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doi: 10.1111/j.1365-2796.2012.02527.x Current knowledge and tomorrows challenges of breast, ovarian and prostate cancer genetics P. Hall From the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Sweden Keywords: breast cancer, genetics, ovarian cancer, prostate cancer. Introduction Collaborative Oncological Gene Environment Study (COGS) is a large-scale genotyping project, funded by the European Commission that was initiated in 2009. The overarching goal of COGS is to identify the genetic alterations associated with the risk of breast, ovarian and prostate cancer. COGS consists of four consortia and more than 150 research groups from all over the world and is coordinated by the Karo- linska Institutet, Stockholm, Sweden. In 2 years, a large number of single-nucleotide polymorphisms (SNPs) have been genotyped in more than 150 000 individuals. The consortium has identified the major- ity of the presently known and established suscepti- bility SNPs for the three cancers. The basis of genetic susceptibility to cancer is slowly unravelling. The initial work of familial-based studies to identify high-penetrance susceptibility genes has been followed by large population-based genetic association studies. Groups within COGS have pub- lished several landmark papers [1–3], and there will be more genetic alterations identified in the years to come. Identification of common low-penetrance suscepti- bility alleles is warranted for several reasons. First, it provides possible insight into the mechanisms of tu- mour biology. Secondly, if the mechanisms can be re- vealed, it may offer potential targets for novel therapy. Lastly, knowledge of susceptibility genes enables identification of individuals at increased risk of can- cer. This in turn provides the opportunity for targeted primary and secondary preventive strategies. On 15 June 2011, a meeting of the COGS members was organized at the Karolinska Institutet. The aims of the meeting were to discuss how knowledge on inheritance of cancer could be used in the clinical set- ting, to provide an update on the wealth of informa- tion on inheritance of cancer generated over the last few years and to speculate on the future develop- ments. Six of the presentations at the meeting, focus- ing on these areas, are included in this issue of the Journal of Internal Medicine. Professor Anthony Howell, Genesis Prevention Cen- tre and Nightingale Breast Screening Centre, Univer- sity Hospital of South Manchester, described the increasing breast cancer incidence seen worldwide and discussed how prevention is one strategy for reducing mortality from breast cancer [4]. Preventive measures are possible through defining women at greatest risk of breast cancer and offering appropri- ate diagnostic and therapeutic interventions. The establishment of genetic counselling units has been shown to improve survival in young women at high risk of breast cancer. Essential for risk reduction is adequate risk prediction that includes both genetic and nongenetic risk factors. Professor Howell de- scribed how preventive measures such as the use of anti-oestrogens and aromatase inhibitors have pro- ven beneficial in large randomized clinical trials. Dr Antonis Antoniou gave a comprehensive presenta- tion on the influence of common genetic variants on high-penetrance mutations, that is, which other ge- netic factors influence the risk in BRCA1 and BRCA2 carriers [5]. Mutations in the tumour suppressor genes BRCA1 and BRCA2 increase the risk of breast and ovarian cancer. There is a large interindividual difference in risk, implying that other factors, genetic and nongenetic, influence the risk of these high-pen- etrance genes. Such factors are likely to cluster in families. Recently, through data from large genome- wide association studies (GWASs), several common alleles have been found to modify breast and or ovar- ian cancer risk for mutation carriers. Dr Jianfeng Xu, Center for Cancer Genomics, Wake Forest University School of Medicine, explained how GWASs have identified hundreds of consistently 318 ª 2012 The Association for the Publication of the Journal of Internal Medicine Introduction |

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doi: 10.1111/j.1365-2796.2012.02527.x

Current knowledge and tomorrows challenges of breast,ovarian and prostate cancer genetics

P. Hall

FromtheDepartmentofMedicalEpidemiologyandBiostatistics,KarolinskaInstitutet,Sweden

Keywords: breast cancer, genetics, ovariancancer,prostatecancer.

Introduction

Collaborative Oncological Gene Environment Study(COGS) is a large-scale genotyping project, fundedbythe European Commission that was initiated in2009. The overarching goal of COGS is to identify thegenetic alterations associated with the risk of breast,ovarian and prostate cancer. COGS consists of fourconsortia and more than 150 research groups fromall over the world and is coordinated by the Karo-linska Institutet, Stockholm, Sweden. In 2 years, alarge number of single-nucleotide polymorphisms(SNPs) have been genotyped in more than 150 000individuals. Theconsortiumhas identified themajor-ity of the presently known and established suscepti-bilitySNPs for the threecancers.

The basis of genetic susceptibility to cancer is slowlyunravelling.The initialworkof familial-basedstudiesto identify high-penetrance susceptibility genes hasbeen followed by large population-based geneticassociation studies. Groups within COGS have pub-lished several landmark papers [1–3], and there willbe more genetic alterations identified in the years tocome.

Identification of common low-penetrance suscepti-bility alleles is warranted for several reasons. First, itprovides possible insight into the mechanisms of tu-mourbiology.Secondly, if themechanismscanbe re-vealed, itmayofferpotential targets fornovel therapy.Lastly, knowledge of susceptibility genes enablesidentification of individuals at increased risk of can-cer. This in turnprovides theopportunity for targetedprimaryandsecondarypreventivestrategies.

On 15 June 2011, a meeting of the COGS memberswas organized at the Karolinska Institutet. The aimsof the meeting were to discuss how knowledge oninheritanceof cancercouldbeused in theclinical set-ting, to provide an update on the wealth of informa-tion on inheritance of cancer generated over the last

few years and to speculate on the future develop-ments. Six of the presentations at themeeting, focus-ing on these areas, are included in this issue of theJournal of InternalMedicine.

Professor Anthony Howell, Genesis Prevention Cen-tre andNightingale Breast Screening Centre, Univer-sity Hospital of South Manchester, described theincreasing breast cancer incidence seen worldwideand discussed how prevention is one strategy forreducingmortality from breast cancer [4]. Preventivemeasures are possible through defining women atgreatest risk of breast cancer and offering appropri-ate diagnostic and therapeutic interventions. Theestablishment of genetic counselling units has beenshown to improve survival in young women at highrisk of breast cancer. Essential for risk reduction isadequate risk prediction that includes both geneticand nongenetic risk factors. Professor Howell de-scribed how preventive measures such as the use ofanti-oestrogens and aromatase inhibitors have pro-venbeneficial in largerandomizedclinical trials.

DrAntonisAntoniougaveacomprehensivepresenta-tion on the influence of common genetic variants onhigh-penetrance mutations, that is, which other ge-netic factors influence the risk inBRCA1 andBRCA2carriers [5]. Mutations in the tumour suppressorgenes BRCA1 and BRCA2 increase the risk of breastand ovarian cancer. There is a large interindividualdifference in risk, implying that other factors, geneticand nongenetic, influence the risk of these high-pen-etrance genes. Such factors are likely to cluster infamilies. Recently, through data from large genome-wide association studies (GWASs), several commonalleleshave been found tomodify breast and ⁄or ovar-iancancer risk formutationcarriers.

Dr Jianfeng Xu, Center for Cancer Genomics, WakeForest University School of Medicine, explainedhowGWASs have identified hundreds of consistently

318 ª 2012 The Association for the Publication of the Journal of Internal Medicine

Introduction |

replicated associations between geneticmarkers andcancer [6]. It was underlined that individually thesemarkers have limited power to predict the risk of can-cer.However,used incombination, thepredictiveper-formance appears to be similar to currently availableclinical predictors. There is clinical concernabout theuse of genetic predictors, and translational projectsareneeded tobenefit fromthenewdiscoveries.

Professor Rosalind Eeles, Institute of Cancer Re-search and Royal Marsden Hospital, described thesusceptibility SNPs associated with the risk of pros-tate cancer and how these findings could be broughtto the clinical setting [7]. Through familial and twinstudies, it has long been known that prostate cancerhas an inherited component, but the discovery ofthese variants hasprovendifficult. However,with theemergenceof large-scaleGWASs, ithasbeenpossibleto identify over 46 susceptibility loci. Professor Eeleshas both a clinical and genetic background and gaveanoutstandingcomprehensivepresentationdescrib-ingcurrentknowledgeand futurechallenges.

DrAndrewBerchuck,DukeCancer Institute,Durham,reviewed the current knowledge of the genetics of epi-thelial ovarian cancer [8]. The ovarian cancer associa-tion consortium (OCAC) was established to facilitatelarge-scale replication analyses for reported geneticassociations. Several GWASs have been conducted,and six established loci for ovarian cancer have beenidentified. Dr Berchuck described the next steps thatare required, including combining established GWASdata and deep sequencing. In common with several ofthe speakers, Dr Berchuck underlined the necessity oftranslating the data into clinical practice but at thesametimeacknowledgedthechallengesahead.

In an attempt to predict future developments in thefield, Professor Julian Knight gave an excellent pre-sentation on the topic Resolving the variable genomeand epigenome in human disease [9]. He describedhow advances in sequencing technologies will makeitpossible todefine thehumangenomeataresolutionnot seen before. He described the concept of func-tional genomics that, through information on thegenomeandepigenome, expressionquantitative traitmapping and analysis of allele-specific gene expres-sion, has the ability to create an integrated picture oftheregulatorygenomic landscape.

The future

A causal link between the common low-penetrancesusceptibility alleles and the development of breast,

ovarian and prostate cancer has yet to be determined.The risk alleles significantly associated with these dis-eases should be seen asmarkers in linkage disequilib-rium with one or more functional variants. It is of ut-most importance that the true causal variants areidentified because these variants will have a strongereffect size than their corresponding markers, whichmeans risk predictions will improve. Furthermore, tocapture theunderlyingbiologyof thegeneticalteration,thetruesusceptibility locimustbe identified.

The next step will be fine mapping of the relevantgenes. As extremely large numbers of samples areneeded to discriminate between correlated variants,future studies need to include groups from differentethnic backgrounds and thereby different patterns oflinkage disequilibrium. Genotyping and sequencingwill be followed by experimental and bioinformaticapproaches to identifySNPswithplausible functionaleffects.

Genetic riskprediction today ismainly based onmuta-tion screening of the high-penetranceBRCA1 ⁄2 genes.It is currently unclear whether the identification of anumber of common genetic susceptibility variants issufficient for reliable risk prediction.We know that therisk associatedwith each SNP is low and that a combi-nationofseveralSNPsisprobablyrequired.

Furthermore, SNPs alone do not entirely determinegenetic risk. Additional heritability will be explainedby gene–environment interactions, gene–gene inter-actions, and epigenetics and variantsmore rare thanmost SNPs. Rarer variants (minor allele frequencies<5%) have already been shown to influence suscepti-bility to, for instance, breast cancer, but there areprobablymanymore such variants to be found. ‘Rarevariants’ chips based on the 1000 Genomes Projectdatawill provide low-frequency variant data. In addi-tion, exome and whole-genome sequencing will becrucial in the quest for rare variants, but these newmethods are still considered too costly.However, thissituation is likely to change rapidly, and in a fewyears,wewillhavewhole-genomesequencingstudiesmimickingthesizeanddesignofanordinaryGWAS.

Conflict of interest statement

Noconflict of interestwasdeclared.

References

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Correspondence: Per Hall, MD, PhD, Department of Medical Epide-

miology and Biostatistics, Karolinska Institutet, 171 77 Stockholm,

Sweden.

(fax:+468314975;e-mail: [email protected]).

P. Hall | Introduction: Future of breast, ovarian and prostate cancer genetics

320 ª 2012 The Association for the Publication of the Journal of Internal Medicine

Journal of Internal Medicine, 2012, 271; 318–320