Abstract
Hereditary mutations in BRCA1/2 genes increase the risk of breast cancer by 60–80% and ovarian cancer by about 20–40% in female carriers. Detection of inherited mutations in asymptomatic carriers allows for the implementation of appropriate preventive measures. BRCA1/2 genotyping is also important for poly(adenosine diphosphate)-ribose polymerase (PARP) inhibitor administration. This work addresses the need for next-generation sequencing (NGS) technology for the detection of BRCA1/2 mutations in Poland where until recently mostly founder mutations have been tested, and whether BRCA diagnostics should be extended beyond the panel of founder mutations in this population. The study comprises 2931 patients who were referred for genetic counseling and tested for founder and recurrent mutations in BRCA1 (5382insC (c.5266dupC; p.Gln1756Profs), c.5370C>T (c.5251C>T; p.R1751*), 300T>G (c.181T>G; p.Cys61Gly), 185delAG (c.68_69delAG; p.Glu23Valfs), and 4153delA (c.4035delA; p.Glu1346Lysfs)) by high-resolution melting/Sanger sequencing. A total of 103 (3.5%) mutations were detected, including 53 (51%) in healthy subjects and 50 (49%) in cancer patients. Then, based on more stringent clinical and pedigree criteria, sequencing of all BRCA1/2 exons was performed in 454 (16%) patients without founder mutations by NGS, which detected 58 mutations (12.8%), 40 (8.8%) of which were pathogenic. In 14 (3.1%) subjects, variants of uncertain significance (VUS) were detected, and in four (0.9%) subjects, the detected mutations were benign. In total, 161 mutations were detected using our two-step algorithm (founder test and NGS), of which 64% were founder mutations, 25% were NGS-detected pathogenic mutations, 9% were VUS, and 2% were benign. In addition, 38 mutations not yet reported in the Polish population were detected. In total, founder mutations accounted for only 64% of all detected mutations, and the remaining mutations (36%) were dispersed across the BRCA1/2 gene sequences. Thus, in Poland, testing for constitutional mutations in BRCA1/2 should be carried out in two stages, where NGS is performed in qualifying subjects if founder mutations are not identified.
Highlights
Hereditary mutations in the BRCA1 and BRCA2 genes (BRCA1/2) increase the risk of female breast cancer by 60–80% and ovarian cancer by about 20–40% [1,2,3]
Healthy women who have first- or second-degree female relatives with breast/reproductive organ tumors, as follows: three relatives with breast cancers (BC), one diagnosed before age 50 (HBCss); one relative with BC diagnosed before age 40 or two relatives with BC, one of whom was diagnosed before age 50 (HBCsusp); three relatives with BC and/or ovarian cancer (OC) one diagnosed before age 50 (HBOCss); two relatives with BC and/or OC one diagnosed before age 50 (HBOCsusp); three relatives with OC, one diagnosed before age 50 (HOCss); two relatives with OC or one diagnosed before age 40 (HOCsusp), or a single case of BC/OC reported in the family
The observed steady increase in patients who qualified for genetic testing during the study period (2014–2016) is associated with increasing awareness among doctors and patients of regarding the role of genetic testing in oncology This increase in genetic testing correlates with the worldwide introduction of poly(adenosine diphosphate)-ribose polymerase (PARP) inhibitors for the treatment of cancers with mutations in BRCA1/2 [13]
Summary
Hereditary mutations in the BRCA1 and BRCA2 genes (BRCA1/2) increase the risk of female breast cancer by 60–80% and ovarian cancer by about 20–40% [1,2,3]. In Poland, until recently, BRCA mutation testing was limited to a few founder mutations [5, 6] This was mainly due to the relative homogeneity of the Polish population and the very high cost of sequencing of whole BRCA1/2 genes. The study of the whole spectrum of mutations in BRCA1/2 enables genetic counseling to be optimally implemented and enables the largest group of women at a high risk of developing BRCA1/2-related breast or ovarian cancer to be identified. It is important for the use of poly(adenosine diphosphate)-ribose polymerase (PARP) inhibitors, which are used for the treatment of certain BRCA1/2-mutated cancers [13]. There are many practical recommendations in the literature on how VUS should be dealt with clinically [14]
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