The association between ATM variants and risk of breast cancer: a systematic review and meta-analysis

Breast Cancer is the most common cancer in women and causes the highest mortality rate in developed and developing countries [1]. Annually, 1.67 million women become infected with this type of cancer and have 522,000 mortality rate each year [2]. According to the World Health Organization (WHO) report, 1 out of 9 women in the world suffers from this type of cancer during their life. The Clinical manifestations of breast cancer are very different in patients and these various manifestations largely depend on the type of genetic mutation. Accurate diagnosis of cancer based on the type of mutation is very helpful for deciding on the treatment and follow up of patients [3].

During the last decade, BRCA1 and BRCA2 mutations (BRCA1/2) have been screened for hereditary breast cancer and results showed that mutations in BRCA1/2 account for 5% of hereditary breast cancer [1, 4]. Besides, a recent large population study showed that other pathogenic gene variants, including ataxia telangiectasia-mutated (ATM) variants, were frequently detected among breast cancer women [5, 6]. The ATM gene is located on 11q22–23 chromosome and consists of 66 exons that encode a 350 kDa protein kinase enzyme [7, 8]. This gene plays an important role in regulating the cell cycle and repairing the DNA damage induced by ionizing radiation. Exposure to ionizing radiation, even in very low doses, can trigger a break down significant amount of cellular inactive homodimer ATM to active monomers [9, 10]. The activated ATM phosphorylates a number of its downstream targets such as p53, chek2 and BRCA1 which stops the cell cycle, repairs DNA or apoptosis, so a mutation in either of these genes causes insufficient cellular repair and ultimately increases the incidence of cancer [9, 11].

Mutations in the ATM gene caused Ataxia Telangiectasia (A-T), an autosomal recessive syndrome that patients have symptoms such as ionizing radiation sensitivity, cerebellar neurodegeneration immunodeficiency and markedly increased risk of cancers like breast cancer [12‐14]. The incidence of breast cancer among female relatives of A-T families was increased [15‐18]. Also, Epidemiologic studies have estimated that obligate heterozygous carriers of an ATM mutation have a 2–5-fold increased risk of breast cancer [13, 19, 20]. In addition, it is reported that breast cancer patients with mutated ATM variants who undergo radiotherapy developed their second tumor sooner than the group with no treatment of radiation and no ATM mutations [21].

Since the detection of the ATM gene in 1995, several studies have been conducted on the association of mutations of this gene and the risk of breast cancer which had contradictory results and to our knowledge, no systematic study was conducted to examine the association between different variants of ATM and breast cancer. Therefore, the current study aims to clarify the pooled relationship between ATM variants and breast cancer.

ATM gene has been recognized in recent years as a low penetrance breast cancer gene, which is a research goal for many studies [31]. Based on the mentioned keywords 18 articles were evaluated and different variants of this gene in three continents of Asia, America and Africa were analyzed. Qualitative assessment of articles was performed by NOS criteria and the results showed that all articles are of medium to high quality, so they met the criteria for entering meta-analysis. The results of the current study indicate that ATM missense variants increase the incidence of breast cancer and people who carry these variants have an increased risk of developing breast cancer.

In the study by Easton DF et al. [32] in 2015, it is reported that relatives of A-T patients encounter breast cancer with a relative risk of 2.8 (90%CI: 2.2–3.7; P < 0.0001) [32]. Another study by van Os NJH et al. [33] in 2016 demonstrated that all women with pathogenic ATM variants developed breast cancer with a relative risk of 3.04 (90%CI: 2.06–4.48; P < 0.0001). Another meta-analysis of 19 studies by Marabelli M et al. [34] in 2016 reported that the women who were the carriers of ATM variants have a breast cancer relative risk of 6.02 (90%CI: 4.58–7.42) by the age of 50 years old and 32.83 (90%CI: 24.55–40.43) by the age of 80 years old [34]. As the same as our findings, all these studies emphasized that there is a strong association between ATM variants and the risk of breast cancer development.

Of the 29 different variants examined in the current study, V2424G (c.7271 T > G) missense variant had the highest association with breast cancer incidence in different subgroups of adjusted case control, non-adjusted case control and cohort studies. Although this association varied across the three subgroups analyses, all revealed that V2424G missense variant was strongly accompanied by an increased risk of breast cancer. Bernstein JL et al. [9] in 2006 reported that women who were carriers with V2424G missense variant had developed breast cancer by the age of 70 years old with a cumulative risk of 52% (95% CI = 28–80%; P < 0.0001). Another study by Goldgar DE et al. [35] in 2011 analyzed 15 different A-T families and revealed that pathogenic V2424G variant accompanied with increased risk of breast cancer with a relative risk of 8 (95% CI: 2.3–27.4; P = 0.0005. In addition, another study by Southey MC et al. [30] in 2016 reported that V2424G missense variant was detected in 12 of 42,671 patients suffered from invasive breast cancer and one of 42,164 normal control population that these statistics results in an OR of 11.0 (95% CI:1.42–85.7; p = 0.0012). Also, Mitui M et al. [36] evaluated the clinical consequences of ATM gene alterations using stable transfection and among the 12 missense variants examined, ATM V2424G variant was one of the variants which were associated with an increased risk of cancer.

The meta-analysis on the adjusted case-control studies revealed that ATM D1853V missense variant has the least association with an increased risk of breast cancer. Gao LB et al. [37] in 2010 revealed that there is significantly no relationship between the D1853V missense variant and the risk of breast cancer development [37] that this finding is congruent with our results.

Another objective of our study was to investigate the association of ATM variants with breast cancer in different regions. Although the incidence of breast cancer is higher in the Americas and Europe than in the Asian continent [38, 39], it is interesting to note that the association between ATM variants and breast cancer is greater in Asian countries than in American and European countries in all three sub-groups analyses that is probably due to racial differences, environmental conditions, patterns of life and the effects of other genes or specific haplotype combinations in that region [39].

The overall risk heterogeneity in our study was 67.4, which could be due to the way we measured, sample-sizes designs, inclusion criteria, family history and BRCA1/2 mutation status and could distort the interpretation of our results, so we performed a sub-group analysis based on variant type, region and heterozygosity to illustrate this heterogeneous factor and thus reduced the heterogeneity up to zero.

This meta-analysis shows that the pathogenic ATM variants are associated with an increased risk of breast cancer. Accordingly, ATM variants, including V2424G have the highest risk of breast cancer incidence while ATM D1853V, L546V, and S707P variants have the least impact on breast cancer incidence.