GNAS, GNAQ, and GNA11 alterations in patients with diverse cancers. Cancer 2018 Oct 15;124(20):4080-4089
Date
09/12/2018Pubmed ID
30204251Pubmed Central ID
PMC6234097DOI
10.1002/cncr.31724Scopus ID
2-s2.0-85053374147 (requires institutional sign-in at Scopus site) 33 CitationsAbstract
BACKGROUND: Advances in deep sequencing technology have uncovered a widespread, protumorigenic role of guanine nucleotide-binding (G protein) α (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.
Author List
Parish AJ, Nguyen V, Goodman AM, Murugesan K, Frampton GM, Kurzrock RAuthor
Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdolescentAdult
Aged
Aged, 80 and over
Child
Child, Preschool
Chromogranins
Cohort Studies
DNA Mutational Analysis
Female
GTP-Binding Protein alpha Subunits
GTP-Binding Protein alpha Subunits, Gq-G11
GTP-Binding Protein alpha Subunits, Gs
Genetic Association Studies
Genetic Predisposition to Disease
High-Throughput Nucleotide Sequencing
Humans
Infant
Male
Middle Aged
Mutation
Neoplasms
Retrospective Studies
Young Adult
