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GNA14, GNA11, and GNAQ Mutations Are Frequent in Benign but Not Malignant Cutaneous Vascular Tumors.

ABSTRACT: Cutaneous vascular tumors consist of a heterogeneous group of benign proliferations, including a range of hemangiomas and vascular malformations, as well as heterogeneous groups of both borderline and malignant neoplasms such as Kaposi's sarcoma and angiosarcomas. The genetics of these tumors have been assessed independently in smaller individual cohorts making comparisons difficult. In our study, we analyzed a representative cohort of benign vascular proliferations observed in a clinical routine setting as well as a selection of malignant vascular proliferations. Our cohort of 104 vascular proliferations including hemangiomas, malformations, angiosarcomas and Kaposi's sarcoma were screened by targeted next-generation sequencing for activating genetic mutations known or assumed to be potentially relevant in vascular proliferations. An association analysis was performed for mutation status and clinico-pathological parameters. Frequent activating hotspot mutations in GNA genes, including GNA14 Q205, GNA11 and GNAQ Q209 were identified in 16 of 64 benign vascular tumors (25%). GNA gene mutations were particularly frequent (52%) in cherry (senile) hemangiomas (13 of 25). In angiosarcomas, activating RAS mutations (HRAS and NRAS) were identified in three samples (16%). No activating GNA or RAS gene mutations were identified in Kaposi's sarcomas. Our study identifies GNA14 Q205, GNA11 and GNAQ Q209 mutations as being the most common and mutually exclusive mutations in benign hemangiomas. These mutations were not identified in malignant vascular tumors, which could be of potential diagnostic value in distinguishing these entities.

SUBMITTER: Jansen P

PROVIDER: S-EPMC8141909 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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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GNA14, GNA11, and GNAQ Mutations Are Frequent in Benign but Not Malignant Cutaneous Vascular Tumors.

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