The therapeutic significance of mutational signatures from DNA repair deficiency in cancer

Abstract

Cancer is fundamentally a disease of the genome and inherited deficiencies in DNA repair pathways are well established to increase lifetime cancer risk. Computational analysis of pan-cancer data has identified signatures of mutational processes thought to be responsible for the pattern of mutations in any given cancer. These analyses identified altered DNA repair pathways in a much broader spectrum of cancers than previously appreciated with significant therapeutic implications. The development of DNA repair deficiency biomarkers is critical to the implementation of therapeutic targeting of repair-deficient tumors, using either DNA damaging agents or immunotherapy for the personalization of cancer therapy.

Fig. 1

An individual’s unique mutational signature is a record of the types of DNA alterations sustained throughout their lifetime and can be studied to identify unique patterns of etiology-specific alterations, including carcinogens or DNA repair pathway defects, the latter of which can be inherited or acquired during oncogenesis. Mutational signatures adapted from COSMIC with permission (http://cancer.sanger.ac.uk)

Fig. 2

Targeting DNA repair deficiency: mechanism of synthetic lethality of PARP inhibitors and alternative synthetic lethal relationships

Fig. 3

The neoantigen hypothesis: the adaptive immune system and DNA repair deficiencies in a DNA repair-deficient tumor cell. A non-synonymous mutation results in an amino acid change which yields a novel peptide which has the potential to be recognized as foreign by the immune system. Defects in multiple DNA repair pathways can increase the number of non-synonymous mutations, including MMR, POLE/D, and even HR

Fig. 4

The STING hypothesis: activation of the innate immune system by DNA repair deficiencies in a DNA repair-deficient tumor cell. Cytosolic double-stranded DNA can be detected by cGAS which subsequently produces cGAMP (a cyclic dinucleotide), which in turn activates STING. Upon activation, STING undergoes a conformational change, complexes with TANK-binding kinase 1 (TBK1) and relocates to peri-nuclear region. There, TBK1 phosphorylates IRF3 and NFKB, which translocate to the nucleus and lead to the expression of immune-related genes, including type I interferons