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MON-212 Genetic Spectrum Of A Canadian Cohort Of Sporadic Pheochromocytomas And Paragangliomas: Higher Prevalence Of Germline Mutations In PGL And NGS Assay With A Multigene Panel Increases The Mutation Rate
Background: Pheochromocytomas (PHEOs) and paragangliomas (PGLs) (PPGLs) are rare tumors with a high heritability. The prevalence of germline mutations in sporadic PPGLs varies depending of series. Objective: To determine the prevalence and spectrum of germline mutations in our cohort of patients wit...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7209502/ http://dx.doi.org/10.1210/jendso/bvaa046.453 |
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author | Salle, Stefanie Parisien-La Dumas, Nadine Jolin, Judith Nolet, Serge Lacroix, André Lévesque, Isabelle Burnichon, Nelly Gimenez-Roqueplo, Anne-Paule Bourdeau, Isabelle |
author_facet | Salle, Stefanie Parisien-La Dumas, Nadine Jolin, Judith Nolet, Serge Lacroix, André Lévesque, Isabelle Burnichon, Nelly Gimenez-Roqueplo, Anne-Paule Bourdeau, Isabelle |
author_sort | Salle, Stefanie Parisien-La |
collection | PubMed |
description | Background: Pheochromocytomas (PHEOs) and paragangliomas (PGLs) (PPGLs) are rare tumors with a high heritability. The prevalence of germline mutations in sporadic PPGLs varies depending of series. Objective: To determine the prevalence and spectrum of germline mutations in our cohort of patients with apparently sporadic PPGLs. Method: We retrospectively reviewed the charts of patients with sporadic pathology-confirmed PPGLs who underwent genetic testing after genetic counselling at our Quaternary center from 2005–2019. Genetic analysis included sequential gene sequencing by Sanger method from 2005–2014 (n = 89) and a multigene sequencing by NGS with a panel (14 susceptibility genes for PPGLs) from 2015–2019 (n = 34). Some patients underwent both (n = 12). Results: Among 230 patients that were treated for PPGLs from 2005- 2019, 135 patients underwent genetic testing (77 females; 58 males and 77.8% French Canadians). There were 60 PGLs (29 head and neck, 21 abdominal and 10 thoracic) and 75 PHEOs, 4 being bilateral. The prevalence of pathogenic germline mutations was 27.4% (37/135). Patients carrying a germline mutation were younger than patients with no mutations (40.7 yo (20 - 67) vs. 49.6 yo (11 - 80)) and had a higher prevalence of metastatic tumors (26.6% vs. 20.4%). The prevalence of germline mutations was 43.3% (26/60) in PGLs and 14.7% (11/75) in PHEOs. In the 26 mutated PGLs, there were 13 SDHC (50.0%), 6 SDHB (23.1%), 4 SDHD (15.4%), 2 SDHA (7.7%) and 1 FH (3.8%) mutations. The recurrent pathogenic SDHC c.397C>T (p.Arg133*) mutation was found in 12 out of the 13 SDHC mutations reflecting the presence of a funder effect in the French Canadian population. In the 11 mutated PHEOs, there were 3 MAX (27.3%), 3 VHL (27.3%), 2 RET (18.2%), 1 SDHB (9.1%), 1 NF1 (9.1%), 1 FH (9.1%) mutations. From 2015- 2019, we proposed NGS assay with the multigene panel to 12 patients (9 PHEOS and 3 PGLs) for whom the initial genetic test was negative. Novel germline mutations were found in 4 (33.3%) of these patients, representing 10.8% (4/37) of the mutation-carriers. Mutations were found in 2/9 PHEOs; a 28 yo female with bilateral PHEOs (MAX (deletion exon 1 and 2)) and a 33 yo male with malignant PHEO (MAX (c.3G>A)), and in 2/3 PGLs; a 31 yo woman with metastatic abdominal PGL (SDHA (c.985C>T) and a 59 yo woman with a thoracic PGL (SDHA (c.1432_1432 + 1del). Variants of uncertain significance (VUS) were identified in 7/60 PGLs (11.6%) and 5/75 PHEOs (6.7%) but the significance of these variants remains to be determined. Conclusion: In our cohort, the prevalence of germline mutations was of 44.3% in apparently sporadic PGLs and 14.7% in PHEOs. Genetic re-evaluation overtime using multigene sequencing by NGS assay in a subgroup of patients led to an increase of mutation rate in PHEOs and PGLs with the identification of germline MAX and SDHA mutations. |
format | Online Article Text |
id | pubmed-7209502 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-72095022020-05-13 MON-212 Genetic Spectrum Of A Canadian Cohort Of Sporadic Pheochromocytomas And Paragangliomas: Higher Prevalence Of Germline Mutations In PGL And NGS Assay With A Multigene Panel Increases The Mutation Rate Salle, Stefanie Parisien-La Dumas, Nadine Jolin, Judith Nolet, Serge Lacroix, André Lévesque, Isabelle Burnichon, Nelly Gimenez-Roqueplo, Anne-Paule Bourdeau, Isabelle J Endocr Soc Adrenal Background: Pheochromocytomas (PHEOs) and paragangliomas (PGLs) (PPGLs) are rare tumors with a high heritability. The prevalence of germline mutations in sporadic PPGLs varies depending of series. Objective: To determine the prevalence and spectrum of germline mutations in our cohort of patients with apparently sporadic PPGLs. Method: We retrospectively reviewed the charts of patients with sporadic pathology-confirmed PPGLs who underwent genetic testing after genetic counselling at our Quaternary center from 2005–2019. Genetic analysis included sequential gene sequencing by Sanger method from 2005–2014 (n = 89) and a multigene sequencing by NGS with a panel (14 susceptibility genes for PPGLs) from 2015–2019 (n = 34). Some patients underwent both (n = 12). Results: Among 230 patients that were treated for PPGLs from 2005- 2019, 135 patients underwent genetic testing (77 females; 58 males and 77.8% French Canadians). There were 60 PGLs (29 head and neck, 21 abdominal and 10 thoracic) and 75 PHEOs, 4 being bilateral. The prevalence of pathogenic germline mutations was 27.4% (37/135). Patients carrying a germline mutation were younger than patients with no mutations (40.7 yo (20 - 67) vs. 49.6 yo (11 - 80)) and had a higher prevalence of metastatic tumors (26.6% vs. 20.4%). The prevalence of germline mutations was 43.3% (26/60) in PGLs and 14.7% (11/75) in PHEOs. In the 26 mutated PGLs, there were 13 SDHC (50.0%), 6 SDHB (23.1%), 4 SDHD (15.4%), 2 SDHA (7.7%) and 1 FH (3.8%) mutations. The recurrent pathogenic SDHC c.397C>T (p.Arg133*) mutation was found in 12 out of the 13 SDHC mutations reflecting the presence of a funder effect in the French Canadian population. In the 11 mutated PHEOs, there were 3 MAX (27.3%), 3 VHL (27.3%), 2 RET (18.2%), 1 SDHB (9.1%), 1 NF1 (9.1%), 1 FH (9.1%) mutations. From 2015- 2019, we proposed NGS assay with the multigene panel to 12 patients (9 PHEOS and 3 PGLs) for whom the initial genetic test was negative. Novel germline mutations were found in 4 (33.3%) of these patients, representing 10.8% (4/37) of the mutation-carriers. Mutations were found in 2/9 PHEOs; a 28 yo female with bilateral PHEOs (MAX (deletion exon 1 and 2)) and a 33 yo male with malignant PHEO (MAX (c.3G>A)), and in 2/3 PGLs; a 31 yo woman with metastatic abdominal PGL (SDHA (c.985C>T) and a 59 yo woman with a thoracic PGL (SDHA (c.1432_1432 + 1del). Variants of uncertain significance (VUS) were identified in 7/60 PGLs (11.6%) and 5/75 PHEOs (6.7%) but the significance of these variants remains to be determined. Conclusion: In our cohort, the prevalence of germline mutations was of 44.3% in apparently sporadic PGLs and 14.7% in PHEOs. Genetic re-evaluation overtime using multigene sequencing by NGS assay in a subgroup of patients led to an increase of mutation rate in PHEOs and PGLs with the identification of germline MAX and SDHA mutations. Oxford University Press 2020-05-08 /pmc/articles/PMC7209502/ http://dx.doi.org/10.1210/jendso/bvaa046.453 Text en © Endocrine Society 2020. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Adrenal Salle, Stefanie Parisien-La Dumas, Nadine Jolin, Judith Nolet, Serge Lacroix, André Lévesque, Isabelle Burnichon, Nelly Gimenez-Roqueplo, Anne-Paule Bourdeau, Isabelle MON-212 Genetic Spectrum Of A Canadian Cohort Of Sporadic Pheochromocytomas And Paragangliomas: Higher Prevalence Of Germline Mutations In PGL And NGS Assay With A Multigene Panel Increases The Mutation Rate |
title | MON-212 Genetic Spectrum Of A Canadian Cohort Of Sporadic Pheochromocytomas And Paragangliomas: Higher Prevalence Of Germline Mutations In PGL And NGS Assay With A Multigene Panel Increases The Mutation Rate |
title_full | MON-212 Genetic Spectrum Of A Canadian Cohort Of Sporadic Pheochromocytomas And Paragangliomas: Higher Prevalence Of Germline Mutations In PGL And NGS Assay With A Multigene Panel Increases The Mutation Rate |
title_fullStr | MON-212 Genetic Spectrum Of A Canadian Cohort Of Sporadic Pheochromocytomas And Paragangliomas: Higher Prevalence Of Germline Mutations In PGL And NGS Assay With A Multigene Panel Increases The Mutation Rate |
title_full_unstemmed | MON-212 Genetic Spectrum Of A Canadian Cohort Of Sporadic Pheochromocytomas And Paragangliomas: Higher Prevalence Of Germline Mutations In PGL And NGS Assay With A Multigene Panel Increases The Mutation Rate |
title_short | MON-212 Genetic Spectrum Of A Canadian Cohort Of Sporadic Pheochromocytomas And Paragangliomas: Higher Prevalence Of Germline Mutations In PGL And NGS Assay With A Multigene Panel Increases The Mutation Rate |
title_sort | mon-212 genetic spectrum of a canadian cohort of sporadic pheochromocytomas and paragangliomas: higher prevalence of germline mutations in pgl and ngs assay with a multigene panel increases the mutation rate |
topic | Adrenal |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7209502/ http://dx.doi.org/10.1210/jendso/bvaa046.453 |
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