Polymorphisms in base excision repair genes: Breast cancer risk and individual radiosensitivity

Abstract

Breast cancer (BC) is the most common cancer among women worldwide. The aetiology and carcinogenesis of BC are not clearly defined, although genetic, hormonal, lifestyle and environmental risk factors have been established. The most common treatment for BC includes breast-conserving surgery followed by a standard radiotherapy (RT) regimen. However, radiation hypersensitivity and the occurrence of RT-induced toxicity in normal tissue may affect patients' treatment. The role of DNA repair in cancer has been extensively investigated, and an impaired DNA damage response may increase the risk of BC and individual radiosensitivity. Single nucleotide polymorphisms (SNPs) in DNA repair genes may alter protein function and modulate DNA repair efficiency, influencing the development of various cancers, including BC. SNPs in DNA repair genes have also been studied as potential predictive factors for the risk of RT-induced side effects. Here, we review the literature on the association between SNPs in base excision repair (BER) genes and BC risk. We focused on X-ray repair cross complementing group 1 (XRCC1), which plays a key role in BER, and on 8-oxoguanine DNA glycosylase 1, apurinic/apyrimidinic endonuclease 1 and poly (ADP-ribose) polymerase-1, which encode three important BER enzymes that interact with XRCC1. Although no association between SNPs and radiation toxicity has been validated thus far, we also report published studies on XRCC1 SNPs and variants in other BER genes and RT-induced side effects in BC patients, emphasising that large well-designed studies are needed to determine the genetic components of individual radiosensitivity.

Keywords: Base excision repair; Breast cancer; Polymorphisms; Radiosensitivity; Susceptibility.

Figure 1

Base-excision repair. Simplified schematic representation of the short-patch base-excision repair pathway showing the key steps and main proteins involved in the repair of a damaged DNA base. Adapted from Costa et al[8]. OGG1: 8-oxoguanine DNA glycosylase 1; APE1: Apurinic/apyrimidinic endonuclease 1; PARP-1: Poly (ADP-ribose) polymerase-1; XRCC1: X-ray repair cross complementing group 1; Polβ: DNA polymerase-β; LIGIII: DNA ligase III.

Figure 2

Domains of the X-ray repair cross-complementing group 1 protein and X-ray repair cross-complementing group 1 gene structure. A: The schematic diagram shows the regions of interaction with other base excision repair proteins; B: The diagram shows the structure of XRCC1 with the locations of the most common and well-studied single nucleotide polymorphisms: 77 T > C, Arg194Trp, Arg280His and Arg 399Gln. Modified from Sterpone et al[14]. XRCC1: X-ray repair cross-complementing group 1; OGG1: 8-oxoguanine DNA glycosylase 1; APE1: Apurinic/apyrimidinic endonuclease 1; PARP-1: Poly (ADP-ribose) polymerase-1; Polβ: DNA polymerase-β; LIGIII: DNA ligase III; NTD: N-terminal domain; NLS: Nuclear localisation signal; BRCT: BRCA1 carbox-terminal domain.