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Anurag Mehta,Shrinidhi Nathany,Aanchal Chopra,Sakshi Mattoo,Dushyant Kumar,Manoj Kumar Panigrahi 대한병리학회 2021 Journal of Pathology and Translational Medicine Vol.55 No.5
Background: A mutation/deletion involving donor or acceptor sites for exon 14 results in splicing out of exon 14 of the mesenchymal epithelial transition (MET) gene and is known as “MET exon 14 skipping” (ΔMET14). The two recent approvals with substantial objective responses and improved progression-free survival to MET inhibitors namely capmatinib and tepotinib necessitate the identification of this alteration upfront. We herein describe our experience of ΔMET14 detection by an mRNA-based assay using polymerase chain reaction followed by fragment sizing. Methods: This is a home brew assay which was developed with the concept that the transcripts from true ΔMET14 will be shorter by ~140 bases than their wild type counterparts. The cases which were called MET exon 14 skipping positive on next-generation sequencing (NGS) were subjected to this assay, along with 13 healthy controls in order to establish the validity for true negatives. Results: Thirteen cases of ΔMET14 mutation were detected on NGS using RNA-based sequencing. Considering NGS as a gold standard, the sizing assay using both gel and capillary electrophoresis that showed 100% specificity for both with concordance rates of 84.6% and 88.2% with NGS, respectively, were obtained. Conclusions: Owing to the cost-effective nature and easy to use procedures, this assay will prove beneficial for small- and medium-sized laboratories where skilled technical personnel and NGS platforms are unavailable.
Founder <i>BRCA1</i> mutations in Nepalese population
Anurag Mehta,Himanshi Diwan,Garima Gupta,Shrinidhi Nathany,Shalini Agnihotri,Surender Dhanda 대한병리학회 2022 Journal of Pathology and Translational Medicine Vol.56 No.4
Background: Founder mutation is a heritable genetic alteration observed with high frequency in a geographically and culturally isolated population where one or more ancestors becomes the forebearer of the altered gene. The current study reports two founder mutations in the <i>BRCA1</i> gene in the Nepalese people.Methods: Germline <i>BRCA</i> testing in all surface epithelial ovarian cancers and the selected case of breast, prostate, and pancreatic cancers has been the standard practice from 2016 to 2021. One thousand one hundred thirtythree probands were screened for germline <i>BRCA</i> variants by next generation sequencing. The variants were classified as per the American Society of Medical Genetics and Genomics recommendations. Pathogenic (class V) and likely pathogenic (class IV) were considered clinically relevant and utilized for cascade screening.Results: Nepalese population made up a subcohort of 5.12% (58/1,133) of probands tested for germline <i>BRCA1/2</i> variants. Twenty-seven of these 58 tested harbored pathogenic genetic alterations in <i>BRCA1/2</i> genes, with 23 being <i>BRCA1</i> mutant. Sixteen of 23 <i>BRCA1</i> mutant cases shared one common pathogenic mutation c.2214_2215insT (p.Lys739Ter) (NM_007294.4). Additionally, a second highly recurrent mutation in <i>BRCA1</i> gene c.5068A>T (p.Lys1690Ter) (NM_007294.4) was noted in six patients from this population.Conclusions: The overwhelming abundance of the above two variants in a geographically confined population confers these two genetic alterations a status of founder mutations amongst the people of Nepal. A more extensive population-based study to reaffirm these findings will help establish a dual site-specific germline testing similar to the “Multisite-3-assay” in Ashkenazi Jews as the primary screening tool, especially in a resource-constrained environment.