Detection of the CHEK2 1100delC mutation by MLPA BRCA1/2 analysis: a worthwhile strategy for its clinical applicability in 1100delC low-frequency populations?

Abstract

Dear Editor, We would like to add some information and thoughts in relation to the letter of Martinez-Bouzas et al. [1] published in your journal, dealing with the presence of the CHEK2 1100delC mutation in Spanish families. Germ-line mutations in the CHEK2 gene (OMIM 604373) have been identified in breast cancer (BC) families negative for BRCA1/2 mutations. The 1100delC variant was initially identified as a susceptibility allele to BC from a study in 718 Western-European and North-American BRCA1/2 negative families. The variant was found in 5.1% of these families and in 1.1% of healthy individuals [2]. The authors estimated that the variant results in a 2-fold increase of BC risk in women, accounting for about 1% of all female BC. This estimate has been confirmed in another population-based study from Denmark [3]. Additionally, having a personal or familial history of bilateral BC increased the probability of finding the 1100delC mutation [4]. Recent data suggest that premenopausal carriers of this variant have a 2-fold increased risk of developing a second BC (mostly contralateral) and a worse 10-year recurrencefree survival [5]. It has also been suggested a 10-fold increased risk for male BC for 1100delC carriers and that this mutation accounts for as much as 9% of all male BC in the population [2]. Although increased risk of prostate cancer has not been confirmed, some data suggest that risks of colon and lung cancer might be higher in female carriers between ages 20 and 50 years than non carriers [6]. Overall, these reports suggest that CHEK2 acts as a lowpenetrance tumour suppressor gene, and that it makes a significant contribution to familial clustering of BC, including families with only two affected relatives. In some populations, the variant has been identified in approximately 3–4% of young BC patients unselected for family history, and between 3% and 6% of non-BRCA1/2 BC families [2, 4, 7, 8]. Nevertheless, a wide variation in the frequency of 1100delC mutation in CHEK2 has been observed in different populations. The 1100delC mutation accounts for a part of BC susceptibility in populations from Northern Europe (Netherlands, Denmark, Finland, UK, Poland), and North America. But it does not seem to play a role in Ashkenazi Jewish families, and in some other countries, such as Australia, Italy and Spain, this association is not so clear [reviewed in 9]. Osorio et al. [10] did not find this mutation in 400 non-BRCA1/2 Spanish BC families, 56 patients with BC diagnosed before 40 years of age without family history, and 400 healthy individuals. The authors stated that its low penetrance and low frequency make this variant irrelevant for the clinical practice in our population. These results were confirmed by two other studies [11, 12]. Bellosillo et al. [11] studied the CHEK2 gene in 28 highrisk and 53 moderate-risk Spanish BC cases negative for BRCA1/2 mutations, and in none of them could the 1100delC mutation nor other variants previously described be detected. Sanchez de Abajo et al. [12] analysed 148 Hereditary non-Polyposis Colorectal Cancer (HNPCC) and 32 Hereditary Breast and Colon Cancer (HBCC) Spanish families and found that this variant was of no clinical relevance in this population. S. Gutierrez-Enriquez M. Baiget O. Diez (&) Servei de Genetica, Hospital de la Santa Creu i Sant Pau, Sant Antoni Maria Claret 167, Barcelona 08025, Spain e-mail: odiez@santpau.es