Using next-generation sequencing (NGS) platform to diagnose pathogenic germline BRCA1/2 mutations from archival tumor specimens.

Autor: Ong PY; Department of Haematology-Oncology, National University Cancer Institute, Singapore (NCIS), Singapore., Poon SL; ACT Genomics Co., Ltd., Tan KT; ACT Genomics Co., Ltd., Putti TC; Department of Pathology, National University Hospital, Singapore, Singapore., Ow SGW; Department of Haematology-Oncology, National University Cancer Institute, Singapore (NCIS), Singapore., Chen SJ; ACT Genomics Co., Ltd., Chen CH; ACT Genomics Co., Ltd., Lee SC; Department of Haematology-Oncology, National University Cancer Institute, Singapore (NCIS), Singapore; Cancer Science Institute, Singapore, Singapore. Electronic address: csilsc@nus.edu.sg.
Jazyk: angličtina
Zdroj: Gynecologic oncology [Gynecol Oncol] 2019 Nov; Vol. 155 (2), pp. 275-279. Date of Electronic Publication: 2019 Aug 31.
DOI: 10.1016/j.ygyno.2019.08.027
Abstrakt: Objective: Clinical genetic testing to diagnose germline mutations often requires blood sample or saliva smear from a cancer-affected individual. This rules out testing in families when cancer-affected individuals are deceased. We explored the use of a next-generation sequencing (NGS) platform to diagnose germline pathogenic mutations from tumors.
Methods: Archival tumors (ovarian = 26, breast = 25, others = 9) were retrieved from 60 cancer patients who have undergone multi-gene panel blood testing. Genomic DNA was extracted and sequenced for BRCA1/2 using a NGS platform. 41/60 specimens were sequenced for 5 other genes (APC, ATM, PALB2, PTEN, TP53). Tumor testing and results interpretation were performed blinded to the blood test result.
Results: All 38 patients with no BRCA1/2 mutations on blood testing were correctly tested negative on tumor. Tumor testing correctly diagnosed BRCA1/2 pathogenic mutations in 15/22 (68%) patients while in 7/22 (32%) patients, the mutation was either detected but incorrectly classified as VUS (n = 3) or not detected at all (n = 4). Overall concordance rate for tumor and blood testing for BRCA1/2 mutations was 88%, with 0% false positive and 32% false negative rate for pathogenic mutations. Tumor testing correctly diagnosed 1/2 pathogenic germline ATM mutation, 1/1 pathogenic germline PALB2 mutation and 2/2 pathogenic germline TP53 mutations. False positive germline mutations were diagnosed in 4 genes at a rate of 2.4%-10.3% (APC = 2.4%, PALB2 = 2.4%, PTEN = 4.9%, TP53 = 10.3%).
Conclusion: Tumor testing for BRCA1/2 germline mutations using an NGS platform is fairly reliable with no false positive findings, and correctly diagnosed more than two-thirds of pathogenic germline BRCA1/2 mutations. However, it is not reliable to diagnose pathogenic germline mutations in genes frequently mutated in sporadic cancers, such as PTEN and TP53.
(Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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