Mutational analysis of the BRAF, RAS and EGFR genes in human adrenocortical carcinomas

Abstract

The serine/threonine kinase B-Raf plays a key role in the Ras/Raf/MEK/ERK pathway that relays extracellular signals for cell proliferation and survival. Several types of human malignancies harbor activating BRAF mutations, most frequently a V600E substitution. The epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase (TK) receptor that mediates proliferation and survival signaling, is expressed in a wide variety of normal and neoplastic tissues. EGFR inhibitors have produced objective responses in patients with non-small cell lung carcinomas harboring activating EGFR TK domain somatic mutations. We evaluated the presence of mutations in BRAF (exons 11 and 15), KRAS (exons 1 and 2), NRAS (exons 1 and 2), and EGFR (exons 18-21) in adrenal carcinomas (35 tumor specimens and two cell lines) by DNA sequencing. BRAF mutations were found in two carcinomas (5.7%). Four carcinomas (11.4%) carried EGFR TK domain mutations. One specimen carried a KRAS mutation, and another carried two NRAS mutations. No mutations were found in the two adrenocortical cell lines. BRAF-and EGFR-mutant tumor specimens exhibited stronger immunostaining for the phosphorylated forms of the MEK and ERK kinases than their wild-type counterparts. EGFR-mutant carcinomas exhibited increased phosphorylation of EGFR (Tyr 992) compared with wild-type carcinomas. We conclude that BRAF, RAS, and EGFR mutations occur in a subset of human adrenocortical carcinomas. Inhibitors of the Ras/Raf/MEK/ERK and EGFR pathways represent candidate targeted therapies for future clinical trials in carefully selected patients with adrenocortical carcinomas harboring respective activating mutations.

Mutational analyses of epidermal growth factor receptor and downstream pathways in adrenocortical carcinoma

“…The presence of BRAF and KRAS mutations in ACC was reported in the literature to be present in only 1.6% (1/59) and 6.7% (1/15) of ACC respectively (21,30). The presence of oncogenic PIK3CA mutations in ACC has not previously been studied.…”

“…Until now, only four mutations of the EGFR TK domain have been reported in ACC (21,22). Kotoula et al described four activating EGFR mutations, three missense (c.2168TOC, exon 18, c.2354COA, exon 20, and c.2533GOA, exon 21) and one non-sense mutation (c.2193GOA, exon 19) in 35 ACCs.…”

Sorafenib combined with gemcitabine in EGFR-TKI-resistant human lung cancer cells

“…The RAS/RAF/MEK/ERK and RAS/PI3K/PTEN/AKT pathways interact with each other to regulate growth and play key roles in the transmission of proliferative signals, in some cases contributing to tumorigenesis. In NSCLC, the activation of KRAS and BRAF leads to ERK1/2 overexpression through the RAF/MEK/ERK signaling pathway (19)(20)(21). Hence, inhibition of the RAS/RAF/MEK/ERK signaling pathway is an important strategy in anticancer drug development.…”

Szlaki molekularne w raku kory nadnercza — od wiedzy o sygnalizacji komórkowej do metod diagnostyki i leczenia

“…Downstream signalling pathways include Ras/Raf/MEK and STAT cascades [81]. Kotoula et al performed a study focused on mutations in the EGFR gene, which were detected in its TK domain in relatively small numbers (11%) of carcinomas [82].…”

“…A few reports regarding Ras proteins describe overexpression of KRAS mRNA and mutations in KRAS gene in benign adrenal alterations [143] and carcinomas [82] as well as mutations in NRAS gene in both ACCs and ACAs [82,144]. However, some other studies have reported a lack of mutation of those genes and HRAS (HRas) in adrenal neoplasms [144][145][146].…”