Implications of the germline variants of DNA damage response genes detected by cancer precision medicine for radiological risk communication and cancer therapy decisions

Abstract

Large-scale cancer-associated gene testing is now being rapidly incorporated into clinical settings, and is leading to incidental identification of the germline variants present in cancer patients. Because many cancer susceptibility genes are related to DNA damage response and repair, the variants may reflect not only the susceptibility to cancer but also the genetically defined radiation sensitivity of the patients and their relatives. When the presence of a certain germline variant increases the risk for developing radiation toxicity or radiation-induced secondary cancers, it will greatly influence the clinical decision-making. In order to achieve optimal radiological risk communication and to select the best cancer management for a given patient based on information from gene testing, healthcare professionals including genetic counselors, risk communicators and clinicians need to increase their knowledge of the health effects of various genetic variants. While germline loss-of-function mutations in both of the alleles of the DNA damage response genes cause rare hereditary diseases characterized by extreme hypersensitivity to radiation, the health effects of the carriers who have germline variants in one allele of such genes would be a matter of debate, especially when the significance of the variants is currently unknown. In this review, we describe the clinical significance of the genetic variants of the important DNA damage response genes, including ATM and TP53, and discuss how we can apply current knowledge to the management of cancer patients and their relatives from a radiological point of view.

Keywords: ATM; TP53; DNA damage response genes; cancer therapy; genetic variant; radiological risk communication.

Fig. 1.

Schematic representation showing the involvement of products of cancer susceptibility genes in DNA damage response and repair. The products of major high-penetrance cancer susceptibility genes are colored in pink and those of other moderate-penetrance cancer susceptibility genes are colored in blue. The proteins colored in gray are not currently established as products of cancer susceptibility genes, but include the products of the genes in which rare hereditary mutations in cancer are reported. In response to double-strand breaks (DSBs), the MRN complex initially recognizes and binds the DSB sites, and recruits and activates the ATM kinase, which transmits the DNA damage signals by phosphorylating a large number of downstream proteins, leading to DNA repair, cell cycle arrest and apoptotic cell death. Homologous recombination (HR) is the most accurate DNA repair pathway for DSBs, and the Fancony anemia (FA) pathway, which plays a key role in the repair of interstrand cross-links (ICLs), also contributes to the activation of HR.

Fig. 2.

The relationship among protein function, type of mutation and classification based on clinical significance of a variant. The degree of protein function, type of mutation and clinical significance are indicated in the upper panel, the middle panel and the lower panel, respectively. Variants are classified into five categories on a range from pathogenic (left) to benign (right) based on their likelihood of affecting the protein functions (upper panel) and their potential clinical significance (lower panel). Since a DNA damage response gene product mostly acts as a tumor suppressor, loss of function of the gene product will be a critical determinant for pathogenicity. The variant which results in a loss, frameshift or nonsense mutation of the gene can be pathogenic or likely pathogenic (left), whereas a variant which results in a silent mutation can be benign or likely benign because it will not affect the function of the gene product (right). A variant which results in a non-truncating missense mutation is usually difficult to interpret, and is classified as a ‘variant of unknown significance (VUS)’.