Various proteins have been linked with pathogenesis for neurodegenerative diseases like Alzheimer’s (AD) and frontotemporal lobar degeneration (FTLD). For instance, mutations within the microtubule-associated protein tau have been shown to cause neurofibrillary tangles, a hallmark of AD. However, a team of Italian investigators at the IRCCS Foundation Carlo Besta Neurological Institute in Milan have now uncovered a novel role for mutated tau protein as a potential risk factor in the development of cancer.
"Our study revealed that the presence of tau mutations raises the risk of developing cancer," explained senior study investigator Fabrizio Tagliavini, M.D., scientific director at the IRCCS Foundation Carlo Besta Neurological Institute. "Furthermore, our bioinformatic analysis highlighted a broader functional environment for the tau protein, which had been previously associated mainly with disease development in the context of neurodegeneration."
Findings from the new study were released today in Cancer Research, in an article entitled “Tau Mutations Serve as a Novel Risk Factor for Cancer.” Tau protein is essential for the stabilization of microtubules, a major element of the eukaryotic cytoskeleton.
"A mutated tau has a reduced ability to bind to microtubules; this leads to microtubule destabilization and cytoskeleton disruption, which is detrimental to cellular survival," noted Dr. Tagliavini. "Additionally, free tau protein can form toxic aggregates within nerve cells, impairing neuronal function."
Previous work in Dr. Tagliavini’s laboratory found that mutations in tau led to chromatin defects and chromosome abnormalities. "It is well-known that chromosome aberrations are often linked to cancer," he remarked. "Therefore, we decided to determine if there was a possible association between tau mutations and cancer."
The researchers analyzed cancer incidence in 15 families bearing seven different tau mutations and affected by FTLD. To calculate cancer risk, each tau-mutated family was matched with three reference families with superimposable pedigrees (control subject's age, gender, and native location matching the person affected with FTLD).
Interestingly, the research team found that 15% of subjects from tau-mutated families developed cancer, while only 9% of subjects from the reference families had cancer. Cancer types in both cohorts were variable—tau mutations were not associated with specific cancers. Following multivariate analysis, the researchers determined that individuals from tau-mutated families were 3.72 times more likely to develop cancer compared to the reference families.
The scientists also used bioinformatics analysis to understand the interactions of tau protein with other proteins. They found that almost a third of proteins that tau interacts with were involved in DNA metabolism and cell cycle control—aberrant regulation of these key processes can lead to cancer.
"Patients carrying tau mutations are usually checked for neurodegeneration," Dr. Tagliavini stated. "However, with further confirmation of our results, these patients could also be monitored for their risk of developing cancer. Clinicians should take into account both of these aspects of tau pathology."
Limitations of the study include missing genetic analyses from several patients and individuals from reference families due to the unavailability of DNA. "The analysis of missing patient data would have allowed a more significant correlation between cancer and tau mutations, which had to be inferred with statistical analysis," Dr. Tagliavini concluded.