draw a clearer picture of the diagnosis of these early cancers. According to the results of the study, published in the scientific journal Clinical Epigenetics, certain rare epigenetic alterations could be behind cases that, at present, have no explanation.
The study involves researchers from IDIBELL, the Dresden University of Technology (TUD, Germany), the Leiden University Medical Center (LUMC, Netherlands), the University of Oviedo, the Catalan Institute of Oncology, the Bellvitge Hospital, CIBERONC and CIBERESP.
Epigenetic alterations in the spotlight
In 5-10% of cases, cancer has a genetic or hereditary origin that is explained by constitutional alterations in specific genes that increase the risk of developing the disease. Hereditary cancer is behind a considerable part of early diagnoses.
Genes involved in hereditary cancer can be affected by genetic mutations (which directly modify the DNA sequence) or, in some rare cases, by epigenetic alterations (which do not directly affect the sequence but change the way it is read and interpreted and, therefore, the gene activity and expression). In this study, Dr. Laura Valle’s team has managed to identify a couple of epigenetic alterations that could be responsible for certain cases of early-onset colorectal cancer. If confirmed in future studies, these alterations could be formally associated with an increased risk of developing this type of cancer.
The genes affected: LTBP4 and BRCA1
Beyond genetic mutations, sometimes the error is found in the promoters of hereditary cancer genes. Promoters function as a kind of genetic “switches,” controlling and inducing the reading of the genes to which they are associated and, therefore, their activity.
Dr. Valle’s team focused on identifying abnormal switches (promoter methylation) in cancer predisposition genes or in genes involved in key colon cancer pathways. Analyzing samples from 46 patients diagnosed with colorectal cancer before the age of 50, they identified a constitutional methylation (in all the patient’s cells) in a promoter of the LTBP4 gene that could be associated with an increased risk of colorectal cancer.
“Despite being a rare alteration per se at the constitutional level, it is quite common in colon tumours, where it leads to lower expression of the gene. This, the close relationship of the affected gene with a pathway traditionally linked to colorectal carcinogenesis (TGF-β), and that its inactivation causes intestinal tumours in animal models, made this alteration a promising candidate to explain some cases of colorectal cancer with no apparent genetic cause,” explains Dr. Valle. Interestingly, the affected patient also had early pulmonary emphysema, a trait observed in both modified mice and paediatric patients with complete inactivation of this gene.
The researchers also identified another anomalous switch, this time on the BRCA1 gene. BRCA1 is known to increase the risk of breast and ovarian cancer. It will now be necessary to confirm whether the epigenetic alterations of its promoter also contribute to an increased risk of colorectal cancer.
A new hereditary cancer syndrome
If it is confirmed that the epigenetic alteration of the LTBP4 gene is associated with an increased risk of colorectal cancer, we would be facing a new hereditary colorectal cancer syndrome, which could be a major diagnostic advance. Detecting it early would be key to identifying individuals susceptible to developing cancer, and to be able to start personalized cancer surveillance and prevention strategies as soon as possible.
The Bellvitge Biomedical Research Institute (IDIBELL) is a research centre created in 2004 and specialising in cancer, neuroscience, translational medicine and regenerative medicine. It has a team of more than 1,500 professionals who, from 73 research groups, publish more than 1,400 scientific articles a year. L’IDIBELL is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Health Institute, the Catalan Institute of Oncology, the University of Barcelona and the City Council of L’Hospitalet de Llobregat.
IDIBELL is a member of the Campus d’Excelencia Internacional of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centres accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the HR Excellence in Research program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Centre of the AECC Scientific Foundation (FCAECC).