High prevalence of BRCA1 stop mutation c.4183C>T in the Tyrolean population: implications for genetic testing

Abstract

Screening for founder mutations in BRCA1 and BRCA2 has been discussed as a cost-effective testing strategy in certain populations. In this study, comprehensive BRCA1 and BRCA2 testing was performed in a routine diagnostic setting. The prevalence of the BRCA1 stop mutation c. 4183C4T, p.(Gln1395Ter), was determined in unselected breast and ovarian cancer patients from different regions in the Tyrol. Cancer registry data were used to evaluate the impact of this mutation on regional cancer incidence. The mutation c.4183C4T was detected in 30.4% of hereditary BRCA1-associated breast and ovarian cancer patients in our cohort. It was also identified in 4.1% of unselected (26% of unselected triple negative) Tyrolean breast cancer patients and 6.8% of unselected ovarian cancer patients from the Lower Inn Valley (LIV) region. Cancer incidences showed a region-specific increase in age-stratified breast and ovarian cancer risk with standardized incidence ratios of 1.23 and 2.13, respectively. We, thus, report a Tyrolean BRCA1 founder mutation that correlates to a local increase in the breast and ovarian cancer risks. On the basis of its high prevalence, we suggest that targeted genetic analysis should be offered to all women with breast or ovarian cancer and ancestry from the LIV region. European Journal of Human Genetics (2016) 24, 258-262; doi:10.1038/ejhg.2015.108; published online 27 May 2015 INTRODUCTIONA central aim of preventive oncology is the identification of patients with a heritable predisposition to cancer. An estimated 1-7% of unselected breast cancer patients 1-4 and 6-17% of women with ovarian cancer 5,6 have hereditary breast and ovarian cancer (HBOC) disposition caused by variants in either BRCA1 or BRCA2 that confer a high risk of developing cancer. In agreement with a widely used terminology, such variants will be called mutations throughout this paper. Because of high costs, comprehensive molecular analyses for HBOC are usually restricted to individuals with a suggestive family history, young age, or several independent tumours. Tumour characteristics (triple-negative breast cancer; TNBC) are also used for the identification of patients with a high probability of carrying a BRCA mutation. 7,8 Reduced costs of novel sequencing methods and better knowledge of the clinical relevance of alterations in BRCA1 and BRCA2 will increase the number of individuals eligible for sequence analysis, although some selection process will still remain necessary in the foreseeable future. Identification of common founder mutations in certain ethnicities allows integration of genetic testing strategies in the routine care of all cancer patients. Here we report the identification of a highly prevalent BRCA1 founder mutation in a particular region of the Tyrol and consider the implications for a screening programme offered to all breast and ovarian cancer patients in this region.

Identification of recurrentBRCA1 mutation and its clinical relevance in Chinese Triple‐negative breast cancer cohort

“…Earlier studies with enormous cohorts have focused on the prevalence of BRCA1/2 mutations in different patient subgroups classified by race, ethnicity or geographical factors [18][19][20][21]. Other TNBC susceptibility genes such as BARD1 and CHEK2 were also detected at relatively high frequency [22,23] which concords with our findings (Table 2).…”