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Pregled bibliografske jedinice broj: 1042763

Association of inherited pathogenic variants in checkpoint kinase 2 (CHEK2) with susceptibility to testicular germ cell tumors


(Regeneron Genetics Center (RGC) Research Team) AlDubayan, Saud H.; Pyle, Louise C.; Gamulin, Marija; Kuliš, Tomislav; Moore, Nathanael D.; Taylor-Weiner, Amaro; Hamid, Anis A.; Reardon, Brendan; Wubbenhorst, Bradley; Godse, Rama et al.
Association of inherited pathogenic variants in checkpoint kinase 2 (CHEK2) with susceptibility to testicular germ cell tumors // JAMA oncology, 5 (2019), 4; 514-522 doi:10.1001/jamaoncol.2018.6477 (međunarodna recenzija, članak, ostalo)


CROSBI ID: 1042763 Za ispravke kontaktirajte CROSBI podršku putem web obrasca

Naslov
Association of inherited pathogenic variants in checkpoint kinase 2 (CHEK2) with susceptibility to testicular germ cell tumors

Autori
AlDubayan, Saud H. ; Pyle, Louise C. ; Gamulin, Marija ; Kuliš, Tomislav ; Moore, Nathanael D. ; Taylor-Weiner, Amaro ; Hamid, Anis A. ; Reardon, Brendan ; Wubbenhorst, Bradley ; Godse, Rama ; Vaughn, David J. ; Jacobs, Linda A. ; Meien, Stefanie ; Grgić, Mislav ; Kaštelan, Željko ; Markt, Sarah C. ; Damrauer, Scott M. ; Rader, Daniel J. ; Kember, Rachel L. ; Loud, Jennifer T. ; Kanetsky, Peter A. ; Greene, Mark H. ; Sweeney, Christopher J. ; Kubisch, Christian ; Nathanson, Katherine L. ; Van Allen, Eliezer M. ; Stewart, Douglas R. ; Lessel, Davor

Kolaboracija
Regeneron Genetics Center (RGC) Research Team

Izvornik
JAMA oncology (2374-2437) 5 (2019), 4; 514-522

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, ostalo

Ključne riječi
cancer-susceptibility ; i157t variant ; phosphorylation ; metaanalysis ; contribute ; activation ; mutations ; protein ; loci ; gene

Sažetak
IMPORTANCE Approximately 50% of the risk for the development of testicular germ cell tumors (TGCTs) is estimated to be heritable, but no mendelian TGCT predisposition genes have yet been identified. It is hypothesized that inherited pathogenic DNA repair gene (DRG) alterations may drive susceptibility to TGCTs. OBJECTIVE To systematically evaluate the enrichment of germline pathogenic variants in the mendelian cancer predisposition DRGs in patients with TGCTs vs healthy controls. DESIGN, SETTING, AND PARTICIPANTS A case-control enrichment analysis was performed from January 2016 to May 2018 to screen for 48 DRGs in 205 unselected men with TGCT and 27 173 ancestry-matched cancer-free individuals from the Exome Aggregation Consortium cohort in the discovery stage. Significant findings were selectively replicated in independent cohorts of 448 unselected men with TGCTs and 442 population-matched controls, as well as 231 high-risk men with TGCTs and 3090 ancestry-matched controls. Statistical analysis took place from January to May 2018. MAIN OUTCOMES AND MEASURES Gene-level enrichment analysis of germline pathogenic variants in individuals with TGCTs relative to cancer-free controls. RESULTS Among 205 unselected men with TGCTs (mean [SD] age, 33.04 [9.67] years), 22 pathogenic germline DRG variants, one-third of which were in CHEK2 (OMIM 604373), were identified in 20 men (9.8% ; 95% CI, 6.1%-14.7%). Unselected men with TGCTs were approximately 4 times more likely to carry germline loss-of-function CHEK2 variants compared with cancer-free individuals from the Exome Aggregation Consortium cohort (odds ratio [OR], 3.87 ; 95% CI, 1.65-8.86 ; nominal P = .006 ; q = 0.018). Similar enrichment was also seen in an independent cohort of 448 unselected Croatian men with TGCTs (mean [SD] age, 31.98 [8.11] years) vs 442 unselected Croatian men without TGCTs (at least 50 years of age at time of sample collection) (OR, >1.4 ; P = .03) and 231 high-risk men with TGCTs (mean [SD] age, 31.54 [9.24] years) vs 3090 men (all older than 50 years) from the Penn Medicine Biobank (OR, 6.30 ; 95% CI, 2.34-17.31 ; P = .001). The low-penetrance CHEK2 variant (p.Ile157Thr) was found to be a Croatian founder TGCT risk variant (OR, 3.93 ; 95% CI, 1.53-9.95 ; P = .002). Individuals with the pathogenic CHEK2 loss-of-function variants developed TGCTs 6 years earlier than individuals with CHEK2 wild-type alleles (5.95 years ; 95% CI, 1.48-10.42 ; P = .009). CONCLUSIONS AND RELEVANCE This multicenter case-control analysis of men with or without TGCTs provides evidence for CHEK2 as a novel moderate-penetrance TGCT susceptibility gene, with potential clinical utility. In addition to highlighting DNA-repair deficiency as a potential mechanism driving TGCT susceptibility, this analysis also provides new avenues to explore management strategies and biological investigations for high-risk individuals.

Izvorni jezik
Engleski

Znanstvena područja
Kliničke medicinske znanosti



POVEZANOST RADA


Ustanove:
Medicinski fakultet, Zagreb,
Klinički bolnički centar Zagreb

Profili:

Avatar Url Tomislav Kuliš (autor)

Avatar Url Željko Kaštelan (autor)

Avatar Url Marija Gamulin (autor)

Poveznice na cjeloviti tekst rada:

doi jamanetwork.com

Citiraj ovu publikaciju:

(Regeneron Genetics Center (RGC) Research Team) AlDubayan, Saud H.; Pyle, Louise C.; Gamulin, Marija; Kuliš, Tomislav; Moore, Nathanael D.; Taylor-Weiner, Amaro; Hamid, Anis A.; Reardon, Brendan; Wubbenhorst, Bradley; Godse, Rama et al.
Association of inherited pathogenic variants in checkpoint kinase 2 (CHEK2) with susceptibility to testicular germ cell tumors // JAMA oncology, 5 (2019), 4; 514-522 doi:10.1001/jamaoncol.2018.6477 (međunarodna recenzija, članak, ostalo)
(Regeneron Genetics Center (RGC) Research Team) (Regeneron Genetics Center (RGC) Research Team) AlDubayan, S., Pyle, L., Gamulin, M., Kuliš, T., Moore, N., Taylor-Weiner, A., Hamid, A., Reardon, B., Wubbenhorst, B. & Godse, R. (2019) Association of inherited pathogenic variants in checkpoint kinase 2 (CHEK2) with susceptibility to testicular germ cell tumors. JAMA oncology, 5 (4), 514-522 doi:10.1001/jamaoncol.2018.6477.
@article{article, author = {AlDubayan, Saud H. and Pyle, Louise C. and Gamulin, Marija and Kuli\v{s}, Tomislav and Moore, Nathanael D. and Taylor-Weiner, Amaro and Hamid, Anis A. and Reardon, Brendan and Wubbenhorst, Bradley and Godse, Rama and Vaughn, David J. and Jacobs, Linda A. and Meien, Stefanie and Grgi\'{c}, Mislav and Ka\v{s}telan, \v{Z}eljko and Markt, Sarah C. and Damrauer, Scott M. and Rader, Daniel J. and Kember, Rachel L. and Loud, Jennifer T. and Kanetsky, Peter A. and Greene, Mark H. and Sweeney, Christopher J. and Kubisch, Christian and Nathanson, Katherine L. and Van Allen, Eliezer M. and Stewart, Douglas R. and Lessel, Davor}, year = {2019}, pages = {514-522}, DOI = {10.1001/jamaoncol.2018.6477}, keywords = {cancer-susceptibility, i157t variant, phosphorylation, metaanalysis, contribute, activation, mutations, protein, loci, gene}, journal = {JAMA oncology}, doi = {10.1001/jamaoncol.2018.6477}, volume = {5}, number = {4}, issn = {2374-2437}, title = {Association of inherited pathogenic variants in checkpoint kinase 2 (CHEK2) with susceptibility to testicular germ cell tumors}, keyword = {cancer-susceptibility, i157t variant, phosphorylation, metaanalysis, contribute, activation, mutations, protein, loci, gene} }
@article{article, author = {AlDubayan, Saud H. and Pyle, Louise C. and Gamulin, Marija and Kuli\v{s}, Tomislav and Moore, Nathanael D. and Taylor-Weiner, Amaro and Hamid, Anis A. and Reardon, Brendan and Wubbenhorst, Bradley and Godse, Rama and Vaughn, David J. and Jacobs, Linda A. and Meien, Stefanie and Grgi\'{c}, Mislav and Ka\v{s}telan, \v{Z}eljko and Markt, Sarah C. and Damrauer, Scott M. and Rader, Daniel J. and Kember, Rachel L. and Loud, Jennifer T. and Kanetsky, Peter A. and Greene, Mark H. and Sweeney, Christopher J. and Kubisch, Christian and Nathanson, Katherine L. and Van Allen, Eliezer M. and Stewart, Douglas R. and Lessel, Davor}, year = {2019}, pages = {514-522}, DOI = {10.1001/jamaoncol.2018.6477}, keywords = {cancer-susceptibility, i157t variant, phosphorylation, metaanalysis, contribute, activation, mutations, protein, loci, gene}, journal = {JAMA oncology}, doi = {10.1001/jamaoncol.2018.6477}, volume = {5}, number = {4}, issn = {2374-2437}, title = {Association of inherited pathogenic variants in checkpoint kinase 2 (CHEK2) with susceptibility to testicular germ cell tumors}, keyword = {cancer-susceptibility, i157t variant, phosphorylation, metaanalysis, contribute, activation, mutations, protein, loci, gene} }

Časopis indeksira:


  • Current Contents Connect (CCC)
  • Web of Science Core Collection (WoSCC)
    • Science Citation Index Expanded (SCI-EXP)
    • SCI-EXP, SSCI i/ili A&HCI
  • Scopus
  • MEDLINE


Citati:





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