High Prevalence of Developmental Venous Anomaly in Diffuse Intrinsic Pontine Gliomas: A Pediatric Control Study

Roux, Alexandre; Boddaert, Nathalie; Grill, Jacques; Castel, David; Zanello, Marc; Zah‐Bi, Gilles; Chrétien, Fabrice; Lefevre, Etienne; Dangouloff‐Ros, Volodia; Zérah, Michel; Puget, Stéphanie; Pallud, Johan; Varlet, Pascale

doi:10.1093/neuros/nyz298

Cited by 15 publications

(6 citation statements)

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“…We found a higher rate of midbrain involvement in AYA cases (80%) than in a previous report based on children (55.2%). 40 We found a decreasing frequency of DIPG H3K27-mutants 1198 Roux et al High-grade gliomas in adolescents and young adults…”

Section: Discussionmentioning

confidence: 61%

High-grade gliomas in adolescents and young adults highlight histomolecular differences from their adult and pediatric counterparts

et al. 2020

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Background Considering that pediatric high-grade gliomas (HGGs) are biologically distinct from their adult counterparts, the objective of this study was to define the landscape of HGGs in adolescents and young adults (AYAs). Methods We performed a multicentric retrospective study of 112 AYAs from adult and pediatric Ile-de-France neurosurgical units, treated between 1998 and 2013 to analyze their clinicoradiological and histomolecular profiles. The inclusion criteria were age between 15 and 25 years, histopathological HGG diagnosis, available clinical data, and preoperative and follow-up MRI. MRI and tumoral samples were centrally reviewed. Immunohistochemistry and complementary molecular techniques such as targeted/next-generation sequencing, whole exome sequencing, and DNA-methylation analyses were performed to achieve an integrated diagnosis according to the 2016 World Health Organization (WHO) classification. Results Based on 80 documented AYA patients, HGGs constitute heterogeneous clinicopathological and molecular groups, with a predominant representation of pediatric subtypes (histone H3-mutants, 40%) but also adult subtypes (isocitrate dehydrogenase [IDH] mutants, 28%) characterized by the rarity of oligodendrogliomas, IDH mutants, and 1p/19q codeletion and the relative high frequency of “rare adult IDH mutations” (20%). H3G34-mutants (14%) represent the most specific subgroup in AYAs. In the H3K27-mutant subgroup, non-brainstem diffuse midline gliomas are more frequent (66.7%) than diffuse intrinsic pontine gliomas (23.8%), contrary to what is observed in children. We found that WHO grade has no prognostic value, but molecular subgrouping has major prognostic importance. Conclusions HGGs in AYAs could benefit from a specific classification, driven by molecular subtyping rather than age group. Collaborative efforts are needed from pediatric and adult neuro-oncology teams to improve the management of HGGs in AYAs. Key Points 1. Pediatric subtypes (H3G34 and H3K27 mutants) were the most common HGGs in AYAs. 2. Contrary to what is observed in children, non-brainstem diffuse midline gliomas are more frequent than diffuse intrinsic pontine gliomas. 3. WHO grade has no prognostic value contrary to molecular subgrouping.

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Section: Discussionmentioning

confidence: 61%

High-grade gliomas in adolescents and young adults highlight histomolecular differences from their adult and pediatric counterparts

et al. 2020

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“…While we are unable to address the presence of PIK3CA mutations in DVA not associated with CCM, it is worth noting that DVAs have been associated with other PI3K-related disorders 36 – 39 , 40 including some cancers and neurological malformations, suggesting that DVA may have a role, possibly even as a genetic primer, in these other phenotypes.…”

Section: Discussionmentioning

confidence: 84%

Developmental venous anomalies are a genetic primer for cerebral cavernous malformations

et al. 2022

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Introductory Paragraph Cerebral cavernous malformations (CCM) are a neurovascular anomaly that may occur sporadically, or be inherited due to autosomal dominant mutations in KRIT1 , CCM2 , or PDCD10 . Individual lesions are caused by somatic mutations which have been identified in KRIT1, CCM2, PDCD10, MAP3K3, and PIK3CA . However, the interactions between mutations, and their relative contributions to sporadic versus familial cases remain unclear. We show that mutations in KRIT1, CCM2, PDCD10, and MAP3K3 are mutually exclusive, but may co-occur with mutations in PIK3CA. We also find that MAP3K3 mutations may cause sporadic, but not familial CCM. Furthermore, we find identical PIK3CA mutations in CCMs and adjacent developmental venous anomalies (DVA), a common vascular malformation frequently found in the vicinity of sporadic CCMs. However, somatic mutations in MAP3K3 are found only in the CCM. This suggests that sporadic CCMs are derived from cells of the DVA which have acquired an additional mutation in MAP3K3 .

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“…While we are unable to address the presence of PIK3CA mutations in DVA not associated with CCM, it is worth noting that DVAs have been associated with other PI3Krelated disorders [36][37][38][39][40][41][42] including some cancers and neurological malformations, suggesting that DVA may have a role, possibly even as a genetic primer, in these other diseases.…”

Section: Discussionmentioning

confidence: 85%

Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations

Snellings

Girard

Lightle

et al. 2021

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Cerebral cavernous malformations (CCM) are a neurovascular anomaly that may occur sporadically in otherwise healthy individuals, or be inherited by autosomal dominant mutations in the genes that encode the proteins of the CCM signaling complex (KRIT1, CCM2, or PDCD10). CCMs have long been known to follow a genetic two-hit model where lesion formation is initiated by somatic mutations resulting in biallelic loss of a CCM complex gene. Recent studies have shown that somatic mutations in MAP3K3 and PIK3CA also contribute to CCM pathogenesis; however, it remains unclear how these mutations contribute to sporadic versus familial cases. Here we show that somatic mutations in MAP3K3 are mutually exclusive with mutations in CCM complex genes and that mutations in MAP3K3 contribute to sporadic, but not familial CCM. Using single-nucleus DNA sequencing, we show that co-occurring MAP3K3 and PIK3CA mutations are present within the same clonal population of cells. Furthermore, we identify PIK3CA mutations in CCM-associated developmental venous anomalies (DVA). It has long been known that sporadic CCM often develop in the vicinity of a DVA. However, the underlying cause of this association is unknown. In this first report of the molecular pathology of CCM-associated DVA, we find that the identical PIKC3A mutation is found in both the DVA and its associated CCM, but that an activating MAP3K3 mutation appears only in the CCM. These results support a mechanism where DVA develop as the result of a PIK3CA mutation, creating a region of the brain vasculature that functions as a genetic primer for CCM development following acquisition of an additional somatic mutation.

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High Prevalence of Developmental Venous Anomaly in Diffuse Intrinsic Pontine Gliomas: A Pediatric Control Study

Cited by 15 publications

References 14 publications

High-grade gliomas in adolescents and young adults highlight histomolecular differences from their adult and pediatric counterparts

High-grade gliomas in adolescents and young adults highlight histomolecular differences from their adult and pediatric counterparts

Developmental venous anomalies are a genetic primer for cerebral cavernous malformations

Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations

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