UCL Institute for Women's Health (IfWH)

Genetic Susceptibility

Lead: Dr Susan Ramus

Background

Family history of ovarian cancer in a first degree relative is associated with an increased risk of ovarian cancer. Several genes that confer high penetrance susceptibility to ovarian cancer have been identified. Two of these, BRCA1 and BRCA2, are responsible for approximately half of all families with two or more ovarian cancer cases in first-degree relatives and most families in which multiple cases of breast and ovarian cancer occur together. The known ovarian cancer susceptibility genes have been estimated to explain approximately 40% of the excess familial risk of ovarian cancer. Several genetic models may explain residual familial clustering but other highly penetrant genes are likely to be rare, because BRCA1/2 are responsible for most families containing >=3 ovarian cancer cases. A more plausible alternative is that the remaining familial clustering is driven by variants is multiple loci, each conferring a more moderate risk of the disease.

Projects

High risk genetic susceptibility to ovarian cancer

We have established high throughput sequence analysis for mutations in the coding regions of the BRCA1 and BRCA2 genes and also multiple ligation dependent probe amplification (MLPA) analysis for large genomic rearrangements.

Ovarian Cancer families. The UK Familial Ovarian Cancer Register and the Gilda Radner Familial Ovarian Cancer Register (USA) contain families with 2 or more confirmed cases of epithelial ovarian cancer in first or second degree relatives. From 283 ovarian cancer families we have identified BRCA1 mutations in 104 families (37%) and BRCA2 mutations in 25 families (9%)[22]. The prevalence of BRCA1/2 mutations correlated with the extent of ovarian and breast cancer in the family. BRCA1 and BRCA2 are responsible for approximately half of all families with two or more ovarian cancer cases in first-degree relatives and most families in which multiple cases of breast and ovarian cancer occur together. Although they are the major susceptibility genes for ovarian cancer other susceptibility genes may exist. The non-BRCA1/2 families represent a valuable resource in our search for additional susceptibility alleles. We will also perform studies on the tumours from these families.

Population based ovarian cancer. We have established the prevalence of BRCA1 and BRCA2 mutations in a population based study of 445 ovarian cancer cases from Denmark. Twenty-six deleterious mutations were identified; 22 mutations in BRCA1 (4.9%) and 4 mutations in BRCA2 (0.9%). Thus, the combined prevalence of BRCA1 and BRCA2 mutations in this series was 5.8% [17]. BRCA1 carriers were diagnosed significantly younger than non-carriers; 23% of BRCA1 mutation carriers were diagnosed <40 years, 15% were 40-49 years, 4% were 50-59 years, and 2% were ≥60 (P=0.00002). These data may have a significant impact on risk assessment and clinical management of BRCA1/2 individuals from Denmark. The non-BRCA1/2 carriers from this population based series of patients are now being analysed in low risk genetic susceptibility studies.

Low-moderate risk genetic susceptibility to ovarian cancer

The most widely used study design in the search for common, low-moderate penetrance alleles is the genetic association study. The aim is to identify polymorphic genetic variants that have a direct causal effect on cancer susceptibility. Very large numbers of samples are required for statistically significant results and therefore the Ovarian Cancer Association Consortium (OCAC) was established in April 2005 to bring together investigators from around the world who are carrying out genetic, case-control association studies in epithelial ovarian cancer, to coordinate genotyping in candidate genes and ensure genotyping quality control in association studies. We have performed candidate gene and pathway analysis to identify single nucleotide polymorphisms (SNPs) associated with risk of ovarian cancer [2, 3, 8, 13, 18, 24] and also survival [4, 14, 15]. The most successful approach to identifying moderate-low penetrance risk alleles common in the population has been the genome wide association study. GWAS is an empirical approach that evaluates the frequency of hundreds of thousands of variants distributed throughout the genome, without prior selection based on putative function. We have performed the first GWAS for ovarian cancer and identified alleles highly significantly associated with risk of ovarian cancer [1]. The functional role of these genes and SNPs in ovarian cancer will be established using molecular pathology and cell biology techniques.

Members of the Genetic Susceptibility Group

• Dr Simon Gayther (Reader)
• Dr Susan Ramus (Lecturer)
• Eva Wozniak (Research Assistant)
• Maria Notaridou (PhD Student)
• Raquel Perez Rubio (PhD Student)

Previous Members

• Lydia Quaye (PhD Student)
• Mark Cox (Research Assistant)
• Lalarukh Khalique (Research Assistant)

Publications

1. Song H*, Ramus SJ*, Tyrer J, Bolton K, Gentry-Maharaj A, Wozniak E, Anton-Culver H, et al. A Genome-Wide Association Study Identifies A Novel Ovarian Cancer Susceptibility Locus On 9p22.2. Nature Genetics (in press)
2. Quaye L, Tyrer J, Ramus SJ, Song H, Wozniak E, DiCioccio RA, McGuire V, et al. Association between Common Germline Genetic Variation in 84 Candidate Genes/Regions and Risks of Ovarian Cancer. PLoS 4(6):e5983 (2009)
3. Song H, Ramus SJ, Krüger Kjaer S, DiCioccio RA, Chenevix-Trench G, Pearce CL, Hogdall E, et al. Association between invasive ovarian cancer susceptibility and 11 candidate SNPs from a breast cancer genome-wide association study. Hum. Mol. Genet. 18:2297-304 (2009)
4. Quaye L*, Dafou D*, Ramus SJ*, Song H, Gentry Maharaj A, Notaridou M, Hogdall E, et al. Functional Complementation Studies Identify Candidate Genes and Common Genetic Variants Associated with Ovarian Cancer Survival. Hum. Mol. Genet. 18:1869-78 (2009)
5. Soegaard M, Frederiksen K, Jensen A, Høgdall E, Høgdall C, Blaakær J, Ramus SJ, et al. Risk Of Ovarian Cancer In Individuals With First Degree Relatives With Cancer. Acta Obstet Gynecol Scand. 88: 449-56. (2009).
6. Ramus SJ, and Gayther SA. The Genetic Contribution of BRCA1 and BRCA2 to Ovarian Cancer. Molecular Oncology 3:138-50. (2009)
7. Fasching PA, Gayther SA, Pearce CL, Schildkraut JM, Goode E, Thiel F, Chenevix-Trench G, et al. Role of genetic polymorphisms and ovarian cancer susceptibility. Molecular Oncology 3:171-181 (2009)
8. Quaye L, Song H, Ramus SJ, Gentry-Maharaj A, Hogdall E, DiCioccio RA, Wu A, et al. Tagging Single Nucleotide Polymorphisms in Candidate Oncogenes and Susceptibility to Ovarian Cancer. Br J Cancer 100:993-1001 (2009)
9. Schildkraut JM, Goode EL, Clyde MA, Iversen ES, Moorman P, Berchuck A, Marks JR, et al. Single Nucleotide Polymorphisms in TP53 and Susceptibility to Invasive Epithelial Ovarian Cancer. Cancer Research 69:2349-57 (2009)
10. Goode EL, Fridley BL, Vierkant RA, Cunningham JM, Phelan CM, Anderson S, Rider DN, et al. Candidate Gene Analysis Using Imputed Genotypes: Cell Cycle Genes and Ovarian Cancer Risk. Cancer Epidemiol Biomarkers Prev. 18:935-44 (2009)
11. Pearce CL, Near A, Van Den Berg D, Ramus SJ, Gentry-Maharaj A, Menon U, Gayther SA, et al. Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium. Br J Cancer 100:412–420 (2009)
12. Palmieri RT, Wilson MA, Iversen ES, Clyde MA, Calingaert B, Moorman PG, Poole CL, et al. Polymorphism in the IL18 gene and epithelial ovarian cancer in non-Hispanic white women. CEBP 17:3567-3572 (2008)
13. Song H, Koessler T, Ahmed S, Ramus SJ, Kruger Kjaer S, DiCioccio RA, Wozniak E, et al. Association of prostate cancer susceptibility variants with invasive ovarian cancer, breast cancer and colorectal cancer. Cancer Research 68:8837-8842 (2008)
14. Mann A, Hogdall E, Ramus SJ, DiCioccio RA, Hogdall C, Quaye L, McGuire V, et al. Mismatch repair gene polymorphisms and survival in invasive ovarian cancer patients. European Journal of Cancer 44:2259-65 (2008)
15. Quaye L, Gayther SA, Ramus SJ, DiCioccio RA, McGuire V, Hogdall E, Hogdall C, et al. Effects Of Common Genetic Variants in Oncogenes On Ovarian Cancer Survival. Clinical Cancer Research 14:5833-9 (2008)
16. Ghoussaini M, Song H, Kössler T, Amin Al Olama A, Kote-Jarai Z, Driver K, Pooley KA, et al. Multiple loci with different cancer-specificities within the 8q24 “gene desert” JNCI 100:962-6 (2008)
17. Søgaard M, Kruger Kjaer S, Cox M, Wozniak E, Hogdall E, Hogdall C, Blaeker J, et al. BRCA1 And BRCA2 Mutation Prevalence And Clinical Characteristics In An Ovarian Cancer Case Population From Denmark Clin. Cancer Res. 14:3761-3767 (2008)
18. Ramus SJ, Vierkant RA, Johnatty S, Pike MC, Van Den Berg DJ, Wu AH, Pearce CL, et al. Consortium Analysis of Seven Candidate SNPs for Ovarian Cancer. IJC 123:380-8 (2008)
19. Song H, Hogdall E, Ramus SJ, DiCioccio RA, Hogdall C, Quaye L,  McGuire V, et al. Effects Of Common Germline Genetic Variation In Cell Cycle Genes On Ovarian Cancer Survival.  Clinical Cancer Research 14:1090-5 (2008)
20. Pearce CL, Wu AH, Gayther SA, Bale AE, Australian Cancer Study (Ovarian Cancer), Australian Ovarian Cancer Study Group, Beck PA, et al. Progesterone Receptor Variation and Risk of Invasive Epithelial Ovarian Cancer:  Results from the Ovarian Cancer Association Consortium Pooled Analysis. Br J Cancer 98:282-8 (2008)
21. Beesley J, Jordan SJ, Spurdle AB, Song H, Ramus SJ, Kjaer SK, Hogdall E, 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. Cancer Epidemiol Biomarkers Prev. 16:2557-65 (2007)
22. Ramus SJ, Harrington P, Pye C, DiCioccio R, Cox M, Garlinghouse-Jones K, Oakley-Girvan I, et al. The contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer. Human Mutation 28:1207-15 (2007)
23. Ramus SJ, Harrington P, Peock S, Pye C, Cook MR, Cox M, Jacobs IJ, et al. Screening For The BRCA1-ins6kbEx13 Mutation: Potential for Misdiagnosis.  Human Mutation 28:525-526 (2007)
24. Gayther SA, Song H, Ramus SJ, Quaye L, Tyre J, Shadforth D, Hogdall E, et al. Tagging Single Nucleotide Polymorphisms In Cell Cycle Control Genes And Susceptibility To Epithelial Ovarian Cancer. Cancer Research 67:3027-35 (2007)
25. Song H, Ramus SJ, Kjaer SK, Hogdall E, Dicioccio RA, Whittemore AS, McGuire V, et al. Tagging Single Nucleotide Polymorphisms in the BRIP1 Gene and Susceptibility to Breast and Ovarian Cancer. PLoS ONE 2:e268 (2007)
26. Smith LD, Tesoriero AA, Ramus SJ, Dite G, Royce SG, Giles GG, McCredie MR, et al. BRCA1 promoter deletions in young women with breast cancer and a strong family history: A population-based study. Eur J Cancer 43:23-7 (2007)
27. Song H, Ramus SJ, Shadforth D, Quaye L, Kruger Kjaer S, DiCioccio R, Dunning A, et al. Common variants in RB1 gene and risk of invasive ovarian cancer. Cancer Research 66:10220-6 (2006)
28. Song H,  Ramus SJ, Quaye L, DiCioccio RA, Tyrer J, Shadforth D, Lomas E, et al. Common Variants in Mismatch Repair Genes and Risk of Invasive Ovarian Cancer. Carcinogenesis 27:2235-42 (2006)