Comparative study of the evolution of human cancer gene duplications across fish

TL;DR

This study compares cancer-related gene copy number variation across 65 fish species, revealing links between gene CNV, lifespan, and potential tumor suppression mechanisms, offering new insights into cancer evolution.

Contribution

First comprehensive analysis of cancer gene CNV in fish, introducing a novel method for ortholog identification and uncovering evolutionary patterns related to lifespan and tumor suppression.

Findings

Higher tumor suppressor gene CNV correlates with longer lifespan.

Oncogene CNV is associated with shorter lifespan.

Species with more tumor suppressors may have stronger cancer defenses.

Abstract

Comparative studies of cancer-related genes allow us to gain novel information about the evolution and function of these genes, but also to understand cancer as a driving force in biological systems and species life histories. So far, comparative studies of cancer genes have focused on mammals. Here, we provide the first comparative study of cancer-related gene copy number variation in fish. As fish are evolutionarily older and genetically more diverse than mammals, their tumour suppression mechanisms should not only include most of the mammalian mechanisms, but also reveal novel (but potentially phylogenetically older) previously undetected mechanisms. We have matched the sequenced genomes of 65 fish species from the Ensemble database with the cancer gene information from the COSMIC database. By calculating the number of gene copies across species using the Ensembl CAFE data (providing species trees for gene copy number counts), we were able to develop a novel, less resource demanding method for ortholog identification. Our analysis demonstrates a masked relationship with cancer-related gene copy number variation (CNV) and maximum lifespan in fish species, suggesting that higher tumour suppressor gene CNV lengthens and oncogene CNV shortens lifespan, when both traits are added to the model. Based on the correlation between tumour suppressor and oncogene CNV, we were able to show which species have more tumour suppressors in relation to oncogenes. It could therefore be suggested that these species have stronger genetic defences against oncogenic processes. Fish studies could yet be a largely unexplored treasure trove for understanding the evolution and ecology of cancer, by providing novel insights into the study of cancer and tumour suppression, in addition to the study of fish evolution, life-history trade-offs, and ecology.