MUC16 gene polymorphisms selected in this study are neither involved in genetic predisposition to epithelial ovarian cancer nor associated with CA125 level.
Epithelial ovarian cancer is composed of distinct histological subtypes with unique genomic characteristics, which are improving the precision and effectiveness of therapy, allowing discovery of predictors of response such as mutations in breast cancer susceptibility genes BRCA1 and BRCA2, and homologous recombination deficiency for DNA damage response pathway inhibitors or resistance (cyclin E1).
A patient with V600E BRAF-mutant melanoma and another with platinum-refractory epithelial ovarian cancer exhibiting PTEN loss and PIK3CA amplification demonstrated partial response by RECIST and GCIG-CA125 criteria, respectively.
Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8).
Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes.
A total of eight tag single-nucleotide polymorphisms (SNPs) were genotyped successfully, and both single SNP and haplotype analyses were performed to detect the potential association of variations in the WNT4 gene with EOC.
Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.
Finally, we identify two EOC susceptibility loci at 9q22.33 (rs1413299 in COL15A1, P(meta) = 1.88 × 10(-8)) and 10p11.21 (rs1192691 near ANKRD30A, P(meta) = 2.62 × 10(-8)), and two consistently replicated loci at 12q14.2 (rs11175194 in SRGAP1, P(meta) = 1.14 × 10(-7)) and 9q34.2 (rs633862 near ABO and SURF6, P(meta) = 8.57 × 10(-7)) (P<0.05 in all three stages).
Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8).
Finally, we identify two EOC susceptibility loci at 9q22.33 (rs1413299 in COL15A1, P(meta) = 1.88 × 10(-8)) and 10p11.21 (rs1192691 near ANKRD30A, P(meta) = 2.62 × 10(-8)), and two consistently replicated loci at 12q14.2 (rs11175194 in SRGAP1, P(meta) = 1.14 × 10(-7)) and 9q34.2 (rs633862 near ABO and SURF6, P(meta) = 8.57 × 10(-7)) (P<0.05 in all three stages).
We identified four novel loci with suggestive evidence of association with EOC (p < 1 × 10<sup>-6</sup> ), including rs4525119 (intronic to AKR1C3), rs7643459 (intronic to LOC101927394), rs4286604 (12 kb 3' of UGT2A2) and rs142091544 (5 kb 5' of WWC1).
Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8).
Additionally, olaparib has been reported to augment the effects of cisplatin and carboplatin on recurrence-free survival and OS in mice bearing BRCA1/2-deficient tumors.Given that hereditary EOC with deleterious BRCA1/2 mutations and BRCAness sporadic EOC are profoundly susceptible to synthetic lethality with PARP inhibition, it is imperative to identify a population of EOC patients that is likely to respond to PARP inhibitors.
A decision model was developed to compare costs and outcomes of two testing strategies for women with EOC: multigene testing (MGT) versus single-gene testing for BRCA1/2.
The clinicopathological parameters of 36 EOC patients carrying germline BRCA1/2 DM were compared to high-grade serous EOC women of the COEUR cohort with known germline BRCA1/BRCA2 mutation carrier status (n = 376 non-carriers, n = 65 BRCA1 and n = 38 BRCA2).
BRCA1 and BRCA2 mutation testing was carried out on index cases from 119 families with site-specific epithelial ovarian cancer or breast-ovarian cancer.
All patients diagnosed in Scotland with epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC) and a germline BRCA1/2 mutation were identified.
Our results suggest that genotyping of the ERCC1 polymorphism Asn118Asn may be useful for predicting the platinum-resistance of epithelial ovarian cancer patients.