Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

Fibroblast Growth Factor Receptor-2 Mutations in Endometrial Cancer (#77)

Yvette Jeske 1 , Sara Byron 2 , Mike Gartside 2 , Amy Schmidt 3 , Nilsa Ramirez 4 , Paul Goodfellow 3 , Pamela Pollock 1
  1. Institute of Health and Biomedical Innovation (IHBI) , kelvin grove, QLD, Australia
  2. Translational Genomics Institute (TGEN), Phoenix, Arizona, USA
  3. Siteman Cancer Centre and Washington University School of Medicine, St Louis, Missouri, USA
  4. Nationwide Children’s Hospital, Columbus, Ohio, USA

Germ line gain-of-function FGFR mutations lead to a variety of developmental skeletal disorders. Many of these same gain-of-function mutations lead to various types of cancer when arising somatically. Mutations in FGFR2 have been identified in ~12% of endometrial carcinomas (EC) and many of these mutations have been shown to be oncogenic when examined in vitro (1-3). Our group previously sequenced FGFR2 in 466 primary tumours obtained from Washington University School of Medicine and report that in early stage patients, mutations are associated with shorter Progression Free Survival (4). To validate these findings we performed PCR-Sequencing of the known hotspot exons (7, 8, 10, 13, 15) in 933 clinically annotated ECs obtained from the multi-institutional Gynaecological Oncology Group (GOG) tissue bank. We identified a total of 147 mutations in 143 patients (14.4%). The most common mutations were S252W, N550K, C383R and K660E known to be frequently mutated in EC (1-4). We identified novel mutations in 14 patients:- V274I, F276E, V294M, V311I, A380S, A380T, Y382D, G385R, D627Y, A629E, K660R, D651Y, Del.I388-M391 and Del.E378-C383.Ins.R. Four patients had known activating mutations in addition to a novel mutation (S252W/ V294L, K660E/N653S and N550K/L551F x2). Preliminary analyses of novel mutations using known FGFR2 3D-Structure and Online Mutation Assessment Software tools (Mutation Assessor, SIFT, Polyphen) indicate a likely effect on protein function for all mutations except V311I and A380S. Further functional analysis of these novel mutations (cell lines, 3D-modelling) is required to show that they are gain-of-function. Outcome analysis by the GOG statistical data centre is pending.

1. Dutt, A., et al., Proc Natl Acad Sci U S A 2008, 105, (25), 8713-7.
2. Pollock, P. M., et al., Oncogene 2007, 26, (50), 7158-62.
3. Mohammadi, M., et al., Cytokine Growth Factor Rev 2005, 16, (2), 107-37.
4. Byron, S., et al., PLoS One 2012, 7, (2), e30801.