Local Laboratory Testing of Germline BRCA Mutations Vs. Myriad: a Single-Institution Experience in Korea

diagnostics Article Local Laboratory Testing of Germline BRCA Mutations vs. Myriad: A Single-Institution Experience in Korea Joohyun Hong 1 , Jiyun Lee 1, Minsuk Kwon 1, Ji-Yeon Kim 1, Jong-Won Kim 2 , Jin Seok Ahn 1, Young-Hyuck Im 1 and Yeon Hee Park 1,* 1 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; [email protected] (J.H.); [email protected] (J.L.); [email protected] (M.K.); [email protected] (J.-Y.K.); [email protected] (J.S.A.); [email protected] (Y.-H.I.) 2 Department of Laboratory Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; [email protected] * Correspondence: [email protected]; Tel.: +82-2-3410-1780 Abstract: Genetic diagnosis for human epidermal growth factor receptor 2-negative metastatic breast cancer patients with the germline BRCA (gBRCA) mutation has been emphasized since the development of polyadenosine diphosphate-ribose polymerase inhibitors. Myriad Genetics, Inc.’s (Salt Lake City, UT, USA) companion diagnostics service is almost exclusively used for genetic testing. The aim of this study was to compare the results of germline BRCA mutation tests returned by a local laboratory and those performed by Myriad. Between April 2014 and February 2018, 31 patients with gBRCA 1/2 mutation test results from both Samsung Medical Center (Seoul, Korea) and Myriad were enrolled. “Discordant: Opposite classification” was observed for only one among 27 (3.7%). Citation: Hong, J.; Lee, J.; Kwon, M.; This discrepancy was due to the detection of a deleterious large genomic rearrangement of BRCA 1 Kim, J.-Y.; Kim, J.-W.; Ahn, J.S.; Im, by Myriad. Samsung Medical Center performed multiple ligation-dependent probe amplifications Y.-H.; Park, Y.H. Local Laboratory Testing of Germline BRCA Mutations (MLPA) to detect large genomic rearrangements only in high-risk patients. This one case was not vs. Myriad: A Single-Institution suspected as high risk and MLPA was not performed. The concordant rate was 74.1% for all 27 Experience in Korea. Diagnostics 2021, patients. “Discordant: Laboratory’s uncertain classification” was found in 22.2% of the sample (six 11, 370. https://doi.org/10.3390/ patients). All discrepancies were generated during interpretation of BRCA 2 gene sequencing. Further diagnostics11020370 studies and standardization of genetic testing for BRCA 1/2 genes are required. Academic Editor: Mauro Keywords: breast carcinoma; genes; mutation G. Mastropasqua Received: 20 January 2021 Accepted: 20 February 2021 1. Introduction Published: 22 February 2021 Breast cancer is a leading cause of cancer and cancer-related death in women world- wide [1]. Breast cancer consists of various types of cancer. Although most breast cancer is Publisher’s Note: MDPI stays neutral sporadic, hereditary breast cancer comprises up to 10% of cases [2]. BRCA 1/2 genes are with regard to jurisdictional claims in tumor suppressor genes that contribute to DNA repair and protect DNA from damage [3]. published maps and institutional affil- iations. Mutated BRCA 1/2 genes are known to cause breast cancer. Carriers of germline BRCA 1 and germline BRCA 2 mutations have 65% and 45% chances of developing breast cancer by age 70, respectively [4]. Due to the number of breast cancer patients with germline BRCA (gBRCA) mutations, not only genetic risk assessment and counseling, but also specific treatments for breast cancer patients with gBRCA mutations, are increasingly Copyright: © 2021 by the authors. emphasized [5]. Licensee MDPI, Basel, Switzerland. Several new drugs have been invented through progress in oncogenomics. Olaparib This article is an open access article and talazoparib, polyadenosine diphosphate-ribose polymerase (PARP) inhibitors, are distributed under the terms and conditions of the Creative Commons associated with significant improvements of progression-free survival for patients with Attribution (CC BY) license (https:// gBRCA mutation human epidermal growth factor receptor 2 (HER2)-negative metastatic creativecommons.org/licenses/by/ breast cancer [6,7]. The PARP inhibitor successfully affects gBRCA mutation HER2-negative 4.0/). metastatic breast cancer by so-called synthetic lethality [8]. Such innovative development of Diagnostics 2021, 11, 370. https://doi.org/10.3390/diagnostics11020370 https://www.mdpi.com/journal/diagnostics Diagnostics 2021, 11, 370 2 of 10 PARP inhibitors has naturally increased the importance of companion diagnostics because gBRCA mutation positivity is necessary to administer these novel drugs. The gBRCA mutation test by Myriad Genetics, Inc. (Salt Lake City, UT, USA) is almost exclusively used as the sole accepted diagnostic test. A companion diagnostic (CDx) from Myriad, BRACAnalysis® CDx, characterizes the entire BRCA 1 and BRCA 2 genes. It utilizes the polymerase chain reaction (PCR) and Sanger sequencing, and the concordant rate is 100% when compared to next-generation sequencing [9]. In addition, large genomic rearrangements, such as deletions and duplications in BRCA 1 and BRCA 2 are detected using multiplex PCR. However, compared to gold standard microarray-based tests, the overall percentage agreement was 94% [9]. This suggests the apparent limitation of false negative results for the BRACAnalysis® CDx Large Rearrangement test. Variants discovered by this test are classified into one of five categories: deleterious mutation, suspected deleterious mutation, variant of uncertain significance, favor polymorphism and polymorphism. The Food and Drug Administration of the United States approved BRACAnalysis® CDx including Myriad’s classification process, considering that novel mutations are still being identified and classified. It is possible that deleterious mutations will change and be reclassified over time [9]. However, there has been criticism because Myriad held a patent for isolated BRCA 1/2 genes and utilized genomic data exclusively for their own profit [10]. After years of lawsuits, Myriad lost their patent on isolated BRCA 1/2 genes, and many other corporations were able to develop their own CDx for gBRCA mutations after 2013. However, the gBRCA mutation test developed by Myriad is still the most popularly used due to its high accuracy, the result of development using data accumulated over more than a decade [11]. Not only sequencing of genes, but also interpretations of sequencing results, are becoming more important because of conflicting interpretations of genetic variants [12–14]. In the era of PARP inhibitors such as olaparib and talazoparib to treat breast cancer, timely diagnosis of gBRCA mutations has become much more important. However, tests of gBRCA mutations by Myriad are more likely to be slower than those conducted by local laboratories because BRACAnalysis® CDx can only be performed on specific serial number-controlled instruments at Myriad and must be analyzed at the Myriad facility in Utah [9]. It is not easy to replace Myriad’s BRACAnalysis® CDx with local tests, because tests by individual laboratories lack reliability. To obtain timely diagnosis of gBRCA mutations, decrease costs associated with gBRCA mutation tests and successfully replace BRACAnalysis® CDx with local tests, the validation of local laboratory tests is mandatory. If such validation is successful, these tests could be used as widely as the human epidermal growth factor receptor 2 (HER2) test. Here, we analyzed data indicating gBRCA mutation status in a sample of 31 patients based on tests conducted by a single local laboratory and by Myriad Genetics. 2. Materials and Methods 2.1. Study Population Between April 2014 and February 2018, 31 patients (mean age, 41.8 years; range, 31–66 years) who underwent BRCA 1/2 gene mutation testing by both Myriad and the Samsung Medical Center (Seoul, Korea) were enrolled in the present study. The pathology of breast cancers was assessed by the Samsung Medical Center. All samples used for BRCA 1/2 gene mutation testing were whole blood. The samples were analyzed and interpreted by both Myriad and the Samsung Medical Center. Among them, we had full mutation test data for BRCA 1/2 genes from Myriad and the Samsung Medical Center for 27 patients. We had full mutation test data for BRCA 1/2 genes from Myriad but only BRCA 1 gene mutation test data from the Samsung Medical Center laboratory for two patients. The remaining two patients had full mutation test data for BRCA 1/2 genes from Myriad, but only BRCA 2 gene mutation data from the Samsung Medical Center laboratory (Figure1.). The latter four patients underwent either BRCA 1 or BRCA 2 gene mutation tests, respectively, for familial mutation studies. Diagnostics 2021, 11, x FOR PEER REVIEW 3 of 10 only BRCA 2 gene mutation data from the Samsung Medical Center laboratory (Figure 1.). Diagnostics 2021, 11The, 370 latter four patients underwent either BRCA 1 or BRCA 2 gene mutation tests, respec- 3 of 10 tively, for familial mutation studies. Figure 1. Study population. Figure 1. Study population. 2.2. Data Collection2.2. Data Collection The variables collectedThe variables in this collected study were in this the study following: were theage, following: sex, hormone age, receptor sex, hormone receptor status of breaststatus cancer of tissue, breast HER2 cancer and tissue, silver HER2 in situ and hybridization silver in situ hybridization(SISH) status, (SISH)BRCA status, BRCA 1/2 gene mutation1/2 gene test result mutation from test My resultriad and from

Load more