Novel germline mutations in DNA damage repair in patients with malignant pleural mesotheliomas Journal Article
| Authors: | Guo, R.; DuBoff, M.; Jayakumaran, G.; Kris, M. G.; Ladanyi, M.; Robson, M. E.; Mandelker, D.; Zauderer, M. G. |
| Article Title: | Novel germline mutations in DNA damage repair in patients with malignant pleural mesotheliomas |
| Abstract: | Introduction: Although next-generation sequencing (NGS) has brought insight into critical mutations or pathways (e.g., DNA damage sensing and repair) involved in the etiology of many cancers and has directed new screening, prevention, and therapeutic approaches for patients and families, it has only recently been used in malignant pleural mesotheliomas (MPMs). Methods: We analyzed the blood samples from patients with MPM using the NGS platform MSK-IMPACT to explore cancer-predisposing genes. The loss-of-function variants or pathogenic entries were identified, and clinicopathologic information was collected. Results: Of 84 patients with MPM, 12% (10 of 84) had pathogenic variants. Clinical characteristics were similar between cohorts, although patients with germline pathogenic variants were more likely to have more than two first-degree family members with cancer than those without germline mutations (40% versus 12%; Fisher's exact test, p < 0.05). Novel, deleterious variants in mesotheliomas included MutS homolog 3 (1% [one of 84]; 95% confidence interval [CI]: 0%–7%), breast cancer gene 1-associated ring domain 1 (1% [one of 84]; 95% CI: 0%–7%), and RecQ-like helicase 4 (2% [two of 84]; 95% CI: 0%–9%). Pathogenic variants previously reported on germline testing in patients with mesotheliomas were breast cancer gene 1-associated protein 1 (4% [three of 84]; 95% CI: 1%–10%), breast cancer gene 2 (1% [one of 84]; 95% CI: 0%–7%), and MRE11 homolog, double strand break repair nuclease (1% [one of 84]; 95% CI: 0%–7%). One patient (1% [one of 84]; 95% CI: 0%–7%) had a likely pathogenic alteration in SHQ1, H/ACA ribonucleoprotein assembly factor that has not been associated with a heritable susceptibility to cancer. Conclusions: Our study lends further support for the role of aberrations in DNA damage repair genes in the pathogenesis of MPMs and suggests that targeting the members of these pathways for screening and treatment warrants further study. © 2019 International Association for the Study of Lung Cancer |
| Keywords: | adult; controlled study; human tissue; aged; human cell; major clinical study; gene deletion; clinical feature; histopathology; pathogenesis; cancer patient; cancer staging; dna damage; gene; dna repair; cohort analysis; smoking; biomarker; gene identification; pleura mesothelioma; mesothelioma; loss of function mutation; genetic testing; asbestos; germline mutation; bap1 gene; brca2 gene; recql4 gene; high throughput sequencing; second-degree relative; human; male; female; priority journal; article; mre11a gene; shq1 gene; double strand break repair protein mre11; bard1 gene; msh3 gene |
| Journal Title: | Journal of Thoracic Oncology |
| Volume: | 15 |
| Issue: | 4 |
| ISSN: | 1556-0864 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2020-04-01 |
| Start Page: | 655 |
| End Page: | 660 |
| Language: | English |
| DOI: | 10.1016/j.jtho.2019.12.111 |
| PUBMED: | 31887429 |
| PROVIDER: | scopus |
| PMCID: | PMC7526793 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 April 2020 -- Source: Scopus |
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