ORIGINAL ARTICLE
Somatic mutations in BRCA1&2 in 201 unselected ovarian carcinoma samples – single institution study
1
Department of Molecular Diagnostics, Holycross Cancer Centre, Kielce, Poland
2
Department of Gynecologic Oncology, Holycross Cancer Center, Kielce, Poland
3
Chair and Department of Obstetrics, Gynecology and Oncology, 2nd Faculty of Medicine, Warsaw Medical University, Poland
4
Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Institute – Oncology Center,
Warsaw, Poland
5
Department of Surgical Pathology, Holycross Cancer Centre, Kielce, Poland
6
Genetic Clinic, Holycross Cancer Centre, Kielce, Poland
7
The Faculty of Mathematics and Natural Sciences, Jan Kochanowski University, Kielce, Poland
8
Clinical Oncology, Holycross Cancer Centre, Kielce, Poland
9
The Faculty of Health Sciences, Jan Kochanowski University, Kielce, Poland
Submission date: 2019-02-06
Acceptance date: 2019-03-10
Publication date: 2019-02-25
Pol J Pathol 2019;70(2):115-126
KEYWORDS
TOPICS
ABSTRACT
Ovarian cancer (OC) is the most lethal among gynecologic malignancies worldwide. Unfortunately, in around 70% of cases cancer is diagnosed in late stages (III-IV) which decreases the 5-year survival rate to 25%. The standard of care in ovarian cancer is debulking surgery followed by chemotherapy regimens based on platinum salts. Since 2014 PARP inhibitors became available for OC patients with germline or/and somatic mutations in BRCA1/2, including maintenance therapy. BRCA1/2 Next Generation Sequencing (NGS)-based analysis of formalin-fixed paraffin-embedded (FFPE) ovarian cancer samples becomes the standard of care. The aim of the present study was to evaluate the frequency of mutations in 201 unselected ovarian cancer tissues using the NGS method. In total, pathogenic mutations in both genes were detected in 24% (49/201) of the ovarian cancer cases tested. For 41 patients the results of testing of DNA isolated from blood sample revealed that 17% (35/201) mutations were germline origin, whereas 3% (6/201) mutations were somatic. In 4% (8/201) cases blood sample was inaccessible. The presence of pathogenic mutations was correlated with younger age at diagnosis and serous subtype. Close cooperation between many specialists (gynecologist, pathologist, oncologist, clinical genetics and molecular biologist) is indispensable for efficient and on-time BRCA1/2 ovarian tumor tissue testing.
REFERENCES (26)
1.
Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015; 65: 87-108.
2.
Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 2013; 49: 1374-1403.
3.
Narod S. Can advanced-stage ovarian cancer be cured? Nat Rev Clin Oncol 2016; 13: 255-261.
4.
Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2014; 15: 852-861.
5.
Alsop K, Fereday S, Meldrum C, et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol 2012; 30: 2654-2663.
6.
Pennington KP, Walsh T, Harrell MI, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res 2014; 20: 764-775.
7.
Górski B, Jakubowska A, Huzarski T, et al. A high proportion of founder BRCA1 mutations in Polish breast cancer families. Int J Cancer 2004; 110: 683-686.
8.
Szwiec M, Jakubowska A, Górski B, et al. Recurrent mutations of BRCA1 and BRCA2 in Poland: an update. Clin Genet 2015; 87: 288-292.
9.
Kowalik A, Siolek M, Kopczynski J, et al. BRCA1 founder mutations and beyond in the Polish population: A single-institution BRCA1/2 next-generation sequencing study. PLoS One 2018; 13: e0201086.
10.
Ratajska M, Krygier M, Stukan M, et al. Mutational analysis of BRCA1/2 in a group of 134 consecutive ovarian cancer patients. Novel and recurrent BRCA1/2 alterations detected by next generation sequencing. J Appl Genet 2015; 56: 193-198.
11.
Wojcik P, Jasiowka M, Strycharz E, et al. Recurrent mutations of BRCA1, BRCA2 and PALB2 in the population of breast and ovarian cancer patients in Southern Poland. Hered Cancer Clin Pract 2016; 14: 5.
12.
Koczkowska M, Krawczynska N, Stukan M, et al. Spectrum and Prevalence of Pathogenic Variants in Ovarian Cancer Susceptibility Genes in a Group of 333 Patients. Cancers (Basel) 2018; 10: pii: E442.
13.
Koczkowska M, Zuk M, Gorczynski A, et al. Detection of somatic BRCA1/2 mutations in ovarian cancer – next-generation sequencing analysis of 100 cases. Cancer Med 2016; 5: 1640-1646.
14.
Weren RD, Mensenkamp AR, Simons M, et al. Novel BRCA1 and BRCA2 Tumor Test as Basis for Treatment Decisions and Referral for Genetic Counselling of Patients with Ovarian Carcinomas. Hum Mutat 2017; 38: 226-235.
15.
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17: 405-424.
16.
Eccles DM, Mitchell G, Monteiro AN, et al. BRCA1 and BRCA2 genetic testing-pitfalls and recommendations for managing variants of uncertain clinical significance. Ann Oncol 2015; 26: 2057-2065.
17.
Kopanos C, Tsiolkas V, Kouris A, et al. VarSome: The Human Genomic Variant Search Engine. Bioinformatics 2018; doi: 10.1093/bioinformatics/bty897.
18.
Dougherty BA, Lai Z, Hodgson DR, et al. Biological and clinical evidence for somatic mutations in BRCA1 and BRCA2 as predictive markers for olaparib response in high-grade serous ovarian cancers in the maintenance setting. Oncotarget 2017; 8: 43653-43661.
19.
Moore K, Colombo N, Scambia G, et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med 2018; 379: 2495-2505.
20.
Do H, Dobrovic A. Sequence artifacts in DNA from formalin-fixed tissues: causes and strategies for minimization. Clin Chem 2015; 61: 64-71.
21.
Ellison G, Huang S, Carr H, et al. A reliable method for the detection of BRCA1 and BRCA2 mutations in fixed tumour tissue utilising multiplex PCR-based targeted next generation sequencing. BMC Clin Pathol 2015; 15: 5.
22.
Ellison G, Ahdesmaki M, Luke S, et al. An evaluation of the challenges to developing tumor BRCA1 and BRCA2 testing methodologies for clinical practice. Hum Mutat 2018; 39: 394-405.
23.
Chao A, Chang TC, Lapke N, et al. Prevalence and clinical significance of BRCA1/2 germline and somatic mutations in Taiwanese patients with ovarian cancer. Oncotarget 2016; 7: 85529-85541.
24.
Mafficini A, Simbolo M, Parisi A, et al. BRCA somatic and germline mutation detection in paraffin embedded ovarian cancers by next-generation sequencing. Oncotarget 2016; 7: 1076-1083.
25.
Teer JK, Yoder S, Gjyshi A, et al. Mutational heterogeneity in non-serous ovarian cancers. Sci Rep 2017; 7: 9728.
26.
Ratajska M, Brozek I, Senkus-Konefka E, et al. BRCA1 and BRCA2 point mutations and large rearrangements in breast and ovarian cancer families in Northern Poland. Oncol Rep 2008; 19: 263-268.
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