Genetic variation in insulin-like growth factor 2 may play a role in ovarian cancer risk.

The insulin-like growth factor (IGF) signaling axis plays an important role in cancer biology. We hypothesized that genetic variation in this pathway may influence risk of ovarian cancer. A three-center study of non-Hispanic whites including 1880 control women, 1135 women with invasive epithelial ovarian cancer and 321 women with borderline epithelial ovarian tumors was carried out to test the association between tag single-nucleotide polymorphisms (tSNPs) (n=58) in this pathway and risk of ovarian cancer. We found no association between variation in IGF1, IGFBP1 or IGFBP3 and risk of invasive disease, whereas five tSNPs in IGF2 were associated with risk of invasive epithelial ovarian cancer at P<0.05 and followed-up one of the associated SNPs. We conducted genotyping in 3216 additional non-Hispanic white cases and 5382 additional controls and were able to independently replicate our initial findings. In the combined set of studies, rs4320932 was associated with a 13% decreased risk of ovarian cancer per copy of the minor allele carried (95% confidence interval 0.81-0.93, P-trend=7.4 × 10(-5)). No heterogeneity of effect across study centers was observed (p(het)=0.25). IGF2 is emerging as an important gene for ovarian cancer; additional genotyping is warranted to further confirm these associations with IGF2 and to narrow down the region harboring the causal SNP.

[1]  F. Berrino,et al.  Circulating levels of insulin‐like growth factor‐I and risk of ovarian cancer , 2002, International journal of cancer.

[2]  A. Whittemore,et al.  A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24 , 2010, Nature Genetics.

[3]  R. Sankila,et al.  [Cancer incidence in the first-degree relatives of ovarian cancer patients]. , 1997, Duodecim; laaketieteellinen aikakauskirja.

[4]  Dalin Li,et al.  Snagger: A user-friendly program for incorporating additional information for tagSNP selection , 2008, BMC Bioinformatics.

[5]  N. Niikawa,et al.  Frequent loss of imprinting of the H19 and IGF-II genes in ovarian tumors. , 1998, American journal of medical genetics.

[6]  M. West,et al.  Patterns of Gene Expression That Characterize Long-term Survival in Advanced Stage Serous Ovarian Cancers , 2005, Clinical Cancer Research.

[7]  A. Yasmeen,et al.  Targeting Insulin and Insulin-Like Growth Factor Pathways in Epithelial Ovarian Cancer , 2010, Journal of oncology.

[8]  Shan Wang-Gohrke,et al.  ESR1/SYNE1 Polymorphism and Invasive Epithelial Ovarian Cancer Risk: An Ovarian Cancer Association Consortium Study , 2010, Cancer Epidemiology, Biomarkers & Prevention.

[9]  R. Ohlsson.  Loss of IGF2 imprinting: mechanisms and consequences. , 2004, Novartis Foundation symposium.

[10]  S. Hankinson,et al.  Common genetic variation in IGF1, IGFBP1 and IGFBP3 and ovarian cancer risk. , 2009, Carcinogenesis.

[11]  A. Whittemore,et al.  Association Between Single-Nucleotide Polymorphisms in Hormone Metabolism and DNA Repair Genes and Epithelial Ovarian Cancer: Results from Two Australian Studies and an Additional Validation Set , 2007, Cancer Epidemiology Biomarkers & Prevention.

[12]  A. Mannermaa,et al.  Loss of heterozygosity at chromosomes 3, 6, 8, 11, 16, and 17 in ovarian cancer: correlation to clinicopathological variables. , 2000, Cancer genetics and cytogenetics.

[13]  A. Berchuck,et al.  High insulin-like growth factor-2 (IGF-2) gene expression is an independent predictor of poor survival for patients with advanced stage serous epithelial ovarian cancer. , 2005, Gynecologic oncology.

[14]  A. Berchuck,et al.  Frequent IGF2/H19 Domain Epigenetic Alterations and Elevated IGF2 Expression in Epithelial Ovarian Cancer , 2006, Molecular Cancer Research.

[15]  Susan Halabi,et al.  Cyclin E Overexpression in Epithelial Ovarian Cancer Characterizes an Etiologic Subgroup , 2008, Cancer Epidemiology Biomarkers & Prevention.

[16]  Matthew Burnell,et al.  Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) , 2009, Journal of Family Planning and Reproductive Health Care.

[17]  K. Frederiksen,et al.  Smoking and Overweight: Negative Prognostic Factors in Stage III Epithelial Ovarian Cancer , 2006, Cancer Epidemiology Biomarkers & Prevention.

[18]  M. Pike,et al.  Hormonal factors and the risk of invasive ovarian cancer: a population-based case-control study. , 2004, Fertility and sterility.

[19]  Mark Sherman,et al.  Single nucleotide polymorphisms in the TP53 region and susceptibility to invasive epithelial ovarian cancer. , 2009, Cancer research.

[20]  A. Whittemore,et al.  Common variants in mismatch repair genes and risk of invasive ovarian cancer. , 2006, Carcinogenesis.

[21]  S. Hankinson,et al.  Common genetic variation in IGF1, IGFBP1 and IGFBP3 and ovarian cancer risk. , 2009, Carcinogenesis.

[22]  D. Katsaros,et al.  IGF-I in epithelial ovarian cancer and its role in disease progression , 2007, Growth factors.

[23]  J. Kaprio,et al.  Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. , 2000, The New England journal of medicine.

[24]  R. Brunham,et al.  Chlamydia trachomatis Serology in Women with and without Ovarian Cancer , 2008, Infectious diseases in obstetrics and gynecology.

[25]  A. Whittemore,et al.  A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2 , 2009, Nature Genetics.

[26]  A. Whittemore,et al.  Relation of contraceptive and reproductive history to ovarian cancer risk in carriers and noncarriers of BRCA1 gene mutations. , 2004, American journal of epidemiology.

[27]  A. Whittemore,et al.  Consortium analysis of 7 candidate SNPs for ovarian cancer , 2008, International journal of cancer.

[28]  J. Buring,et al.  Insulin-like Growth Factors and Ovarian Cancer Risk: A Nested Case-Control Study in Three Cohorts , 2007, Cancer Epidemiology Biomarkers & Prevention.

[29]  M. Fukumoto,et al.  Monoallelic expression of the insulin-like growth factor-2 gene in ovarian cancer. , 1996, The American journal of pathology.

[30]  L. Giudice.  IGFs in the Female Reproductive System , 1999 .

[31]  N. Weiss,et al.  Menopausal Hormone Therapy and Risk of Epithelial Ovarian Cancer , 2007, Cancer Epidemiology Biomarkers & Prevention.

[32]  M. Pike,et al.  Markers of inflammation and risk of ovarian cancer in Los Angeles County , 2009, International journal of cancer.

[33]  Shan Wang-Gohrke,et al.  Association between invasive ovarian cancer susceptibility and 11 best candidate SNPs from breast cancer genome-wide association study. , 2009, Human molecular genetics.

[34]  A. Whittemore,et al.  Common variants at 19p13 are associated with susceptibility to ovarian cancer , 2010, Nature Genetics.

[35]  M. Wan,et al.  Histologically benign or low-grade malignant tumors adjacent to high-grade ovarian carcinomas contain molecular characteristics of high-grade carcinomas. , 1993, Cancer research.

[36]  E. Ghigo,et al.  The IGF system , 2011, Acta Diabetologica.

[37]  M. Pollak,et al.  Insulin and insulin-like growth factor signalling in neoplasia , 2008, Nature Reviews Cancer.

[38]  Chris Cheadle,et al.  Development of a highly specialized cDNA array for the study and diagnosis of epithelial ovarian cancer. , 2002, Cancer research.

[39]  D. Ward,et al.  Diagnostic Markers for Early Detection of Ovarian Cancer , 2008, Clinical Cancer Research.

[40]  D. Yee,et al.  Expression of insulin-like growth factor I, its binding proteins, and its receptor in ovarian cancer. , 1991, Cancer research.

[41]  D. Easton,et al.  Risk prediction models for familial breast cancer. , 2006, Future oncology.

[42]  J. Chang-Claude,et al.  Serum IGF-I, its major binding protein (IGFBP-3) and epithelial ovarian cancer risk: the European Prospective Investigation into Cancer and Nutrition (EPIC). , 2007, Endocrine-related cancer.

[43]  M. Milivojevic,et al.  SERUM PROTEIN MARKERS FOR EARLY DETECTION OF OVARIAN CANCER , 2009 .

[44]  R. Berkowitz,et al.  A novel 4-cM minimally deleted region on chromosome 11p15.1 associated with high grade nonmucinous epithelial ovarian carcinomas. , 1997, Cancer research.

[45]  C. Mantzoros,et al.  IGF axis gene expression patterns are prognostic of survival in epithelial ovarian cancer. , 2007, Endocrine-related cancer.