Analysis of the FGFR4 Single Nucleotide Polymorphism in Pheochromocytomas and Paragangliomas.
Clarissa A Cassol, Sylvia L Asa. University Health Network, Toronto, ON, Canada
Background: FGFR4 harbors a common SNP at codon 388, which results in Gly to Arg substitution at the transmembrane domain of the protein in aproximately 50% of the population. Recent studies have associated the FGFR4 Arg388 allele with tumor progression and bad prognosis in several malignancies. To date, no studies have examined the impact of this SNP in pheochromocytomas (PCT) and paragangliomas (PGL).
Design: We collected tissue for DNA extraction and tissue microarray (TMA) construction from 115 PCT/PGL patients identified in our institutional files of 2001-2009. Exon 9 of fgfr4 was PCR amplified and RFLP digested with BstN1 to distinguish 3 FGFR4 genotypes: wild type (Gly/Gly), heterozigous Gly388 (Gly/Arg) and homozygous Arg388 (Arg/Arg). TMA slides were stained with anti-FGFR4 antibody (SC-124) (Santa Cruz Biotech), scanned with ScanScope (Aperio) and analyzed using Spectrum Plus Color Deconvolution Algorithm (Aperio). Relevant clinical data and patient outcomes were recorded. Logistic regression was performed using SPSS 11.0 with statistical significance at p<0.05.
Results: We successfully genotyped 105 patients; 39 had PCT and 66 had PGL. Of these, 65 were female and 35 were male. Mean age at diagnosis was 46.7 years (±12.5). 17.1% of patients had bilateral or multiple tumors and 8.6% had a family history of PCT/PGL. Five patients had metastatic disease, 3 experienced local recurrence, and two died from metastatic disease, all with PGL. Two additional patients died of unrelated causes. FGFR4 genotyoping revealed 38 patients (36.2%) were Gly/Gly, 66 (62.9%) Gly/Arg and only one (1%) Arg/Arg. There was no significant difference in the distribution of these alleles between PCTs and PGLs. No correlation was found between FGFR4 genotype and FGFR4 expression, nor with individual or combined negative outcomes, age, gender, bilateral/multiple tumors, and family history.
Conclusions: The distribution of FGFR4 alleles in our pheochromocytoma/paraganglioma cohort differs from that of the normal population suggesting a possible predisposition of FGFR4R388 to this disorder. However, no significant correlation was found between genotype and clinical characteristics or outcomes. This may be due to the small number of patients in our study, particularly the low frequency of negative outcomes in our cohort, which hinders the strength of statistical correlations. Since these are relatively indolent neoplasms, a longer follow-up period might be necessary to uncover possible prognostic correlations with FGFR4 alleles.
Monday, February 28, 2011 9:00 AM
Platform Session: Section H 1, Monday Morning