RRM2B is frequently amplified across multiple tumor types: non-oncogenic addiction and therapeutic opportunities

Abstract

RRM2B plays a crucial role in DNA replication, repair and oxidative stress. While germline RRM2B mutations have been implicated in mitochondrial disorders, its relevance to cancer has not been established. Here, using TCGA data, we investigated RRM2B alterations in cancer. We found that RRM2B is highly amplified in multiple tumor types, particularly in MYC-amplified tumors, and is associated with increased RRM2B mRNA expression. We also observed that the chromosomal region 8q22.3-8q24, is amplified in multiple tumors, and includes RRM2B, MYC along with several other cancer-associated genes. An analysis of genes within this 8q-amplicon showed that cases that have both RRM2B-amplified along with MYC have a distinct pattern of amplification compared to unaltered cases or cases that have amplifications in RRM2B or MYC only. These other 8q-proteins were shown to interact functionally within the RRM2B network of DNA repair, hypoxia and apoptosis regulating proteins. Notably, RRM2B-amplified tumors are characterized by mutation signatures of defective DNA repair and oxidative stress, and in some cancers also associated with poor clinical outcome. These findings suggest that some cancers may require RRM2B for cellular survival, providing novel therapeutic opportunities in these cancers.