Obstetrics and Gynaecology - Research Publications

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Author: QUINN, MICHAEL × End date: 2009 × Start date: 2009 ×

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    Validating genetic risk associations for ovarian cancer through the international Ovarian Cancer Association Consortium
    Pearce, CL ; Near, AM ; Van Den Berg, DJ ; Ramus, SJ ; Gentry-Maharaj, A ; Menon, U ; Gayther, SA ; Anderson, AR ; Edlund, CK ; Wu, AH ; Chen, X ; Beesley, J ; Webb, PM ; Holt, SK ; Chen, C ; Doherty, JA ; Rossing, MA ; Whittemore, AS ; McGuire, V ; DiCioccio, RA ; Goodman, MT ; Lurie, G ; Carney, ME ; Wilkens, LR ; Ness, RB ; Moysich, KB ; Edwards, R ; Jennison, E ; Kjaer, SK ; Hogdall, E ; Hogdall, CK ; Goode, EL ; Sellers, TA ; Vierkant, RA ; Cunningham, JC ; Schildkraut, JM ; Berchuck, A ; Moorman, PG ; Iversen, ES ; Cramer, DW ; Terry, KL ; Vitonis, AF ; Titus-Ernstoff, L ; Song, H ; Pharoah, PDP ; Spurdle, AB ; Anton-Culver, H ; Ziogas, A ; Brewster, W ; Galitovskiy, V ; Chenevix-Trench, G (NATURE PUBLISHING GROUP, 2009-01-22)
    The search for genetic variants associated with ovarian cancer risk has focused on pathways including sex steroid hormones, DNA repair, and cell cycle control. The Ovarian Cancer Association Consortium (OCAC) identified 10 single-nucleotide polymorphisms (SNPs) in genes in these pathways, which had been genotyped by Consortium members and a pooled analysis of these data was conducted. Three of the 10 SNPs showed evidence of an association with ovarian cancer at P< or =0.10 in a log-additive model: rs2740574 in CYP3A4 (P=0.011), rs1805386 in LIG4 (P=0.007), and rs3218536 in XRCC2 (P=0.095). Additional genotyping in other OCAC studies was undertaken and only the variant in CYP3A4, rs2740574, continued to show an association in the replication data among homozygous carriers: OR(homozygous(hom))=2.50 (95% CI 0.54-11.57, P=0.24) with 1406 cases and 2827 controls. Overall, in the combined data the odds ratio was 2.81 among carriers of two copies of the minor allele (95% CI 1.20-6.56, P=0.017, p(het) across studies=0.42) with 1969 cases and 3491 controls. There was no association among heterozygous carriers. CYP3A4 encodes a key enzyme in oestrogen metabolism and our finding between rs2740574 and risk of ovarian cancer suggests that this pathway may be involved in ovarian carcinogenesis. Additional follow-up is warranted.
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    CRP identifies homeostatic immune oscillations in cancer patients: a potential treatment targeting tool?
    Coventry, BJ ; Ashdown, ML ; Quinn, MA ; Markovic, SN ; Yatomi-Clarke, SL ; Robinson, AP (BMC, 2009-11-30)
    The search for a suitable biomarker which indicates immune system responses in cancer patients has been long and arduous, but a widely known biomarker has emerged as a potential candidate for this purpose. C-Reactive Protein (CRP) is an acute-phase plasma protein that can be used as a marker for activation of the immune system. The short plasma half-life and relatively robust and reliable response to inflammation, make CRP an ideal candidate marker for inflammation. The high- sensitivity test for CRP, termed Low-Reactive Protein (LRP, L-CRP or hs-CRP), measures very low levels of CRP more accurately, and is even more reliable than standard CRP for this purpose. Usually, static sampling of CRP has been used for clinical studies and these can predict disease presence or recurrence, notably for a number of cancers. We have used frequent serial L-CRP measurements across three clinical laboratories in two countries and for different advanced cancers, and have demonstrated similar, repeatable observations of a cyclical variation in CRP levels in these patients. We hypothesise that these L-CRP oscillations are part of a homeostatic immune response to advanced malignancy and have some preliminary data linking the timing of therapy to treatment success. This article reviews CRP, shows some of our data and advances the reasoning for the hypothesis that explains the CRP cycles in terms of homeostatic immune regulatory cycles. This knowledge might also open the way for improved timing of treatment(s) for improved clinical efficacy.