Tumor BRCA Testing in High Grade Serous Carcinoma: Mutation Rates and Optimal Tissue Requirements
Background: Approximately 25% of women diagnosed with tubo-ovarian high-grade serous carcinoma have germline deleterious mutations in <i>BRCA1</i> or <i>BRCA2</i>, characteristic of hereditary breast and ovarian cancer syndrome, while somatic mutations have been detected in 3...
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doaj-cd729762bd034c6f8f5053bc404894ef2020-11-25T04:00:26ZengMDPI AGCancers2072-66942020-11-01123468346810.3390/cancers12113468Tumor BRCA Testing in High Grade Serous Carcinoma: Mutation Rates and Optimal Tissue RequirementsGulisa Turashvili0Conxi Lazaro1Shengjie Ying2George Charames3Andrew Wong4Krista Hamilton5Denise Yee6Evangeline Agro7Martin Chang8Aaron Pollett9Jordan Lerner-Ellis10Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, ON M5G 1X5, CanadaDepartment of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, ON M5G 1X5, CanadaDepartment of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, ON M5G 1X5, CanadaDepartment of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, ON M5G 1X5, CanadaDepartment of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, ON M5G 1X5, CanadaDepartment of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, ON M5G 1X5, CanadaDepartment of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, ON M5G 1X5, CanadaDepartment of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, ON M5G 1X5, CanadaDepartment of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, ON M5G 1X5, CanadaDepartment of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, ON M5G 1X5, CanadaDepartment of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, ON M5G 1X5, CanadaBackground: Approximately 25% of women diagnosed with tubo-ovarian high-grade serous carcinoma have germline deleterious mutations in <i>BRCA1</i> or <i>BRCA2</i>, characteristic of hereditary breast and ovarian cancer syndrome, while somatic mutations have been detected in 3–7%. We set out to determine the BRCA mutation rates and optimal tissue requirements for tumor BRCA testing in patients diagnosed with tubo-ovarian high-grade serous carcinoma. Methods: Sequencing was performed using a multiplexed polymerase chain reaction-based approach on 291 tissue samples, with a minimum sequencing depth of 500X and an allele frequency of >5%. Results: There were 253 surgical samples (87%), 35 biopsies (12%) and 3 cytology cell blocks (1%). The initial failure rate was 9% (25/291), including 9 cases (3%) with insufficient tumor, and 16 (6%) with non-amplifiable DNA. Sequencing was successful in 78% (228/291) and deemed indeterminate due to failed exons or variants below the limit of detection in 13% (38/291). Repeat testing was successful in 67% (28/42) of retested samples, with an overall success rate of 86% (251/291). Clinically significant (pathogenic, likely pathogenic) variants were identified in 17% (48/276) of complete and indeterminate cases. Successful sequencing was dependent on sample type, tumor cellularity and size (<i>p</i> ≤ 0.001) but not on neoadjuvant chemotherapy or age of blocks (<i>p</i> > 0.05). Conclusions: Our study shows a 17% tumor BRCA mutation rate, with an overall success rate of 86%. Biopsy and cytology samples and post-chemotherapy specimens can be used for tumor <i>BRCA</i> testing, and optimal tumors measure ≥5 mm in size with at least 20% cellularity.https://www.mdpi.com/2072-6694/12/11/3468high-grade serous carcinomaBRCAtumor sequencingPARP inhibitors |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Gulisa Turashvili Conxi Lazaro Shengjie Ying George Charames Andrew Wong Krista Hamilton Denise Yee Evangeline Agro Martin Chang Aaron Pollett Jordan Lerner-Ellis |
spellingShingle |
Gulisa Turashvili Conxi Lazaro Shengjie Ying George Charames Andrew Wong Krista Hamilton Denise Yee Evangeline Agro Martin Chang Aaron Pollett Jordan Lerner-Ellis Tumor BRCA Testing in High Grade Serous Carcinoma: Mutation Rates and Optimal Tissue Requirements Cancers high-grade serous carcinoma BRCA tumor sequencing PARP inhibitors |
author_facet |
Gulisa Turashvili Conxi Lazaro Shengjie Ying George Charames Andrew Wong Krista Hamilton Denise Yee Evangeline Agro Martin Chang Aaron Pollett Jordan Lerner-Ellis |
author_sort |
Gulisa Turashvili |
title |
Tumor BRCA Testing in High Grade Serous Carcinoma: Mutation Rates and Optimal Tissue Requirements |
title_short |
Tumor BRCA Testing in High Grade Serous Carcinoma: Mutation Rates and Optimal Tissue Requirements |
title_full |
Tumor BRCA Testing in High Grade Serous Carcinoma: Mutation Rates and Optimal Tissue Requirements |
title_fullStr |
Tumor BRCA Testing in High Grade Serous Carcinoma: Mutation Rates and Optimal Tissue Requirements |
title_full_unstemmed |
Tumor BRCA Testing in High Grade Serous Carcinoma: Mutation Rates and Optimal Tissue Requirements |
title_sort |
tumor brca testing in high grade serous carcinoma: mutation rates and optimal tissue requirements |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2020-11-01 |
description |
Background: Approximately 25% of women diagnosed with tubo-ovarian high-grade serous carcinoma have germline deleterious mutations in <i>BRCA1</i> or <i>BRCA2</i>, characteristic of hereditary breast and ovarian cancer syndrome, while somatic mutations have been detected in 3–7%. We set out to determine the BRCA mutation rates and optimal tissue requirements for tumor BRCA testing in patients diagnosed with tubo-ovarian high-grade serous carcinoma. Methods: Sequencing was performed using a multiplexed polymerase chain reaction-based approach on 291 tissue samples, with a minimum sequencing depth of 500X and an allele frequency of >5%. Results: There were 253 surgical samples (87%), 35 biopsies (12%) and 3 cytology cell blocks (1%). The initial failure rate was 9% (25/291), including 9 cases (3%) with insufficient tumor, and 16 (6%) with non-amplifiable DNA. Sequencing was successful in 78% (228/291) and deemed indeterminate due to failed exons or variants below the limit of detection in 13% (38/291). Repeat testing was successful in 67% (28/42) of retested samples, with an overall success rate of 86% (251/291). Clinically significant (pathogenic, likely pathogenic) variants were identified in 17% (48/276) of complete and indeterminate cases. Successful sequencing was dependent on sample type, tumor cellularity and size (<i>p</i> ≤ 0.001) but not on neoadjuvant chemotherapy or age of blocks (<i>p</i> > 0.05). Conclusions: Our study shows a 17% tumor BRCA mutation rate, with an overall success rate of 86%. Biopsy and cytology samples and post-chemotherapy specimens can be used for tumor <i>BRCA</i> testing, and optimal tumors measure ≥5 mm in size with at least 20% cellularity. |
topic |
high-grade serous carcinoma BRCA tumor sequencing PARP inhibitors |
url |
https://www.mdpi.com/2072-6694/12/11/3468 |
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