Journal of Pathology and Translational Medicine

Original Articles

Founder BRCA1 mutations in Nepalese population: Anurag Mehta, Himanshi Diwan, Garima Gupta, Shrinidhi Nathany, Shalini Agnihotri, Surender Dhanda; J Pathol Transl Med. 2022;56(4):212-216. Published online June 15, 2022; DOI: https://doi.org/10.4132/jptm.2022.05.02

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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 BRCA1 gene in the Nepalese people.
Methods
Germline BRCA 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 BRCA 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 BRCA1/2 variants. Twenty-seven of these 58 tested harbored pathogenic genetic alterations in BRCA1/2 genes, with 23 being BRCA1 mutant. Sixteen of 23 BRCA1 mutant cases shared one common pathogenic mutation c.2214_2215insT (p.Lys739Ter) (NM_007294.4). Additionally, a second highly recurrent mutation in BRCA1 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.

Citations

Citations to this article as recorded by

Finding significance: New perspectives in variant classification of the RAD51 regulators, BRCA2 and beyond
Hayley L. Rein, Kara A. Bernstein
DNA Repair.2023; 130: 103563. CrossRef
Digital PCR as a Highly Sensitive Diagnostic Tool: A Review
K. V. Kopylova, Ed. W. Kasparov, I. V. Marchenko, M. V. Smolnikova
Molecular Biology.2023; 57(5): 793. CrossRef
Digital PCR as a Highly Sensitive Diagnostic Tool: a Review
K. V. Kopylova, Ed. W. Kasparov, I. V. Marchenko, M. V. Smolnikova
Молекулярная биология.2023; 57(5): 771. CrossRef

Robust home brew fragment sizing assay for detection of MET exon 14 skipping mutation in non–small cell lung cancer patients in resource constrained community hospitals: Anurag Mehta, Shrinidhi Nathany, Aanchal Chopra, Sakshi Mattoo, Dushyant Kumar, Manoj Kumar Panigrahi; J Pathol Transl Med. 2021;55(5):324-329. Published online September 2, 2021; DOI: https://doi.org/10.4132/jptm.2021.07.15

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Abstract PDF

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.

Citations

Citations to this article as recorded by

MET: A narrative review of exon 14 skipping mutation in non-small-cell lung carcinoma
Shrinidhi Nathany, Ullas Batra
Cancer Research, Statistics, and Treatment.2022; 5(2): 284. CrossRef

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