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
Bibliographic record
Abstract
Abstract 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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".