Detection rate and mutational landscape in extracranial arteriovenous malformations: a cohort study.
This study aimed to assess the detection rate and spectrum of pathogenic variants (PVs) and candidate variants (variants of uncertain significance, VUS) in AVM patients.
In this retrospective multicenter cohort study, tissue and blood samples were collected from 114 patients with extracranial AVMs during treatment or when clinically indicated, for dedicated molecular genetic analyses. PVs (solved) and VUS were detected by targeted sequencing on DNA using gene panels analyzing genes suspected to be associated with AVMs. Unsolved cases were further categorized into unrestricted and restricted, with the latter reflecting methodological limitations. Subgroup analyses were carried out based on affected genes to explore associated genotype-phenotype correlations.
PVs were identified in 80.7% (92/114) and VUS in 5.3% (6/114), resulting in a total detection rate of 86.0% (98/114). Unsolved cases accounted for 11.4% (13/114) including 6/13 (46.2%) with methodological restrictions. Somatic PVs were most frequent in KRAS (21.1%, 24/114), MAP2K1 (17.5%, 20/114), HRAS (8.8%, 10/114), and BRAF (7.9%, 9/114). Germline variants were found in RASA1 (7.0%, 8/114), PTEN (5.3%, 6/114), and EPHB4 (3.5%, 4/114). In a few cases, somatic variants in RASA1 (1.8%, 2/114) and PTEN (2.6%, 3/114) were identified. Additional PVs occurred in PIK3CA (3.5%, 4/114), SOS1 (2.6%, 3/114), GNAQ (1.8%, 2/114), and RIT1, RAF1, and GNA14 (each 0.9%, 1/114). Within the RAS/MAPK pathway, RAS variants (KRAS, HRAS) were linked to more severe clinical stages (65.6% vs. 40.0% MAP2K1 and 37.5% BRAF, p = 0.027) and higher relapse rates (55.6% vs. 43.8% MAP2K1 and 0% BRAF, p = 0.049). Germline variants showed a distinct distribution pattern with more syndromic presentations (61.1% vs. 15.6%, p < 0.001) compared to mosaic variants.
Broad and sensitive testing enables a high detection rate of causative variants in AVMs. PVs and VUS detected reveal a broader genetic spectrum than previously recognized. Somatic RAS PVs were associated with more advanced disease stages and higher relapse rates than MAP2K1 and BRAF variants, while germline variants were more frequently linked to syndromic patterns.
In this retrospective multicenter cohort study, tissue and blood samples were collected from 114 patients with extracranial AVMs during treatment or when clinically indicated, for dedicated molecular genetic analyses. PVs (solved) and VUS were detected by targeted sequencing on DNA using gene panels analyzing genes suspected to be associated with AVMs. Unsolved cases were further categorized into unrestricted and restricted, with the latter reflecting methodological limitations. Subgroup analyses were carried out based on affected genes to explore associated genotype-phenotype correlations.
PVs were identified in 80.7% (92/114) and VUS in 5.3% (6/114), resulting in a total detection rate of 86.0% (98/114). Unsolved cases accounted for 11.4% (13/114) including 6/13 (46.2%) with methodological restrictions. Somatic PVs were most frequent in KRAS (21.1%, 24/114), MAP2K1 (17.5%, 20/114), HRAS (8.8%, 10/114), and BRAF (7.9%, 9/114). Germline variants were found in RASA1 (7.0%, 8/114), PTEN (5.3%, 6/114), and EPHB4 (3.5%, 4/114). In a few cases, somatic variants in RASA1 (1.8%, 2/114) and PTEN (2.6%, 3/114) were identified. Additional PVs occurred in PIK3CA (3.5%, 4/114), SOS1 (2.6%, 3/114), GNAQ (1.8%, 2/114), and RIT1, RAF1, and GNA14 (each 0.9%, 1/114). Within the RAS/MAPK pathway, RAS variants (KRAS, HRAS) were linked to more severe clinical stages (65.6% vs. 40.0% MAP2K1 and 37.5% BRAF, p = 0.027) and higher relapse rates (55.6% vs. 43.8% MAP2K1 and 0% BRAF, p = 0.049). Germline variants showed a distinct distribution pattern with more syndromic presentations (61.1% vs. 15.6%, p < 0.001) compared to mosaic variants.
Broad and sensitive testing enables a high detection rate of causative variants in AVMs. PVs and VUS detected reveal a broader genetic spectrum than previously recognized. Somatic RAS PVs were associated with more advanced disease stages and higher relapse rates than MAP2K1 and BRAF variants, while germline variants were more frequently linked to syndromic patterns.
Authors
Schmidt Schmidt, Schanze Schanze, Brill Brill, Loeser Loeser, Uller Uller, Doppler Doppler, Cangir Cangir, Hengst Hengst, Vielsmeier Vielsmeier, Pech Pech, Obereisenbuchner Obereisenbuchner, Schirren Schirren, Sint Sint, Puhr-Westerheide Puhr-Westerheide, Deniz Deniz, Weiß Weiß, Häberle Häberle, Hartel Hartel, Fröba-Pohl Fröba-Pohl, Haehl Haehl, Holm Holm, Sporns Sporns, Scherf Scherf, Ricke Ricke, Lassmann Lassmann, Seidensticker Seidensticker, Wohlgemuth Wohlgemuth, Kimm Kimm, Zenker Zenker, Wildgruber Wildgruber, Kapp Kapp,
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