Shedding light on the dark genome: Insights into the genetic, CRISPR-based, and pharmacological dependencies of human cancers and disease aggressiveness

Abstract

Investigating the human genome is vital for identifying risk factors and devising effective therapies to combat genetic disorders and cancer. Despite the extensive knowledge of the "light genome”, the poorly understood "dark genome" remains understudied. In this study, we integrated data from 20,412 protein-coding genes in Pharos and 8,395 patient-derived tumours from The Cancer Genome Atlas (TCGA) to examine the genetic and pharmacological dependencies in human cancers and their treatment implications. We discovered that dark genes exhibited high mutation rates in certain cancers, similar to light genes. By combining the drug response profiles of cancer cells with cell fitness post-CRISPR-mediated gene knockout, we identified the crucial vulnerabilities associated with both dark and light genes. Our analysis also revealed that tumours harbouring dark gene mutations displayed worse overall and disease-free survival rates than those without such mutations. Furthermore, dark gene expression levels significantly influenced patient survival outcomes. Our findings demonstrated a similar distribution of genetic and pharmacological dependencies across the light and dark genomes, suggesting that targeting the dark genome holds promise for cancer treatment. This study underscores the need for ongoing research on the dark genome to better comprehend the underlying mechanisms of cancer and develop more effective therapies.