The CHEK2 del5395 is a founder mutation without direct effects for cancer risk in the latvian population

Checkpoint kinase 2 (CHEK2) phosphorylates P53 and BRCA1 proteins at a checkpoint of double-stranded DNA break signal transduction pathway to cell cycle control, apoptosis and DNA repair [1]. Walsh et al. [2] were the first to report a big truncation mutation of CHEK2 del5395 (g.27417113-27422508del, NC_000022.11) in the Czech and Slovak Republics’ patients with a family history of breast cancer. Similar to further studies carried out in Poland, the del5395 mutation can also be found in the Polish population, so it was assumed to be an Eastern European founder mutation [3]. The frequency of the del 5395 mutation among Czech, Slovak and Polish populations is 0.9-1.3% [2-4].

The association between del5395 and cancers is still to be established. According to Cybulski et al. [4], the presence of the del5395 mutation increased the odds ratio (OR) of breast cancer development to 2.0. However, in another Polish study by Myszka et al. [5], no associations between del5395 and breast cancer development was found. In cases of colorectal cancer, Cybulski et al. [6] observed no association between the del5395 mutation and increased cancer risk, while the missense mutation I157T was found to play a role in cancer development. Presence of the del 5395 mutation is associated with an increased prostate cancer risk [3]. On the other hand, the CHEK2 mutations, including del5395, decrease the risk of lung and laryngeal cancers [7].

Most of the del5395 research is based on the Polish population. Thus, due to the lack of studies conducted in other Eastern European countries, we undertook to find out the following: 1) whether the del5395 is a founder mutation in the Latvian population, 2) if there is an association between CHEK2 del5395 mutation and a cancer risk, and 3) and whether CHEK2 del5395 mutation impacts cancer predisposition in Chernobyl disaster liquidators (the civil and military personnel who were called upon to deal with consequences of the 1986 nuclear disaster) as well as geriatric populations.

In cancer groups, the del5395 mutation was most frequently observed in the ovarian cancer group with a frequency of 1.00% [OR = 1.32; 95% confidence interval (CI) 0.24-7.13; p = 0.73), whereas in cases of prostate cancer its frequency was the lowest 0.24% (OR = 0.31; 95% CI 0.06-3.7; p = 0.39) (Table 1). As far as the control groups are concerned, the healthy donors’ group was marked by the most frequent del5395 mutation (0.76%), whereas its frequency in the Chernobyl liquidators group and the geriatric group was 0.83% (OR = 1.09; 95% CI 0.20-5.90; p = 1.0) and 0.68% (OR = 0.89; 95% CI 0.13-5.28; p = 1.0), respectively (Table 1). For both the cancer and control groups OR appeared to be >1 only in ovarian cancer patients. However, OR rates showed no statistical significance in either cancer or control groups, with the p value fluctuating within the range of 0.39-1.00.

Results obtained in this study support the assumption that del5395 is a founder mutation in the Eastern European population, although statistically significant relationship between the del5395 mutation and cancers risks could not be established. The frequency of del5395 in breast cancer patients (0.68%) was slightly lower than that reported in Poland [4,5], Czech Republic and Slovakia [2], whereas in ovarian cancer patients (1.0%) it was similar to that in the above reports. However, higher frequency of del5395 in the healthy control group significantly lowered the OR of each cancer group in this study. The Chernobyl liquidators had been exposed to high radiation that had caused DNA damage and higher cancer development risk [8].

Radiation is one of the factors activating the CHEK2 protein. In response to DNA damage, the CHEK2 protein interacts with several other proteins, including tumor protein 53 (that is produced from the TP53 gene). These proteins halt cell division and determine whether a cell will repair the damage or self-destruct in a controlled manner (undergo apoptosis). This process keeps cells with mutated or damaged DNA from dividing, thus helping to prevent the development of tumors [1].

It was assumed that the CHEK2 mutation carriers would be more sensitive to ionizing radiation and thus have a higher predisposition towards cancer development. Of the 51 cancer patients with different types of cancer in the Chernobyl liquidators group in this study (9.6%), none had the del5395 mutation. The geriatric control group was designed to estimate the strength of the del5395 mutation against mortality. If del5395 correlates with an increase in the rates of oncological diseases and mortality in the population, the geriatric group should have lower frequency of del5395. Nevertheless, we did not observe any statistically significant difference in the frequency of del5395 between the healthy control group and the geriatric group (OR = 0.89; 95% CI 0.13-5.28; p = 1). In the 51 Chernobyl liquidators with different localization of cancers, the del5395 mutation was not identified (data not shown).

We concluded that the CHEK2 gene del5395 is a founder mutation in the Latvian population, which, however, does not have a direct impact on genetic predisposition toward colorectal, breast, ovarian and prostate cancer. Moreover, we believe that the del5395 mutation requires further research to identify additional genetic and/or environmental factors, which in combination with the above mutation, increase the odds of cancer development.

This study was supported by the State research program “Biomedicine for Public Health (BIOMEDICINE).” The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.