Loss of the intrinsic FGF7/FGF10-type 2 FGF receptor (FGFR2) pathway and gain of the ectopic type 1 FGF receptor (FGFR1) pathway are associated with the progression to malignancy in prostate cancer (PCa) and many other epithelial originating lesions.
Application of this assay on prospective patient samples uncovered OLFM4 as a novel RET fusion partner in a small-bowel cancer and led to the discovery of a KLK2-FGFR2 fusion in a patient with prostate cancer who subsequently underwent treatment with a pan-fibroblast growth factor receptor inhibitor.
Abnormalities of FGFR2 have been shown in advanced prostate cancer or prostate cancer cell lines, and we previously demonstrated the tumor-suppressive effects of the restoration of FGFR2IIIb in prostate cancer cells.
Through a prospective clinical sequencing program for advanced cancers, four index cases were identified which harbor gene rearrangements of FGFR2, including patients with cholangiocarcinoma, breast cancer, and prostate cancer.
These findings propose that decreased expression of not only FGFR2(IIIb) but also FGFR2(IIIc) isoforms may be a critical step in prostate cancer progression and furthermore suggest that FGFR2(IIIb) expression could be used as a marker for prostate cancer evolution from androgen-dependent to androgen-independent status.
In most cases of prostate cancer there are no changes in alternative splicing of FGF receptors, but in a subgroup there is increased expression of the FGFR-2 IIIc isoform.
In addition, we have observed overexpression of both FGFR-1 and FGFR-2 in the prostate cancer epithelial cells in a subset of prostate cancers and that such overexpression is correlated with poor differentiation.
These findings lend support to the hypothesis that that loss of FGF-R2(IIIb) may be one step in a series of events which lead to progression of human prostate cancer.