BRCA1 founder mutations and beyond in the Polish population: A single-institution BRCA1/2 next-generation sequencing study
| Autor: | Joanna Kalisz, Pawel Macek, Janusz Kopczyński, Monika Siołek, Stanisław Góźdź, Sebastian Zięba, Jowita Furmańczyk, Ewelina Nowak-Ozimek, Jolanta Smok-Kalwat, Elżbieta Wypiórkiewicz, Beata Kozak-Klonowska, Artur Kowalik, Kamila Krawiec, Małgorzata Chłopek |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Heredity Genotyping Techniques Gene Identification and Analysis lcsh:Medicine 0302 clinical medicine Breast Tumors Medicine and Health Sciences lcsh:Science Frameshift Mutation Early Detection of Cancer Genetics Sanger sequencing education.field_of_study Multidisciplinary BRCA1 Protein Cancer Risk Factors High-Throughput Nucleotide Sequencing Nonsense Mutation Middle Aged Ovarian Cancer Oncology 030220 oncology & carcinogenesis symbols Female Research Article Adult Genetic counseling Genetic Causes of Cancer Population Breast Neoplasms Genetic Counseling Biology White People DNA sequencing 03 medical and health sciences symbols.namesake Breast cancer Diagnostic Medicine Breast Cancer Cancer Detection and Diagnosis medicine Humans Genetic Predisposition to Disease education Mutation Detection Genotyping Aged BRCA2 Protein lcsh:R Biology and Life Sciences Cancers and Neoplasms Cancer medicine.disease 030104 developmental biology Mutation lcsh:Q Poland Gynecological Tumors Asymptomatic carrier |
| Zdroj: | PLoS ONE PLoS ONE, Vol 13, Iss 7, p e0201086 (2018) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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