Genetic susceptibility to sporadic ovarian cancer: A systematic review

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<ul><li><p>Risk assessmentReviewPolymorphism</p><p>o of positive and negative studies, and the false-positive report probability (FPRP).</p><p>. . .</p><p>. . .on crite. . .</p><p>2.5. Data interpretation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134</p><p>Biochimica et Biophysica Acta 1816 (2011) 132146</p><p>Contents lists available at ScienceDirect</p><p>Biochimica et Biophysica Acta3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1353.1. Quality assessment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1353.2. Genome-wide association studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1353.3. Candidate gene studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135</p><p>3.3.1. Sex steroid hormone genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1403.3.2. Cell cycle genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1403.3.3. DNA repair genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1413.3.4. Oncogenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1413.3.5. Miscellaneous candidate genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1413.3.6. Genomic regions initially identied by GWAS for other cancers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141</p><p>3.3.7. Lack of overlap with resu</p><p>3.4. Stratication based on quality mea</p><p> Corresponding author at: Julius Center for HealthNetherlands. Tel.: +31 88 75 59367; fax: +31 88 75 55</p><p>E-mail addresses: M.G.M.Braem@umcutrecht.nl (M.GPA.vandenBrandt@EPID.unimaas.nl (P.A. den Brandt), N</p><p>0304-419X/$ see front matter 2011 Elsevier B.V. Adoi:10.1016/j.bbcan.2011.05.002. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133</p><p>. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133</p><p>. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133</p><p>2.3. Data items. . . . . . . . . . .2.4. Quality assessment. . . . . . .Contents</p><p>1. Introduction . . . . . . . . . .2. Materials and methods . . . . .</p><p>2.1. Search strategy and selecti2.2. Data processing . . . . .genes and 20 intergenic regions. Genetic variants with the strongest evidence for an association with ovariancancer include the rs2854344 in the RB1 gene and SNPs on chromosomes 9p22.2, 8q24, 2q31, and 19p13.Promising genetic pathways for ovarian cancer include the cell cycle, DNA repair, sex steroid hormone andoncogenic pathway.Concluding, this review shows that many genetic association studies have been performed, but only a fewgenetic variants show strong evidence for an association with ovarian cancer. More research is needed toelucidate causal genetic variants, taking into consideration genegene and geneenvironment interactions,combined effects of common and rare variants, and differences between histological subtypes of this cancer.</p><p> 2011 Elsevier B.V. All rights reserved.</p><p>. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133</p><p>. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133ria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133lts from GWAS . . . . . . . . . . . . . . . .sures. . . . . . . . . . . . . . . . . . . . .</p><p>Sciences and Primary Care, University Medical Center U485..M. Braem), Lj.Schouten@EPID.unimaas.nl (L.J. Schouten.C.Onland@umcutrecht.nl (N.C. Onland-Moret).</p><p>ll rights reserved.around 1100 genetic variants in more than 200 candidate</p><p>Genetic susceptibilityGenetic variantsThe authors reviewed three genome-wide association studies (GWAS) and 147 candidate gene studies,published from 1990 to October 2010, includingOvarian cancer positive replications, the rati</p><p>Keywords:</p><p>A comprehensive and systemcancer was carried out. The eReview</p><p>Genetic susceptibility to sporadic ovarian cancer: A systematic review</p><p>M.G.M. Braem a, L.J. Schouten b, P.H.M. Peeters a, P.A. van den Brandt b, N.C. Onland-Moret a,a Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Stratenum 6.131, P.O. Box 85500, 3508 GA Utrecht, The Netherlandsb Maastricht University, GROW, School for Oncology and Developmental Biology, Department Epidemiology, P.O. Box 616, 6200 MD Maastricht, The Netherlands</p><p>a b s t r a c ta r t i c l e i n f o</p><p>Article history:Received 26 February 2011Received in revised form 18 May 2011Accepted 18 May 2011Available online 25 May 2011</p><p>Ovarian cancer is a highly lethal disease. Many researchers have, therefore, attempted to identify high riskpopulations. In this perspective, numerous genetic association studies have been performed to discovercommon ovarian cancer susceptibility variants. Accordingly, there is an increasing need to synthesize theevidence in order to identify true associations.</p><p>atic assessment of all available data on genetic susceptibility to sporadic ovarianvidence of statistically signicant ndings was evaluated based on the number of</p><p>j ourna l homepage: www.e lsev ie r.com/ locate /bbacan. . . . . . . . . . . . . . . . . . . . . . . . . 141</p><p>. . . . . . . . . . . . . . . . . . . . . . . . . 141</p><p>trecht, Mailbox Str 6.131, P.O. Box 85500, 3508 GA Utrecht, The</p><p>), P.H.M.Peeters@umcutrecht.nl (P.H.M. Peeters),</p></li><li><p>. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141</p><p>. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143</p><p>. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143</p><p>. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143</p><p>. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143</p><p>. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143</p><p>cancer.</p><p>Repetitive Sequences, Nucleic Acid). We subsequently searchedfor additional publications through HuGE Navigator's Phenopedia,querying for Ovarian Neoplasms. Additional publications werefound by hand searching reference lists of original articles and</p><p>Criteria Number of replications Negative/positive FPRP</p><p>133M.G.M. Braem et al. / Biochimica et Biophysica Acta 1816 (2011) 1321462. Materials and methods</p><p>2.1. Search strategy and selection criteria</p><p>We searchedMedline (PubMed) and Embase for publications from1990 onwards by using following Medical Subject Headings (MeSH)</p><p>study ratio</p><p>Very likely 2 positive replications b1 b 0.5Likely 2 positive replications 0 N0.5</p><p>1 positive replication b1 b0.50 replications b0.5</p><p>Possibly 1 positive replication 0 N0.52 positive replications 01 N0.5</p><p>Uncertain 1 positive replication N1 N0.50 replications N0.51. Introduction</p><p>Ovarian cancer is the fth most common cancer among women inEurope and the United States [1,2]. This aggressive type of cancer ismainly diagnosed at a progressed stage and has the highest mortalityrate among gynecologic malignancies [1]. It is, therefore, important toidentify causal factors that inuence a woman's risk to this type ofcancer. Several risk-reducing factors have already been identied,including increasing number of children, oral contraceptive use, earlyage at menopause, shorter menstrual lifespan, and hysterectomy [35]. There is also growing evidence that genetic factors inuencesusceptibility to ovarian cancer. Family based linkage studies havediscovered ovarian cancer genes with strong penetrance, such asBRCA1/2 and DNA mismatch repair genes (MMR; MLH1, MSH2, MSH6and PMS2) [612]. These family-based linkage studies have proven tobe successful in the past decades, particularly for monogeneticdiseases. In the late nineties the common disease-common varianthypothesis was formulated, stating that several common diseasealleles together play a role in the etiology of common complexdiseases, such as sporadic ovarian cancer. For studying geneticvariants under this common disease-common variant hypothesis,candidate gene association studies seemed more suitable [13]. Thecandidate gene approach uses knowledge of the functional role ofgenes in disease etiology to identify causal variants, genotyping thesevariants in a population and comparing its frequencies between casesand controls [14,15]. With the completion of the human genomesequence [16], technological advances, the initiation of the Interna-tional HapMap Project [17], and other initiatives such as theSNP500Cancer project [18], a transition has recently been observedfrom the hypothesis-driven candidate gene approach to an agnosticapproach, using large-scale association testing. These genome-wideassociation studies (GWAS) compare genotype frequencies of hun-dreds of thousands of single nucleotide polymorphisms (SNPs)distributed throughout the genome between large numbers of casesand unaffected controls [19]. Three such GWAS scans for ovariancancer have been published so far [2022].</p><p>Numerous genetic variants have been studied in association withovarian cancer, showing inconsistent results. Therefore, there is anincreasing need to summarize the evidence to identify true geneticassociations. Some reviews on the genetic epidemiology of ovariancancer have already been published, but these were very descriptive[2326]. No search strategies and arguments for inclusion or exclusionof genes and genetic pathways were described. Moreover, thesereviews lacked systematic data and quality assessment, as well assystematic evaluation and interpretation of ndings. The aim of thisreview is to systematically present and evaluate all available datafrom genome-wide association and candidate gene studies of ovarian4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . .5. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . .6. Conict of interest . . . . . . . . . . . . . . . . . . . . . . . .7. Authors contributions . . . . . . . . . . . . . . . . . . . . . .Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . .References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .terms: Ovarian Neoplasms AND (Polymorphism, Genetic ORreviews. Results were manually assessed by reviewing titles andabstracts, and those reporting genetic factors related to sporadicovarian cancer susceptibility involving human participants of any agegroup, and published in English were included. Studies in whichtumor DNA from cases was compared with genomic DNA fromcontrols were excluded. We selected all papers that were publisheduntil October 2010. In case of overlapping reports, only one study wasretained.</p><p>2.2. Data processing</p><p>A single reviewer (M.G.M.B.) identied, selected and processed thestudies to ensure consistency in selection and processing of thepublications. Data were extracted using structured forms. Thereproducibility of the data extraction form was examined byextracting 10 randomly chosen papers by an additional reviewerindependently (NCOM).</p><p>2.3. Data items</p><p>All publications were sought for following information: authors,publication year, gene or loci, SNPid, genotype, additional genotypeinformation, measure of association, 95% condence interval (CI), Pvalue or Bayes factor (BF), study design, ethnicity or country, samplesize (number of cases and number of controls), and genotypingmethods. We used the HuGE Navigator's Variant Name Mapper [27],dbSNP [28], and ALFRED [29] to uncover lacking genetic referencenumbers.</p><p>2.4. Quality assessment</p><p>Quality assessment was performed independently by two re-viewers (M.G.M.B. and N.C.O.M.). A 16-item score list was developedbased on published criteria for genetic association studies (i.e.,STREGA and NCI-NHGRI Working Group criteria) [30,31]. A nalquality score was obtained by adding up scores from all criteria andsubsequently transforming these to a 0- to 10-point scale. The qualityassessment included items regarding study design, sample size,</p><p>Table 1Credibility criteria for statistically signicant ndings.Abbreviations: FPRP, false positive report probability.</p></li><li><p>power and actions to prevent bias in general. Regarding thegenotyping process, we assessed whether quality control measureswere carried out, as genotyping errors may lead to incorrect alleleidentication or incorrect allele frequencies, causing misclassication.We also assessed whether any methods were used to assess oraddress population stratication, as this might confound the associ-ation between genetic variant and ovarian cancer. When multiplegenetic variants were investigated in one study, we checked whetherany methods were described to adjust for multiple testing.</p><p>2.5. Data interpretation</p><p>other signicant SNPs in this gene. To straightforwardly examinethe number of positive and negative results, we calculated the ratioof negative on positive studies. Thus, a ratio larger than 1 meansthat more negative than positive studies were published, a ratiosmaller than 1 represents more positive than negative studies, and aratio of 0 stands for only positive studies. The FPRP is determinedby the magnitude of the P value, the statistical power and thefraction of tested hypotheses that is true. In other words, the higherthe FPRP value, the higher the chance of a false-positive report. Weestimated this FPRP for each statistically signicant nding, using aBayesian method proposed by Wacholder et al.[34]. As suggested bythe authors, we preset the FPRP value at 0.5. We calculated the</p><p>1065 </p><p>865 200 </p><p>95 105 </p><p>66 2 </p><p>38 </p><p>19 </p><p>Investigated genetic variants </p><p>Statistically significant variants </p><p>Not attempted to replicate </p><p>Never positively replicated </p><p>Positively replicated by at least one study</p><p>Exclusively positively replicated </p><p>Included in replication studies </p><p>FPRP &lt; 0.5 </p><p>Fig. 1. Flowchart summarizing the number of investigated genetic variants among candidate gene studies.</p><p>134 M.G.M. Braem et al. / Biochimica et Biophysica Acta 1816 (2011) 132146A common problem with genetic association studies is thepublication of false-positive ndings, as a consequence of chancendings (type I error) [14,32,33]. Statistically signicant ndingsfrom candidate gene studies were, therefore, evaluated based on thenumber of positive replications, the number of positive and negativestudies and the false-positive report probability (FPRP; theprobability of no association given a statistically signicantnding). For two-stage studies, the second stage was considereda separate replication study of the rst stage (the initial study).When different SNPs in one gene were signicantly associated withovarian cancer, we tested whether these SNPs were in LD withFig. 2. Chromosomal location of identied ovFPRP for a low prior probability of association (0.001...</p></li></ul>

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