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.
Highlights
Thyroid cancer is the most common endocrine malignancy with complex carcinogenesis mechanisms
We determine the prevalence of somatic mutations in this pathway (LPAR4, PIK3CA and PTEN in 323 thyroid samples consisting of 17 multinodular goiters (MNG), 89 pediatric Differentiated thyroid cancer (DTC), 204 adult DTCs, and 13 aggressive thyroid cancers including 10 poorly differentiated (PDTC) and 3 anaplastic thyroid cancer (ATC) from another ethnic population
PIK3CA mutations occurred in 2.24% (2/89) of pediatric DTC and in 1.5% of (3/204) adult DTC [two in follicular variant papillary thyroid cancer (PTC) (FV-PTC) and one in tall cell variant (TPTC)]
Summary
Thyroid cancer is the most common endocrine malignancy with complex carcinogenesis mechanisms. Major advances in DNA sequencing technologies revealed various molecular abnormalities in coding [4, 5] and non-coding genes [6] of several signaling pathways in thyroid cancer. Previous studies reported some point mutations in the genes of metabolic and regulatory pathways which include IDH1 [17] and TERT. Somatic alterations of these genes are strongly associated with distinct clinicopathological features of the tumors [18, 19]. Next-generation whole genome sequencing (WGS) of PTCs revealed additional somatic driver alterations that include EIF1AX, PPM1D, and CHEK2 [4]. In addition to the frequent occurrence of the oncogenic mutations of BRAFV600E and NRAS, mutations in the other critical genes such as TERT, TP53, EIF1AX, PIK3CA, PTEN, ALK, and mTOR mutations were frequently detected in PDTC and ATC [5, 7, 8, 21, 22, 23]
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