Journal of Pathology and Translational Medicine

Original Article

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

Case Study

TTF1-positive SMARCA4/BRG1 deficient lung adenocarcinoma: Anurag Mehta, Himanshi Diwan, Divya Bansal, Manoj Gupta; J Pathol Transl Med. 2022;56(1):53-56. Published online November 16, 2021; DOI: https://doi.org/10.4132/jptm.2021.09.16

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Abstract PDF

SMARCA4/BRG1-deficient lung adenocarcinoma (SD-LUAD) is being recognized as a distinct subtype based on subtle differences in its clinical, morphological, and immunophenotypic attributes compared to other non–small cell lung carcinomas. We present here a case of SD-LUAD with curious thyroid transcription factor 1 (TTF1) expression in a morphologically heterogenous lung adenocarcinoma. The better differentiated area showed preservation of TTF1 expression, and a poorly differentiated tumor had loss of TTF1 expression with universal BRG1 loss.

Citations

Citations to this article as recorded by

One Case of Non-Small Cell Lung Cancer with SMARCA4 Deletion Was Reported
允龙宋
Medical Diagnosis.2024; 14(01): 137. CrossRef
Delineation of a SMARCA4-specific competing endogenous RNA network and its function in hepatocellular carcinoma
Lei Zhang, Ting Sun, Xiao-Ye Wu, Fa-Ming Fei, Zhen-Zhen Gao
World Journal of Clinical Cases.2022; 10(29): 10501. CrossRef
Novel germline SMARCA4 mutation in Small Cell Carcinoma of the Ovary, Hypercalcemic Type
Anurag Mehta, Himanshi Diwan, Diksha Karki, Divya Bansal, Meenakshi Kamboj, Anila Sharma, Shrinidhi Nathany, Sakshi Mattoo, Dushyant Kumar
Current Problems in Cancer: Case Reports.2022; 8: 100205. CrossRef

Original Articles

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

SMARCA4/BRG1 protein-deficient thoracic tumors dictate re-examination of small biopsy reporting in non–small cell lung cancer: Anurag Mehta, Divya Bansal, Rupal Tripathi, Ankush Jajodia; J Pathol Transl Med. 2021;55(5):307-316. Published online June 21, 2021; DOI: https://doi.org/10.4132/jptm.2021.05.11

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Abstract PDF

Background
SMARCA4/BRG1 protein–deficient lung adenocarcinomas and thoracic sarcoma are recently described entities that lack distinctive histological features, transcription termination factor 1 (TTF1) reactivity, and actionable driver mutations. The current diagnostic path for small lung biopsies as recommended by the World Health Organization (WHO, 2015) is likely to categorize these as non– small cell carcinoma–not otherwise specified (NSCC-NOS). The present study attempts to define the subtle but distinctive clinicopathologic features of SMARCA4/BRG1 protein-deficient thoracic tumors; highlight their unique biology; and addresses the unmet need to segregate these using a new, tissue-proficient diagnostic pathway.
Methods
All lung biopsies and those from metastatic sites in patients with suspected advanced lung cancer and classified as NSCC-NOS as per WHO (2015) guidelines were subjected to BRG1 testing by immunohistochemistry. SMARCA4/BRG1 protein–deficient thoracic tumors were evaluated by an extended immunohistochemistry panel. Predictive biomarker and programmed death–ligand 1 testing was conducted in all cases.
Results
Of 110 cases, nine were found to be SMARCA4/BRG1 protein-deficient; six were identified as SMARCA4/BRG1 protein–deficient lung adenocarcinomas, and three were SMARCA4/BRG1 protein-deficient thoracic sarcomas. The histology ranged from poorly differentiated to undifferentiated to rhabdoid. None of the cases showed significant expression of TTF1 or p40, and no actionable mutation was identified.
Conclusions
It is difficult to separate BRG1-deficient lung adenocarcinomas and thoracic sarcomas based on morphology alone. We propose a diagnostic pathway for small biopsies of thoracic tumors to segregate these distinct entities so that they can be studied more efficaciously for new biomarkers and therapeutic options.

Citations

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Case report: The first account of undifferentiated sarcoma with epithelioid features originating in the pleura
Ling-Xi Xiao, Li Liu, Wang Deng
Frontiers in Medicine.2024;[Epub] CrossRef
Chemotherapy and Immune Checkpoint Inhibitors in a Case of SMARCA4-dUT: A Case Report and Review of Literature
Akriti Pokhrel, Ruchi Yadav, Kapil Kumar Manvar, Richard Wu, Vijay Jaswani, Carrie Brooke Wasserman, Jen C. Wang
Journal of Investigative Medicine High Impact Case Reports.2023; 11: 232470962311762. CrossRef
TTF1-positive SMARCA4/BRG1 deficient lung adenocarcinoma
Anurag Mehta, Himanshi Diwan, Divya Bansal, Manoj Gupta
Journal of Pathology and Translational Medicine.2022; 56(1): 53. CrossRef
Delineation of a SMARCA4-specific competing endogenous RNA network and its function in hepatocellular carcinoma
Lei Zhang, Ting Sun, Xiao-Ye Wu, Fa-Ming Fei, Zhen-Zhen Gao
World Journal of Clinical Cases.2022; 10(29): 10501. CrossRef
Artificial intelligence platform, RADR®, aids in the discovery of DNA damaging agent for the ultra-rare cancer Atypical Teratoid Rhabdoid Tumors
Joseph McDermott, Drew Sturtevant, Umesh Kathad, Sudhir Varma, Jianli Zhou, Aditya Kulkarni, Neha Biyani, Caleb Schimke, William C. Reinhold, Fathi Elloumi, Peter Carr, Yves Pommier, Kishor Bhatia
Frontiers in Drug Discovery.2022;[Epub] CrossRef

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