Endometrial carcinoma is often refractory to chemotherapy when tumours are persistent or recurrent. Pamela Pollock, Paul Goodfellow and colleagues have now identified common mutations in fibroblast growth factor receptor 2 ( FGFR2 ), providing a rationale for targeting FGFR2 to treat patients with refractory endometrial tumours.

The Cancer Genome Project of the Sanger Centre, UK, identified FGFR2 variants in three uterine cancer cell lines, two of which were derived from endometrial tumours, prompting Pollock, Goodfellow and colleagues to investigate the spectrum and frequency of FGFR2 mutations in endometrial cancer. Germline mutations that activate the FGFR are associated with syndromes characterized by craniosynostosis (the premature ossification and closure of the sutures of the skull) and chondrodysplasia (abnormal bone development and growth). Most germline mutations in FGFR2 and FGFR3 are localized to 6 exons, so the authors sequenced these exons in 187 primary tumour samples, representing the major histological subtypes of endometrial carcinoma. FGFR mutations were identified in 10% of all tumour samples, with 16% of those tumours with an endometrioid histology carrying a mutation. Importantly, they identified 12 different mutations in the extracellular, transmembrane and kinase domains of FGFR, seven of which are the same as those associated with the craniosynostosis and chondrodysplasia syndromes.

The most common cancer-associated mutation they identified, FGFR2-S252W, is associated with the craniosynostosis syndrome, Apert syndrome; the cancer predisposition of these patients is not yet clear. It was previously shown that this mutation confers increased ligand-binding affinity and abrogates ligand-binding specificity, thought to result in abnormal activation of the receptor. Consistently, the other mutations identified are also thought to confer FGFR activation.

The authors found no association between FGFR2 mutation and the survival of patients with endometrioid endometrial cancer. However, the prevalence of these mutations provides a rationale for using FGFR inhibitors as an adjuvant therapy to treat patients. Indeed, one FGFR inhibitor (TK1258) is currently undergoing phase I clinical validation for the treatment of multiple myeloma. It is also interesting to note the parallel between the association of Ras mutations with developmental syndromes that, like those syndromes associated with FGFR mutations, do not appear to be associated with a strong cancer predisposition.