Reply to the letter to the editor

Abstract

Reply to the letter to the editor Dear Sir,We read with great interest the Letter to the Editor by Aubertin et al. 1 in which they reported that 100% of 39 tested oral squamous cell carcinoma (OSCC) samples contained wild-type sequence in codon 697 of the FGF receptor 3 gene. These results appear to contradict our own finding that 62% of 71 tested OSCC samples possessed a somatic missense mutation, which resulted in a glycine to cysteine substitution at position 697 (G697C) of FGFR3. 2 As we also found that this mutated form of FGFR3 had higher autophosphorylation activity than wild-type FGFR3, we suggested that FGFR3 and the G697C activating mutation might play an important role in the development of SCC in oral epithelia. As pointed out by Aubertin et al., the patient populations in these 2 studies were different: their OSCC patients were likely Caucasians from northeastern France while our patients were exclusively Japanese. We suspect that the discrepancy in our experimental results stem from these different patient populations. There may be ethnic, lifestyle or environmental factors, which are not found in northeastern France, that predispose OSCC patients in the Hiroshima area to develop tumors via a mechanism involving the G697C mutation. These potential variations in patient populations are reminiscent of somatic mutations in the epidermal growth factor receptor that rendered Japanese patients with nonsmall cell lung carcinoma generally more responsive to gefitinib (Iressa) than nonsmall cell lung carcinoma patients in the United States. 3,4 Our report and that of Aubertin et al. serve to emphasize that there are likely multiple mechanistic pathways leading to OSCC. We believe that a survey of 110 OSCC patients from 2 geographic areas is insufficiently large to determine whether or not FGFR3 G697C is a common oncogenic mutation in OSCC. However, for OSCC patients with G697C-positive tumors, this diagnosis may have prognostic value.Yours sincerely,

Preclinical characterization of CPL304110 as a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3 for gastric, bladder, and squamous cell lung cancer

“…Moreover, CPL304110 inhibited the FGFR3 variant with activating G697C mutation that was observed in 62% (44/71) of the examined oral squamous cell carcinoma (OSCC). It is possible that the activating potential of this mutation could be context-dependent and may involve interaction with other genes (7,9).…”

“…Multiple studies have already shown that activation of the FGFR signaling cascade is involved in the proliferation of tumor cells (7)(8)(9)11). Thus, the antiproliferative activity of CPL304110 was determined in a panel of human tumor cell lines of different origins that are dependent on FGFR signaling.…”

“…For example, FGFR1 is amplified in lung and breast cancers and rarely in pancreatic and squamous cell lung cancers, whereas FGFR2 amplification mainly occurs in gastric and breast cancers. Bladder cancer is characterized by genetic aberrations in FGFR3 (9). Various somatic mutations of FGFR family members also lead to carcinogenesis, such as mutations in FGFR1 sequence in lung tumors and gliomas, FGFR2 in carcinomas, and FGFR3 in bladder carcinomas and multiple myelomas (10).…”