GPCR-mediated PI3K pathway mutations in pediatric and adult thyroid cancer

Abstract

Whole exome sequencing (WES) recently identified frequent mutations in the genes of GPCR-mediated PI3K pathway ( LPAR4 , PIK3CA , and PTEN ) in a Chinese population with papillary thyroid cancers (PTCs). The study found LPAR4 mutations as novel gene mutations in adult population with differentiated thyroid cancer (DTC). Here, we determine the prevalence of somatic mutations in this pathway ( LPAR4 (exon 1), PIK3CA (exons 9 and 20) and PTEN (exons 5, 6, 7 and 8) in 323 thyroid samples consisting of 17 multinodular goiters (MNG), 89 pediatric DTCs, 204 adult DTCs, and 13 aggressive thyroid cancers including 10 poorly differentiated (PDTC) and 3 anaplastic thyroid cancer (ATC) from another ethnic population. We found 3.37% and 2.45% (includes Q214H, a novel PTEN mutation) in GPCR-mediated PI3K pathway of pediatric and adult DTCs, respectively. Analyses of 507 DTCs from thyroid Cancer Genome Atlas data (TCGA) revealed a low prevalence of mutations in this pathway (1.18%). In 13 cases with PDTC and ATC, we found no mutation in genes of this pathway. By contrast, analyses of 117 aggressive thyroid cancers (PDTC and ATC) from TCGA showed 13% of mutations in this pathway. Moreover, analyses of 1080 pan-cancer cell lines and 9020 solid tumors of TCGA data revealed high rates of mutations in this pathway (cell lines, 24.8%; tumors, 24.8%). In addition, PIK3CA + PTEN ( p = <0.001) and LPAR4 + PIK3CA ( p = 0.003) significantly co-occurred. Our study reveals a low prevalence of GPCR-mediated PI3K pathway mutations both in pediatric and adult DTCs corroborating the TCGA data and suggests a significant role of this pathway only in a small portion of DTCs. The high prevalence of mutations in this pathway in other solid malignancies suggests an important role in their pathogenesis making it an attractive target for therapeutic intervention both in a small subset of DTCs and other solid cancers.

Analysis of ALK, IDH1, IDH2 and MMP8 somatic mutations in differentiated thyroid cancers

“…Moreover, the mutational incidence of DTC-specific genes including BRAF, TERT, RAS and PIK3CA, in the Saudi Arabian cohort was comparable to that of the incidence of the Western cases (10,11,35). The limitation of this study is a failure to analyze the ALK gene fusion which is considerably detected in thyroid cancers (9,27).…”

“…Two other more aggressive subtypes of thyroid cancer include the poorly differentiated (PDTC) and anaplastic thyroid cancer (ATC) (4). Genetic alterations in DTC involve many genes and include RET/PTC, BRAF, RAS, PAX8/PPAR-γ, EGFR, EIF1AX, PPM1D, CHEK2, with a low prevalence of PIK3CA and PTEN genes (5)(6)(7)(8)(9)(10)(11). TERT promoter mutations have been demonstrated to be a major determinant of poor outcomes in DTCs (12)(13)(14).…”

Systematically integrative analysis identifies diagnostic and prognostic candidates and small-molecule drugs for lung adenocarcinoma

“…Despite their broad physiological and pathological functions, as well as acting as favorable sites for drug development, the roles of GPCRs have been underappreciated for a long time in tumor biology ( 83 ). With the discovery of more GPCRs associated with cancers, researchers have recognized the importance of the functions of GPCRs in tumor biology and paid more attention to GPCRs in many aspects such as molecular machinery ( 87 - 89 ) and tumor-related drug development ( 86 , 90 ). In this study, we found that two key GPCR genes played roles in LUAD by a comprehensive analysis, which indicates that GPCRs provide important functions in tumor biology.…”