What can chimpanzees tell us about cancer propensity in humans?

A recent study published in the renowned journal Cell Reports finds evidence for reduced functional activity of certain human cancer genes (such as breast cancer 2 gene or BRCA2), following the divergence from the chimpanzee-human last common ancestor.

Study: Evidence for reduced BRCA2 functional activity in Homo sapiens after divergence from the chimpanzee-human last common ancestor. Image Credit: Lili Aini / Shutterstock

Cancer has been well-documented as a genetic disease because of the activation of tumor-suppressor genes as well as the activation of oncogenes. On average, mutations or alterations in 3-5 cancer genes are needed for the development of an infiltrating malignant tumor.

All known cancer driver genes to date basically underpin three core cellular processes: cell fate, cell durability, and genome maintenance. Even though this is true for cancers in general, different tissues can have specific patterns with respect to cancers and genes targeted within these core processes

Chimpanzees have more than 98% genome sequence similarity with humans. However, since divergence from the chimpanzee-human last common ancestor, we have evolved in association with a plethora of geographic, environmental, social and behavioral modifications.

In this new study by researchers from the Memorial Sloan Kettering Cancer Center and American Museum of Natural History in New York (USA) hypothesized that pursuing a systematic analysis of cancer-gene evolution between humans and non-human primates would reveal different mechanisms linked to cancer propensity.

A mix of evolutionary theory and bioinformatics

In order to prove this hypothesis, these scientists have performed a systematic analysis of humans and 12 non-human primates to investigate variations in 401 cancer genes during evolutionary divergence from the chimpanzee-human last common ancestor. Genetic substitutions in non-human primate cancer genes were compared with human gene sequences.

Moreover, to comprehend the identified substitutions, this research team filtered 499 human-specific, non-silent substitutions by comparing them with the 1000 Genomes Project database (i.e., a catalog of common human genetic variations) to pinpoint those fixed in the contemporary human population.

Additional experiments were conducted to particularly appraise the selection of primate BRCA2 genes by using a series of evolutionary methods. Of note, mutations in this gene confer an increased risk of developing breast or ovarian cancer in women.

A catalog of specific substitutions

In short, the researchers have found 395 human-specific and non-silent substitutions that emerged during human evolution. Robust bioinformatic approaches that they have employed helped unveil a myriad of substitutions that can alter the function of proteins.

One of these substitutions was specifically found in the most evolutionarily conserved domain of human BRCA2. Of note, the conserved gene in this context means that it has remained basically unchanged throughout the evolutionary process; hence, this is a significant finding.

In addition, the substitution triggers a 20% reduction in recombinational DNA repair ability, which means damage response is relaxed, and the affected individual is more prone to developing a malignant tumor.

Implications beyond cancer research

These findings demonstrate how powerful the merge of evolutionary theory with cancer genomics actually is if the goal is to identify new properties of cancer genes. Consequently, this may have plenty of utility beyond cancer research (and potentially cancer treatment).

“A similar strategy may have value in identifying potentially novel disease-related variants in other major causes of morbidity and mortality in humans, for example, neurodegenerative or cardiovascular disease,” argue study authors in this paper published in the journal Cell Reports.

In any case, exploring this hypothesis was not just an academic exercise, considering the fact that approximately twenty million cases of malignant diseases will be reported every year by 2025 worldwide. Therefore, similar research endeavors will be warranted to obtain a complete insight into this complex research puzzle.

Written by

Dr. Tomislav Meštrović

Dr. Tomislav Meštrović is a medical doctor (MD) with a Ph.D. in biomedical and health sciences, specialist in the field of clinical microbiology, and an Assistant Professor at Croatia's youngest university – University North. In addition to his interest in clinical, research and lecturing activities, his immense passion for medical writing and scientific communication goes back to his student days. He enjoys contributing back to the community. In his spare time, Tomislav is a movie buff and an avid traveler.