Absence of the CHEK2 c.1100delC mutation in familial breast and ovarian cancer in Colombia: a case-control study

Introduction

Breast cancer (BC) is the most common type of cancer among women¹, and in Colombia, it is the main cause of death by cancer in women¹. Of all cases of BC, approximately 5–10% have a strong inherited component, of which 25% is explained by germline mutations in the genes BRCA1² and BRCA2^3,4. To explain the BRCA1/2-negative cases, a polygenic model in which a large number of low- to moderate-penetrance genes as collectively responsible for the disease has been proposed^5–7.

CHEK2 has been proposed as a moderate penetrance BC susceptibility gene⁸. This gene controls cell cycle and apoptosis and is activated in response to DNA double-strand breakage⁸. Several mutations in the CHEK2 gene have been found, being the CHEK2 c.1100delC mutation the most studied; this is a truncating mutation in exon 10 that abolishes kinase activity of the protein⁹. The role of this mutation in breast cancer was confirmed by Meijers-Heijboer et al⁸. and in several other studies^10–22. The mutation CHEK2 c.1100delC was identified in approximately 5% of families with BC that did not have mutations in either BRCA1 or BRCA2 and was estimated to confer moderate risk (20–25%) of developing breast cancer for female mutation carriers²³.

Data on the contribution of moderate- or low-penetrance alleles to BC in South American populations are scarce. In this study, using a case-control design, we studied the CHEK2 c.1100delC mutation in order to investigate the potential influence of this variant on familial Breast and Ovarian Cancer (BOC) susceptibility in a Colombian cohort.

Materials and Methods

This was a case-control study conducted from 2009 to 2013 with 131 cases and 131 controls, which was carried out to determine the–association between the CHEK2 c.1100delC mutation and increased risk of developing breast cancer. This study was approved by the Ethical Board of the School of Medicine of the University of Valle. Informed consent was obtained from all the participants.

Results

A total of 262 samples (131 study cases and 131 matched-controls) were analyzed for the presence of the CHEK2 c.1100delC mutation. The clinical characteristics of the families included in this study are listed in Table 1 (Also see Dataset 1). After allele-specific PCR analysis, none of the cases or controls showed the CHEK2 c.1100delC mutation. All the samples showed only the heavier band (534bp) (Supplementary Figure 1). This indicates that the all the samples were homozygotes for the normal allele.

Discussion

This is the first study conducted in the Colombian population for CHEK2 c.1100delC mutation. Our results have shown that none of the 262 analyzed samples carried the CHEK2 c.1100delC mutation, suggesting that the frequency of this mutation is extremely low (or not present) in the Colombian population.

Similar results have been reported for populations in other South American countries. Although studies are scarce, in the few populations that have been evaluated for the presence of this variant, it has not been found in Chile²⁶ and Mexico²⁷, or has been found at very low frequencies in Brazilian population^10,22,28,29.

Worldwide, CHEK2 c.1100delC is absent in Spain^30–31 and all Asian populations studied to date, including those in India³², Japan³³, China³⁴, Korea³⁵, Singapore³⁶, the Philippines²², Pakistan³⁷ and Malaysia³⁸. The mutation is present in populations of Galicia (northwest Spain)^39–41, 1.4% of the Northern European countries including Finland, the UK and the Netherlands^8,11,42 and the United States^43–45.

An explanation for this variability, proposes CHEK2 c.1100delC as an allele whose frequency is distributed along a population-gradient, which would have originated in populations of Northern Europe (with high frequencies) and decreasing towards the regions of Southern Europe (Basque Country, Spain and Italy)³⁹. This may explain the absence of the allele in the Colombian population., which is a mixture, in different proportions, of European-Spanish, African and Native American ancestry⁴⁶. Hence, the probability that the allele would have reached our population is low. As reported in several studies, it is evident that the contribution of CHEK2 c.1100delC mutation to the burden of cancer varies according to the ethnic group, and from country to country⁴⁷.

We found that the CHEK2 c.1100delC mutation is not present or is present at an extremely low frequency in familial BOC cases and controls in our Colombian cohort.

Based on our findings, we suggest that genotyping of the CHEK2 c.1100delC mutation in genetic testing for breast cancer susceptibility in the Colombian population should not be recommended. However, further studies are required to confirm the contribution of this variant in the Colombian population.

The study of CHEK2 mutations in the Latin American population has been focused mainly in the c.1100delC mutation. However, databases like ExAC (Exome Aggregation Consortium) showed the presence of other germline mutations in the CHEK2 gene in Latin American samples that could generate cancer susceptibility⁴⁸. Accordingly, it would be important to examine other mutations in the Colombian population and its association with the development of familial BOC.

Data availability

Dataset 1: Raw data for “Genotype and type of cancer present in the studied patients and their families” 10.5256/f1000research.13368.d207084⁴⁹