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Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma.

ABSTRACT: Congenital hemangioma is a rare vascular tumor that forms in utero. Postnatally, the tumor either involutes quickly (i.e., rapidly involuting congenital hemangioma [RICH]) or partially regresses and stabilizes (i.e., non-involuting congenital hemangioma [NICH]). We hypothesized that congenital hemangiomas arise due to somatic mutation and performed massively parallel mRNA sequencing on affected tissue from eight participants. We identified mutually exclusive, mosaic missense mutations that alter glutamine at amino acid 209 (Glu209) in GNAQ or GNA11 in all tested samples, at variant allele frequencies (VAF) ranging from 3% to 33%. We verified the presence of the mutations in genomic DNA using a combination of molecular inversion probe sequencing (MIP-seq) and digital droplet PCR (ddPCR). The Glu209 GNAQ and GNA11 missense variants we identified are common in uveal melanoma and have been shown to constitutively activate MAPK and/or YAP signaling. When we screened additional archival formalin-fixed paraffin-embedded (FFPE) congenital cutaneous and hepatic hemangiomas, 4/8 had GNAQ or GNA11 Glu209 variants. The same GNAQ or GNA11 mutation is found in both NICH and RICH, so other factors must account for these tumors' different postnatal behaviors.

SUBMITTER: Ayturk UM

PROVIDER: S-EPMC4833432 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma.

Ayturk Ugur M UM Couto Javier A JA Hann Steven S Mulliken John B JB Williams Kaitlin L KL Huang August Yue AY Fishman Steven J SJ Boyd Theonia K TK Kozakewich Harry P W HP Bischoff Joyce J Greene Arin K AK Warman Matthew L ML

American journal of human genetics 20160401 4

Congenital hemangioma is a rare vascular tumor that forms in utero. Postnatally, the tumor either involutes quickly (i.e., rapidly involuting congenital hemangioma [RICH]) or partially regresses and stabilizes (i.e., non-involuting congenital hemangioma [NICH]). We hypothesized that congenital hemangiomas arise due to somatic mutation and performed massively parallel mRNA sequencing on affected tissue from eight participants. We identified mutually exclusive, mosaic missense mutations that alter ...[more]

PMID: 27058448

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Project description:ImportanceChoroidal hemangiomas are defined by a thickened choroid owing to vessel overgrowth, which may increase the intraocular pressure and lead to glaucoma. Choroidal hemangioma and glaucoma often co-occur in patients with Sturge-Weber syndrome, a rare neurocutaneous disorder characterized by capillary malformations.ObjectiveTo determine whether the mutation found in most capillary malformations, GNAQ R183Q (c.548G>A), was present in the choroidal hemangioma of a patient with Sturge-Weber syndrome.Design, setting, and participantUsing laser-capture microdissection, choroidal blood vessels were isolated from paraffin-embedded tissue sections, and genomic DNA was extracted for mutational analysis. Choroidal sections were analyzed in parallel. A patient with choroidal hemangioma and Sturge-Weber syndrome who had undergone enucleation was analyzed in this study at Boston Children's Hospital. Negative controls were choroidal tissue from an eye with retinoblastoma and unaffected lung tissue; brain tissue from a different patient with Sturge-Weber syndrome served as a positive control. Infantile hemangioma was analyzed as well. Data were analyzed in 2018.Main outcomes and measuresThe mutant allelic frequency of GNAQ R183 and GNAQ Q209L/H/P was determined by droplet digital polymerase chain reaction on isolated genomic DNA. The infantile hemangioma marker glucose transporter-1 was visualized by immunofluorescent staining of tissue sections.ResultsThe GNAQ R183Q mutation was present in the patient's choroidal vessels (21.1%) at a frequency similar to that found in brain tissue from a different patient with Sturge-Weber syndrome (25.1%). In contrast, choroidal vessels from a case of retinoblastoma were negative for the mutation (0.5%), as was lung tissue (0.2%). The patient's choroidal tissue was negative for the 3 GNAQ mutations associated with congenital hemangioma and for the infantile hemangioma marker glucose transporter-1.Conclusions and relevanceThe results suggest that a more accurate description for choroidal hemangioma in patients with Sturge-Weber syndrome is choroidal capillary malformation. This finding may explain why propranolol, used to treat infantile hemangiomas, has been largely ineffective in patients with choroidal hemangioma. Further studies are needed to corroborate this finding.

Project description:BACKGROUND:Advances in deep sequencing technology have uncovered a widespread, protumorigenic role of guanine nucleotide-binding (G protein) ? (GNA) subunits, particularly GNA subunits Gs (GNAS), Gq (GNAQ), and G11 (GNA11) (GNA*), in a diverse collection of malignancies. The objectives of the current study were: 1) to determine GNA* aberration status in a cohort of 1348 patients with cancer and 2) to examine tumor mutational burden, overall survival rates, and treatment outcomes in patients with GNA*-positive tumors versus those with tumors that had wild-type GNA*. METHODS:For each patient, clinical and genomic data were collected from medical records. Next-generation sequencing was performed for each patient (range, 182-236 genes). RESULTS:Aberrations of GNA* genes were identified in a subset of patients who had 8 of the 12 cancer types examined, and a significant association was observed for appendiceal cancer and ocular melanoma (P < .0001 for both; multivariate analysis). Overall, 4.1% of the cancer population was affected. GNA* abnormalities were associated with higher numbers of co-alterations in univariate (but not multivariate) analysis and were most commonly accompanied by Aurora kinase A (AURKA), Cbl proto-oncogene (CBL), and LYN proto-oncogene (LYN) co-alterations (all P < .0001; multivariate analysis). GNA* alterations were correlated with a trend toward lower median overall survival (P = .085). The median tumor mutational burden was 4 mutations per megabase in both GNA*-altered and GNA* wild-type tumors. For this limited sample of GNA*-positive patients, longer survival was not correlated with any specific treatment regimens. CONCLUSIONS:In the current sample, the genes GNAS, GNAQ, and GNA11 were widely altered across cancer types, and these alterations often were accompanied by specific genomic abnormalities in AURKA, CBL, and LYN. Therefore, targeting GNA* alterations may require drugs that address the GNA* signal and important co-alterations. Cancer 2018;00:000-000. © 2018 American Cancer Society.

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Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma.

Publications

Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma.

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